Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. METHODS: Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. RESULTS: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. CONCLUSIONS: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Renal denervation in patients with heart failure secondary to Chagas' disease: A pilot randomized controlled trial.

INTRODUCTION: Chagas disease is one of the most relevant endemic parasitic diseases in Latin America, affecting approximately 6 million people. Overt Chagas heart disease is an ominous condition, occurring in 20-30% of infected individuals, which has besides the persistent myocarditis a peculiar intracardiac ganglionic neuronal depletion and dysautonomy. This study aims to evaluate the safety and feasibility of renal denervation for patients with advanced symptomatic Chagas cardiomyopathy. METHODS: Open-label prospective pilot study that randomized patients with Chagas heart disease to either renal denervation or conservative treatment (2:1 ratio). The primary endpoint was the incidence of major adverse events at 9 months, defined as a composite of all-cause death, myocardial infarction, stroke, need for renal artery invasive treatment, or worsening renal function. RESULTS: A total of 17 patients were allocated for renal denervation (n = 11) or conservative treatment (n = 6). Included patients had severe symptomatic heart disease, with markedly depressed left ventricular function (average ejection fraction 26.7 ± 4.9%). For patients randomized to renal denervation, the procedure was performed successfully and uneventfully. After 9 months, the primary endpoint occurred in 36.4% of patients in the renal denervation group and 50.0% in the control arm (p = .6). After 9 months, clinical, laboratory, functional, echocardiographic, and quality of life parameters were similar between groups. CONCLUSIONS: This pilot study suggests that renal denervation is safe and feasible in patients with Chagas cardiomyopathy, warranting future studies to better evaluate the clinical efficacy of the interventional strategy in improving the prognosis of this high-risk population.

Effectiveness of sacubitril-valsartan in patients with cancer therapy-related cardiac dysfunction: a systematic review of clinical and preclinical studies.

INTRODUCTION: Cancer therapy-related cardiac dysfunction (CTRCD) is a critical problem with an impact on both oncological and cardiovascular prognosis, especially when it prevents patients from receiving cancer treatment. However, there are very limited data on the efficacy of sacubitril/valsartan in the prevention and treatment of cardiotoxicity. This systematic review aimed to evaluate the potential benefit of sacubitril/valsartan in patients with CTRCD. EVIDENCE ACQUISITION: The databases included MEDLINE, Embase, LILACS, Scopus and Cochrane Central up to January 20, 2022. All pre-clinical and clinical studies including observational studies (cohorts, case-control, cross-sectional and case reports) that used sacubitril/valsartan for prevention or treatment of CTRCD. The primary effectiveness endpoints was CTRCD, defined as a clinically significant change in left ventricular ejection fraction (LVEF) at the end of the follow-up. EVIDENCE SYNTHESIS: And after applying the eligibility criteria, 12 articles (9 in humans and 3 preclinical studies) were included in this systematic review. The 3 preclinical studies demonstrated beneficial effects in preventing, attenuating and/or delaying the onset of myocardial damage at the cellular level, ventricular dysfunction and remodeling. Regardind human studies, most of them were composed of case reports. The largest study consisted of a retrospective multicentric cohort with 64 patients. CONCLUSIONS: All clinical studies have demonstrated that used Sac/Val in human showed a significant increase in LVEF, and when reported, a reduction in left ventricular volume and NT-proBNP (or BNP). Randomized clinical trials are needed to confirm this hypothesis.

Heart rate response to exercise and cardiorespiratory fitness of young women at high familial risk for hypertension: effects of interval vs continuous training.

Exercise training is an effective intervention for treating and preventing hypertension, but its effects on heart rate (HR) response to exercise and cardiorespiratory fitness (CRF) of non-hypertensive offspring of hypertensive parents (FH+) has not been studied. We compared the effects of three times per week equal-volume high-intensