World Stroke Organization Brain & hEart globAl iniTiative Program.

INTRODUCTION: The World Stroke Organization (WSO) Brain & Heart Task Force developed the Brain & hEart globAl iniTiative (BEAT), a pilot feasibility implementation program to establish clinical collaborations between cardiologists and stroke physicians who work at large healthcare facilities. METHODS: The WSO BEAT pilot project focused on atrial fibrillation (AF) and patent foramen ovale (PFO) detection and management, and poststroke cardiovascular complications known as the stroke-heart syndrome. The program included 10 sites from 8 countries: Brazil, China, Egypt, Germany, Japan, Mexico, Romania, and the USA The primary composite feasibility outcome was the achievement of the following 3 implementation metrics (1) developing site-specific clinical pathways for the diagnosis and management of AF, PFO, and the stroke-heart syndrome; (2) establishing regular Neurocardiology rounds (e.g., monthly); and (3) incorporating a cardiologist to the stroke team. The secondary objectives were (1) to identify implementation challenges to guide a larger program and (2) to describe qualitative improvements. RESULTS: The WSO BEAT pilot feasibility program achieved the prespecified primary composite outcome in 9 of 10 (90%) sites. The most common challenges were the limited access to specific medications (e.g., direct oral anticoagulants) and diagnostic (e.g., prolonged cardiac monitoring) or therapeutic (e.g., PFO closure devices) technologies. The most relevant qualitative improvement was the achievement of a more homogeneous diagnostic and therapeutic approach. CONCLUSION: The WSO BEAT pilot program suggests that developing neurocardiology collaborations is feasible. The long-term sustainability of the WSO BEAT program and its impact on quality of stroke care and clinical outcomes needs to be tested in a larger and longer duration program.

Monocyte-to-lymphocyte ratio as predictor of cancer therapy-related cardiotoxicity in patients with breast cancer: a pilot cohort study.

BACKGROUND: Elevated pre-treatment baseline inflammation has been associated with cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer. Monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio and systemic immune-inflammation index (NLR × platelets) have emerged in clinical context as markers of disease-related inflammation. OBJECTIVES: To evaluate development of CTRCD according to pre-treatment blood inflammatory biomarkers in patients with breast cancer. METHODS: Pilot cohort study including consecutive female patients ≥ 18 years with HER2-positive early breast cancer who consulted at the institution's breast oncology outpatient clinic between march/2019 and march/2022. CTRCD: absolute reduction in LVEF > 10% to below 53% (2D-echocardiogram). Survival analysis was performed using Kaplan-Meier curves, compared by the log-rank test, and discrimination ability was evaluated through AUC-ROC. RESULTS: Forty-nine patients (53.3 ± 13.3 y) were included and followed-up for a median of 13.2 months. CTRCD was observed in 6 (12.2%) patients. Patients with high blood inflammatory biomarkers had lower CTRCD-free survival (P < 0.050 for all). MLR showed statistically significant AUC (0.802; P = 0.017). CTRCD was observed in 27.8% of patients with high MLR versus 3.2% with low MLR (P = 0.020); negative predictive value was 96.8% (95%CI 83.3-99.4%). CONCLUSION: In patients with breast cancer, elevated pre-treatment inflammatory markers were associated with increased risk of cardiotoxicity. Among these markers, MLR had good discriminatory performance and high negative predictive value. The incorporation of MLR might improve risk evaluation and selection of patients for follow-up during cancer therapy.

MIBG cardiac imaging compared to ejection fraction in evaluation of cardiotoxicity: a systematic review.

BACKGROUND: Advances in diagnosis and treatment of cancer has improved survival but resulted in increased cardiotoxic effects. The decrease in left ventricular ejection fraction (EF), one of the pillars of diagnosis of cardiotoxicity, seems to be a late process in the evolution of the disease, so 123I-metaiodobenzylguanidine (MIBG) cardiac imaging has been proposed to detect early cardiac impairment. The aim of this systematic review was to evaluate the performance of MIBG cardiac scan in this scenario. METHODS AND RESULTS: A systematic search was conducted in five international databases comparing MIBG parameters with EF for evaluation of cardiotoxicity. Twelve studies were included and separated in three groups. First, studies evaluating patients with established cardiotoxicity, in which EF was reduced and MIBG parameters were abnormal. Second, studies analyzing patients during or after treatment compared to controls, with MIBG parameters significantly different between groups in most studies, even when EF remained normal. Finally, studies analyzing anthracycline (ATC) dose-related changes, with alteration in MIBG parameters occurring even when EF was preserved. CONCLUSION: Although studies had high methodological variability, cardiac sympathetic innervation imaging seems to be a promising tool for assessing early cardiotoxicity. Further studies are needed to analyze its diagnostic value in this scenario.

Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial.

AIMS: Although loop diuretics are widely used to treat heart failure (HF), there is scarce contemporary data to guide diuretic adjustments in the outpatient setting. METHODS AND RESULTS: In a prospective, randomized and double-blind protocol, we tested the safety and tolerability of withdrawing low-dose furosemide in stable HF outpatients at 11 HF clinics in Brazil. The trial had two blindly adjudicated co-primary outcomes: (i) symptoms assessment quantified as the area under the curve (AUC) of a dyspnoea score on a visual-analogue scale evaluated at 4 time-points (baseline, Day 15, Day 45, and Day 90) and (ii) the proportion of patients maintained without diuretic reuse during follow-up. We enrolled 188 patients (25% females; 59 ± 13 years old; left ventricular ejection fraction = 32 ± 8%) that were randomized to furosemide withdrawal (n = 95) or maintenance (n = 93). For the first co-primary endpoint, no significant difference in patients' assessment of dyspnoea was observed in the comparison of furosemide withdrawal with continuous administration [median AUC 1875 (interquartile range, IQR 383-3360) and 1541 (IQR 474-3124), respectively; P = 0.94]. For the second co-primary endpoint, 70 patients (75.3%) in the withdrawal group and 77 patients (83.7%) in the maintenance group were free of furosemide reuse during follow-up (odds ratio for additional furosemide use with withdrawal 1.69, 95% confidence interval 0.82-3.49; P = 0.16). Heart failure-related events (hospitalizations, emergency room visits, and deaths) were infrequent and similar between groups (P = 1.0). CONCLUSIONS: Diuretic withdrawal did not result in neither increased self-perception of dyspnoea nor increased need of furosemide reuse. Diuretic discontinuation may deserve consideration in stable outpatients with no signs of fluid retention receiving optimal medical therapy. CLINICALTRIALS.GOV IDENTIFIER: NCT02689180.

Cardiac hypertrophy in mice submitted to a swimming protocol: influence of training volume and intensity on myocardial renin-angiotensin system.

Exercise promotes physiological cardiac hypertrophy and activates the renin-angiotensin system (RAS), which plays an important role in cardiac physiology, both through the classical axis [angiotensin II type 1 receptor (AT1R) activated by angiotensin II (ANG II)] and the alternative axis [proto-oncogene Mas receptor (MASR) activated by angiotensin-(1-7)]. However, very intense exercise could have deleterious effects on the cardiovascular system. We aimed to analyze the cardiac hypertrophy phenotype and the classical and alternative RAS axes in the myocardium of mice submitted to swimming exercises of varying volume and intensity for the development of cardiac hypertrophy. Male Balb/c mice were divided into three groups, sedentary, swimming twice a day without overload (T2), and swimming three times a day with a 2% body weight overload (T3), totaling 6 wk of training. Both training groups developed similar cardiac hypertrophy, but only T3 mice improved their oxidative capacity. We observed that T2 had increased levels of MASR, which was followed by the activation of its main downstream protein AKT; meanwhile, AT1R and its main downstream protein ERK remained unchanged. Furthermore, no change was observed regarding the levels of angiotensin peptides, in either group. In addition, we observed no change in the ratio of expression of the myosin heavy chain ß-isoform to that of the α-isoform. Fibrosis was not observed in any of the groups. In conclusion, our results suggest that increasing exercise volume and intensity did not induce a pathological hypertrophy phenotype, but instead improved the oxidative capacity, and this process might have the participation of the RAS alternative axis.

Rational and design of a randomized, double-blind, multicenter trial to evaluate the safety and tolerability of furosemide withdrawal in stable chronic outpatients with heart failure: The ReBIC-1 trial.

AIMS: Furosemide is commonly prescribed for symptom relief in heart failure (HF) patients. Although few data support the continuous use of loop diuretics in apparently euvolemic HF patients with mild symptoms, there is concern about safety of diuretic withdrawal in these patients. The ReBIC-1 trial was designed to evaluate the safety and tolerability of withdrawing furosemide in stable, euvolemic, chronic HF outpatients. This multicenter initiative is part of the Brazilian Research Network in Heart Failure (ReBIC) created to develop clinical studies in HF and composed predominantly by university tertiary care hospitals. METHODS: The ReBIC-1 trial is currently enrolling HF patients in NYHA functional class I-II, left ventricular ejection fraction ≤45%, without a HF-related hospital admission within the last 6 months, receiving a stable dose of furosemide (40 or 80 mg per day) for at least 6 months. Eligible patients will be randomized to maintain or withdraw furosemide in a double-blinded protocol. The trial has two co-primary outcomes: (1) dyspnea assessment using a visual-analogue scale evaluated at 4 time points and (2) the proportion of patients maintained without diuretics during the follow-up period. Total sample size was calculated to be 220 patients. Enrolled patients will be followed up to 90 days after randomization, and diuretic will be restarted if clinical deterioration or signs of congestion are detected. Pre-defined sub-group analysis based on NT-proBNP levels at baseline is planned. PERSPECTIVE: Evidence-based strategies aiming to simplify HF pharmacotherapy are needed in clinical practice. The ReBIC-1 trial will determine the safety of withdrawing furosemide in stable chronic HF patients.

Cytosolic H2O2 mediates hypertrophy, apoptosis, and decreased SERCA activity in mice with chronic hemodynamic overload.

Oxidative stress in the myocardium plays an important role in the pathophysiology of hemodynamic overload. The mechanism by which reactive oxygen species (ROS) in the cardiac myocyte mediate myocardial failure in hemodynamic overload is not known. Accordingly, our goals were to test whether myocyte-specific overexpression of peroxisomal catalase (pCAT) that localizes in the sarcoplasm protects mice from hemodynamic overload-induced failure and prevents oxidation and inhibition of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), an important sarcoplasmic protein. Chronic hemodynamic overload was caused by ascending aortic constriction (AAC) for 12 wk in mice with myocyte-specific transgenic expression of pCAT. AAC caused left ventricular hypertrophy and failure associated with a generalized increase in myocardial oxidative stress and specific oxidative modifications of SERCA at cysteine 674 and tyrosine 294/5. pCAT overexpression ameliorated myocardial hypertrophy and apoptosis, decreased pathological remodeling, and prevented the progression to heart failure. Likewise, pCAT prevented oxidative modifications of SERCA and increased SERCA activity without changing SERCA expression. Thus cardiac myocyte-restricted expression of pCAT effectively ameliorated the structural and functional consequences of chronic hemodynamic overload and increased SERCA activity via a post-translational mechanism, most likely by decreasing inhibitory oxidative modifications. In pressure overload-induced heart failure cardiac myocyte cytosolic ROS play a pivotal role in mediating key pathophysiologic events including hypertrophy, apoptosis, and decreased SERCA activity.

Transcoronary gradient of plasma microRNA 423-5p in heart failure: evidence of altered myocardial expression.

CONTEXT: Elevated plasmatic microRNAs (miRs) are observed in heart failure (HF). However, the cardiac origin of these miRs remains unclear. OBJECTIVE: We calculated transcoronary gradients of miR-29b, miR-133a and miR-423-5p in 17 outpatients with stable systolic HF and in controls without structural cardiac disease. MATERIALS AND METHODS: MicroRNAs were measured by quantitative real-time polymerase chain reaction. RESULTS: Positive transcoronary miR gradients were observed in patients with HF but not in controls (p = 0.03). B-type natriuretic peptide (BNP) moderately correlated with the transcoronary gradients of miR-133a and miR-423-5p. DISCUSSION AND CONCLUSIONS: The difference in transcoronary gradients between HF outpatients and controls suggests that miR-423-5p has a cardiac origin. The positive correlation between miR-423-5p and BNP transcoronary gradients supports this hypothesis.

Anemia in heart failure: association of hepcidin levels to iron deficiency in stable outpatients.

BACKGROUND: Anemia is a prevalent condition in heart failure with multiple potential causes. The complex interaction between iron stores, hepcidin, inflammation and anemia is poorly comprehended. We tested the hypothesis that, in stable heart failure patients with anemia, hepcidin is associated with iron deficiency status irrespective of inflammation. METHODS AND RESULTS: Stable systolic heart failure outpatients with and without anemia underwent a complete iron panel, erythropoietin, hepcidin and tumor necrosis factor (TNF)-α assessment. Sixty outpatients were studied. Anemic patients (n = 38, mean hemoglobin 11.4 ± 1 g/dl) were older (69.6 ± 9.6 vs. 58 ± 10.8 years old, p < 0.01) compared with nonanemic patients (n = 22, mean hemoglobin 13.8 ± 1.1 g/dl). Iron deficiency was present in 42% of patients with anemia. TNF-α and hepcidin were 29 and 21% higher in patients with anemia, respectively, compared to nonanemic patients; however, no correlations were found between hepcidin and TNF-α levels. Hepcidin levels in the lower tertile (<31.7 ng/ml) were strongly associated with iron deficiency (OR 16.5, 95% CI 2.2-121.2; p < 0.01). CONCLUSION: In stable heart failure patients with anemia, hepcidin levels may be more importantly regulated by patients' iron stores than by inflammation.

Lung ultrasound in congestion assessment of patients with advanced heart failure referred for heart transplant: Correlations with right heart catheterization findings.

Background: In advanced heart failure (HF), diagnostic performance of physical exam may be poor. Physical examination associated with lung ultrasound (LUS) may be an important tool to facilitate congestion screening. Objective: To evaluate performance of LUS for congestion screening in advanced HF referred for transplant, as compared to findings of right heart catheterization (RHC). Methods: Prospective study of 23 subjects with advanced HF referred for RHC. LUS was performed in association with clinical congestion score (CCS), analogue-visual dyspnea scale (AVDS) and presence of trepopnea/bendopnea prior to catheterization. Congestion was assessed by the number of B-lines in the LUS, and by findings of physical examination as well as by NT-proBNP serum values. Results: Congestion was present in 43.4 % of patients by LUS (B-lines ≥ 15), as compared to 21.7 % by CCS (score greater than or equal to 5), 56.5 % by NT-proBNP (>1000 pg/ml), and 60.8 % by pulmonary capillary wedge pressure (PCWP) (>15 mm Hg). The number of B-lines was correlated to cardiac index (CI) (rho = -0.619; p 0.002), but not with PCWP (rho 0.190; p 0.386), RAP (rho -0.244; p 0.262), CCS (rho 0.198; p 0.36) and neither with NT-proBNP (rho 0.282; p 0.193). Otherwise, NT-proBNP was correlated with PCWP (rho = 0.636; p = 0.001) and with CI (rho -0.667 p 0.001). Conclusions: In advanced HF patients referred for transplant, number of B-lines in LUS was not correlated with PCWP or RAP. Advanced HF patients seem to have increased filling pressures, but no interstitial pulmonary congestion that LUS could detect.

Health-Related Quality of Life and Long-Term Outcomes after Mildly Symptomatic COVID-19: The Post-COVID Brazil Study 2 Protocol. / Qualidade de Vida Relacionada à Saúde e Desfechos em Longo Prazo após COVID-19 Sintomática Leve: Protocolo do Estudo Pós-COVID Brasil 2.

BACKGROUND: The long-term effects of mild COVID-19 on physical, cognitive, and mental health are not yet well understood. OBJECTIVE: The purpose of this paper is to describe the protocol for the ongoing "Post-COVID Brazil" study 2, which aims to evaluate the factors associated with health-related quality of life and long-term cardiovascular and non-cardiovascular outcomes one year after a mild episode of symptomatic COVID-19. METHODS: The "Post-COVID Brazil" study 2 is a prospective multicenter study that plans to enroll 1047 patients (NCT05197647). Centralized, structured telephone interviews are conducted at 1, 3, 6, 9, and 12 months after COVID-19 diagnosis. The primary outcome is the health-related quality-of-life utility score, assessed using the EuroQol-5D-3L (EQ-5D-3L) questionnaire at 12 months. Secondary endpoints include the EQ-5D-3L at 3, 6, and 9 months, as well as all-cause mortality, major cardiovascular events, hospitalization, return to work or education, persistent symptoms, new disabilities in instrumental activities of daily living, cognitive impairment, anxiety, depression, and post-traumatic stress symptoms at 3, 6, 9, and 12 months after SARS-CoV-2 infection. A p-value < 0.05 will be considered statistically significant for all analyses. RESULTS: The primary endpoint will be presented as the overall frequency of the EQ-5D-3L domains 12 months after SARS-CoV-2 infection. Main analysis will explore the association of independent variables with the study outcomes. CONCLUSION: The "Post-COVID Brazil" study 2 aims to clarify the impact of long COVID on the quality of life and cardiovascular and non-cardiovascular outcomes of Brazilian patients who have had mild COVID-19.

FUNDAMENTO: Os efeitos em longo prazo da COVID-19 leve sobre a saúde física, mental e cognitiva ainda não são bem conhecidos. OBJETIVO: Este artigo visa descrever o protocolo para o estudo em andamento Pós-COVID Brasil 2, o qual tem como objetivo avaliar os fatores associados à qualidade de vida associada à saúde e desfechos cardiovasculares e não cardiovasculares de longo prazo um ano após um episódio de COVID-19 sintomática leve. MÉTODOS: O estudo "Pós-COVID Brasil 2" é um estudo multicêntrico prospectivo que pretende incluir 1047 pacientes (NCT05197647). Entrevistas estruturas, centralizadas são conduzidas em um mês, e aos três, seis, nove e 12 meses após o diagnóstico de COVID-19. O desfecho primário é o escore de utilidade da qualidade de vida relacionada à saúde, avaliado usando o questionário EuroQol-5D-3L (EQ-5D-3L) aos 12 meses. Desfechos secundários incluem o EQ-5D-3L aos três, seis e nove meses, mortalidade por todas as causas, eventos cardiovasculares maiores, hospitalização, retorno ao trabalho ou à escola, sintomas persistentes, novas incapacidades em atividades instrumentais diárias, déficit cognitivo, ansiedade, depressão, e sintomas de transtorno do estresse pós-traumático as três, seis, nove e doze meses após a infecção pelo SARS-CoV-2. Um valor de p<0,05 será considerado estatisticamente significativo para as análises. RESULTADOS: O desfecho primário será apresentado como frequência dos domínios do EQ-5D-3L doze meses após a infecção por SARS-CoV-2. A análise principal explorará a associação das variáveis independentes com os desfechos do estudo. CONCLUSÃO: O estudo "Pós-COVID Brasil 2" tem como objetivo elucidar o impacto da COVID longa sobre a qualidade de vida e desfechos cardiovasculares e não cardiovasculares de brasileiros pacientes que apresentaram COVID-19 leve.

Long-term Health-Related Quality of Life and Outcomes after Hospitalization for COVID-19 in Brazil: Post-COVID Brazil 1 Study Protocol. / Qualidade de Vida em Longo Prazo e Desfechos após Internação por COVID-19 no Brasil: Protocolo do Estudo Pós-COVID Brasil 1.

BACKGROUND: The long-term impact of hospitalization for COVID-19 on patients' physical, mental, and cognitive health still needs further assessment. OBJECTIVES: This study aims to evaluate factors associated with quality of life and cardiovascular and non-cardiovascular outcomes 12 months after hospitalization for COVID-19. METHODS: This prospective multicenter study intends to enroll 611 patients hospitalized due to COVID-19 (NCT05165979). Centralized telephone interviews are scheduled to occur at three, six, nine, and 12 months after hospital discharge. The primary endpoint is defined as the health-related quality-of-life utility score assessed by the EuroQol-5D-3L (EQ-5D-3L) questionnaire at 12 months. Secondary endpoints are defined as the EQ-5D-3L at three, six and nine months, return to work or education, persistent symptoms, new disabilities in instrumental activities of daily living, cognitive impairment, anxiety, depression, and post-traumatic stress symptoms, major cardiovascular events, rehospitalization, as well as all-cause mortality at 3, 6, 9, and 12 months after SARS-CoV-2 infection. A p-value <0.05 will be assumed as statistically significant for all analyses. RESULTS: The primary endpoint will be presented as the frequency of the EQ-5D-3L score 12 months after COVID-19 hospitalization. A sub-analysis to identify possible associations of independent variables with study outcomes will be presented. CONCLUSIONS: This study will determine the impact of COVID-19 on the quality of life and cardiovascular and non-cardiovascular outcomes of hospitalized patients 12 months after discharge providing insights to the public health system in Brazil.

FUNDAMENTO: O impacto em longo prazo da hospitalização por COVID-19 sobre a saúde física, mental e cognitiva dos pacientes requer mais investigação. OBJETIVOS: Este artigo visa avaliar os fatores associados com a qualidade de vida e desfechos cardiovasculares e não cardiovasculares 12 meses após a internação hospitalar por COVID-19. MÉTODOS: Este estudo multicêntrico prospectivo pretende incluir 611 pacientes internados por COVID-19 (NCT05165979). Entrevistas telefônicas centralizadas estão programadas para ocorrer em três, seis, nove e 12 meses após a alta hospitalar. O desfecho primário é definido como o escore de utilidade de qualidade de vida relacionada à saúde avaliada pelo questionário EuroQol-5D-3L (EQ-5D-3L) aos 12 meses. Desfechos secundários são definidos como o EQ-5D-3L aos três, seis e nove meses, retorno ao trabalho ou à escola, sintomas persistentes, novas incapacidades em atividades instrumentais diárias, déficit cognitivo, ansiedade, depressão, e sintomas de transtorno do estresse pós-traumático, eventos cardiovasculares maiores, reinternação, e mortalidade por todas as causas aos três, seis, nove e 12 meses após a infecção pelo SARS-CoV-2. Um valor de p<0,05 será considerado estatisticamente significativo para as análises. RESULTADOS: O desfecho primário será apresentado como frequência do escore EQ-5D-3L 12 meses após a internação por COVID-19. Uma subanálise para identificar possíveis associações das variáveis independentes com desfechos do estudo será apresentada. CONCLUSÃO: Este estudo determinará o impacto da COVID-19 sobre a qualidade de vida e de desfechos cardiovasculares e não cardiovasculares de pacientes internados 12 meses após a alta, e fornecerá novas informações ao sistema público de saúde no Brasil.

Polymorphisms of endothelial nitric oxide synthase gene in systolic heart failure: an haplotype analysis.

BACKGROUND: Endothelial nitric oxide synthase (eNOS) gene polymorphisms have been associated with the pathogenesis of cardiovascular diseases, but few studies have evaluated the role of eNOS haplotypes on the risk and prognosis of heart failure (HF). This prospective study was designed to analyze the impact of three eNOS polymorphisms (T-786C, VNTR4a/b and Glu298Asp) and their haplotypes on the susceptibility and clinical outcomes in HF outpatients with systolic dysfunction. METHODS AND RESULTS: We conducted a case-control and a cohort study in which 316 HF patients and 360 healthy controls were recruited from a tertiary care university hospital. DNA was extracted from peripheral blood and eNOS polymorphisms were detected by PCR or PCR-RFLP. Patients were predominantly men, had a mean left ventricular ejection fraction of 31% and were followed-up for a median of 41months; there were 96 deaths, including 58 HF-related deaths. Genotype distribution of the eNOS T-786C, VNTR 4a/b and Glu298Asp was similar between HF patients and controls. Haplotype frequencies differed between HF patients and controls only in African-Brazilians (p=0.043). African-Brazilian patients that carried the haplotype -786C/4b/Asp298 had a better prognosis than patients that carried other haplotypes (log rank p value=0.016 for all-cause mortality). In a Cox proportional hazard model adjusted for clinical variables of risk, the -786C/4b/Asp298 haplotype remained as an independent genetic predictor of survival (adjusted HR=0.11; 95% CI=0.01-0.83; p=0.03). CONCLUSIONS: The -786C/4b/Asp298 eNOS haplotype had a significant impact on HF susceptibility and prognosis, particularly in African-Brazilian patients.

Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo-inositol trispyrophosphate.

A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles. myo-Inositol trispyrophosphate (ITPP) is a recently identified membrane-permeant molecule that causes allosteric regulation of Hb oxygen binding affinity. In normal mice, i.p. administration of ITPP (0.5-3 g/kg) caused a dose-related increase in the oxygen tension at which Hb is 50% saturated (p50), with a maximal increase of 31%. In parallel experiments, ITPP caused a dose-related increase in maximal exercise capacity, with a maximal increase of 57 +/- 13% (P = 0.002). In transgenic mice with severe heart failure caused by cardiac-specific overexpression of G alpha q, i.p. ITPP increased exercise capacity, with a maximal increase of 63 +/- 7% (P = 0.005). Oral administration of ITPP in drinking water increased Hb p50 and maximal exercise capacity (+34 +/- 10%; P < 0.002) in normal and failing mice. Consistent with increased tissue oxygen availability, ITPP decreased hypoxia inducible factor-1alpha mRNA expression in myocardium. It had no effect on myocardial contractility in isolated mouse cardiac myocytes and did not affect arterial blood pressure in vivo in mice. Thus, ITPP decreases the oxygen binding affinity of Hb, increases tissue oxygen delivery, and increases maximal exercise capacity in normal mice and mice with severe heart failure. ITPP is thus an attractive candidate for the therapy of patients with reduced exercise capacity caused by heart failure.

Polymorphisms of matrix metalloproteinases in systolic heart failure: role on disease susceptibility, phenotypic characteristics, and prognosis.

BACKGROUND: The role of matrix metalloproteinases (MMPs) polymorphisms on heart failure (HF) susceptibility, phenotypic characteristics, and prognosis has been poorly explored. METHODS AND RESULTS: We studied 313 HF patients with left ventricular systolic dysfunction and 367 healthy control subjects. Genotyping of MMP-1 (-1607 1G/2G), MMP-3 (-1171 5A/6A), and MMP-9 (-1562 C/T) polymorphisms was performed by polymerase chain reaction. Allelic and genotypic frequencies of MMP-1, -3, and -9 were similar in HF patients and controls. MMP1 2G allele carriers were positively associated to ischemic etiology and history of myocardial infarction (all P values <.05). Patients were followed-up for a median of 40 months and 58 HF-related deaths occurred during this period. HF-related survival was significantly better in MMP1 2G allele carriers (71% versus 42% for 1G/1G patients, P = .002) and in MMP-3 6A allele carriers (70% versus 61% for 5A/5A patients, P = .064), particularly in non-ischemic patients (P = .039). MMP1 2G allele was independently associated to HF survival after adjustment for several other predictors of risk (hazard ratio 0.47, 95% confidence interval 0.27 to 0.82; P = .008). CONCLUSIONS: MMP-1, -3, and -9 polymorphisms were not associated to HF susceptibility. However, MMP1 2G allele carriers were related to a higher prevalence of ischemic etiology among patients with systolic HF and better HF-related prognosis.

Dynamics in insulin resistance and plasma levels of adipokines in patients with acute decompensated and chronic stable heart failure.

BACKGROUND: Patients with heart failure (HF) develop metabolic derangements including increased adipokine levels, insulin resistance, inflammation and progressive catabolism. It is not known whether metabolic dysfunction and adipocyte activation worsen in the setting of acute clinical decompensation, or conversely, improve with clinical recovery. METHODS AND RESULTS: We assessed insulin resistance using homeostasis model assessment of insulin resistance (HOMA-IR), and measured plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), adiponectin, visfatin, resistin, leptin, and tumor necrosis factor (TNF) α in 44 patients with acute decompensated HF (ADHF) due to left ventricular (LV) systolic dysfunction and again early (<1 wk) and late (> 6 mo) after clinical recovery, in 26 patients with chronic stable HF, and in 21 patients without HF. NT-proBNP was not increased in control subjects, mildly elevated in patients with stable HF, markedly elevated in patients with ADHF, and decreased progressively early and late after treatment. Compared to control subjects, plasma adiponectin, visfatin, leptin, resistin, and TNF-α were elevated in patients with chronic stable HF and increased further in patients with ADHF. Likewise, HOMA-IR was increased in chronic stable HF and increased further during ADHF. Adiponectin, visfatin, and HOMA-IR remained elevated at the time of discharge from the hospital, but returned to chronic stable HF levels. Adipokine levels were not related to body mass index in HF patients. HOMA-IR correlated positively with adipokines and TNF-α in HF patients. CONCLUSIONS: ADHF is associated with worsening of insulin resistance and elevations of adipokines and TNF-α, indicative of adipocyte activation. These metabolic abnormalities are reversible, but they temporally lag behind the clinical resolution of decompensated HF.

A systematic review of microRNAs in patients with hypertrophic cardiomyopathy.

BACKGROUND: Several microRNAs (miRNA) have been associated with hypertrophic cardiomyopathy (HCM), but studies differ regarding methods employed. In an attempt to understand their role in the disease, we performed a systematic review of studies assessing miRNAs and their association with HCM. METHODS: The literature search was based on The Medical Subject Headings (MeSH) terms "Hypertrophic Cardiomyopathy" and "MicroRNA" combined with other synonyms on Embase, Medline and LILACS databases in April 2020. The selected studies and data extraction were independently evaluated. Only human reports with a clear definition of HCM diagnosis were included. RESULTS: The search found 68 studies, 13 fulfilled the selection criteria, with a total of 329 patients. Eighty-seven miRNA were differentially expressed in HCM patients, being mir-21, mir-29a and mir-133 the most reported. The miRNA were mainly up-regulated, where mir-29a was up-regulated in 6 studies, followed by mir-133 in 4 and mir-21 in 3. The other miRNAs were mainly up-regulated. Blood samples were evaluated in the majority of patients (86%), but a greater number of miRNAs (79%) were assessed in myocardium. Six studies evaluating the phenotype correlation demonstrated that several miRNAs, mainly mir-1-3p, mir-19b, mir-21, mir-29a, mir-155, and mir-221, were related to either hypertrophy or fibrosis. Mir-29a showed a more consistent phenotypic correlation. CONCLUSION: Eighty-seven miRNAs were differentially expressed in HCM patients, the majority in up-regulation. Mir-21, mir-29a and mir-133 were the most reported. Correlation with left ventricular hypertrophy and fibrosis was evaluated in six studies for several miRNAs, nevertheless, mir-29a showed more consistent findings and seems to be a promising biomarker.

Right ventricular function during trastuzumab therapy for breast cancer.

Cardiotoxicity (CDT) is the main adverse effect related to trastuzumab (TTZ). The role of the right ventricle (RV) in this context is not clear. We aimed to evaluate the longitudinal changes in RV function during TTZ therapy and to determine RV function changes associated with subclinical CDT. Breast cancer patients underwent echocardiograms at the beginning of TTZ treatment (Exam 1) and every 3 months during the first year (Exams 2, 3, and 4). Subclinical CDT was defined as ≥ 12% relative reduction of left ventricle global longitudinal strain (LV GLS). Twenty-five women (52.1 ± 13.1 y-o) were included. We found a decrease in LV ejection fraction between the first and fourth exams (Ex1: 64.1% ± 4.9 vs Ex4: 60.9% ± 4.9, p = 0.003) and the LV GLS gradually decreased during follow-up (Ex1: - 20.6% ± 2.0; Ex2: - 19.4% ± 2.1; Ex3: - 19.2% ± 1.8; Ex4: - 19.0% ± 2.1, all p < 0.05). RV GLS changed from baseline to 3 month and to 6 month (Ex1: - 23.9% ± 1.6; Ex2: - 22.5% ± 2.1; Ex3: - 22.5% ± 2.3, all p < 0.05), and the RV Fractional Area Change was lower in the third exam (Ex1: 44.3% ± 6.6 vs Ex3: 39.9% ± 6.0, p = 0.004). We found subclinical CDT in 13 patients (52%); worsening in RV parameters did not differ between those with and without subclinical CDT. In this sample, the RV function decreased during TTZ therapy and the decrease was not associated to the observed LV cardiotoxicity.

Effects of a diuretic adjustment algorithm protocol on heart failure admissions: A randomized clinical trial.

INTRODUCTION: The aim of this study was to evaluate the effectiveness of a diuretic adjustment algorithm (DAA) in maintaining clinical stability and reducing HF readmissions using telemonitoring technologies. METHODS: Randomized clinical trial of patients with an indication for furosemide dose adjustment during routine outpatient visits. In the intervention group (IG), the diuretic dose was adjusted according to the DAA and the patients received telephone calls for 30 days. In the control group (CG), the diuretic dose was adjusted by a physician at baseline only. Co-primary outcomes were hospital readmission and/or emergency department visits due to decompensated HF within 90 days, and a 2-point change in the Clinical Congestion Score and/or a deterioration in New York Heart Association functional class within 30 days. RESULTS: A total of 206 patients were included. Most patients were male (n=119; 58%), with a mean age of 62 (SD 13) years. Four patients (2%) in the IG and 14 (7%) in the CG were hospitalized for HF (odds ratio (OR) 0.31 (0.10-0.91); p=0.04). Multivariate analysis showed a reduction of 67% in readmissions and/or emergency department visits due to decompensated HF in the IG compared with the CG (95% CI 0.13-0.88; p=0.027). Regarding the combined outcome of HF readmission and/or emergency department visits or clinical instability, the IG had 20% fewer events than the CG within 30 days (IG: n=48 (23%), CG: n=70 (34%); OR 0.80 (0.63-0.93); p=0.03). DISCUSSION: Using DAA improved the combined outcome in these outpatients, with favorable and significant results that included a reduction in HF admissions and in clinical instability. (NCT02068937).

Revisiting heart failure assessment based on objective measures in NYHA functional classes I and II.

OBJECTIVE: New York Heart Association (NYHA) functional class plays a central role in heart failure (HF) assessment but might be unreliable in mild presentations. We compared objective measures of HF functional evaluation between patients classified as NYHA I and II in the Rede Brasileira de Estudos em Insuficiência Cardíaca (ReBIC)-1 Trial. METHODS: The ReBIC-1 Trial included outpatients with stable HF with reduced ejection fraction. All patients had simultaneous protocol-defined assessment of NYHA class, 6 min walk test (6MWT), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and patient's self-perception of dyspnoea using a Visual Analogue Scale (VAS, range 0-100). RESULTS: Of 188 included patients with HF, 122 (65%) were classified as NYHA I and 66 (35%) as NYHA II at baseline. Although NYHA class I patients had lower dyspnoea VAS Scores (median 16 (IQR, 4-30) for class I vs 27.5 (11-49) for class II, p=0.001), overlap between classes was substantial (density overlap=60%). A similar profile was observed for NT-proBNP levels (620 pg/mL (248-1333) vs 778 (421-1737), p=0.015; overlap=78%) and for 6MWT distance (400 m (330-466) vs 351 m (286-408), p=0.028; overlap=64%). Among NYHA class I patients, 19%-34% had one marker of HF severity (VAS Score >30 points, 6MWT <300 m or NT-proBNP levels >1000 pg/mL) and 6%-10% had two of them. Temporal change in functional class was not accompanied by variation on dyspnoea VAS (p=0.14). CONCLUSIONS: Most patients classified as NYHA classes I and II had similar self-perception of their limitation, objective physical capabilities and levels of natriuretic peptides. These results suggest the NYHA classification poorly discriminates patients with mild HF.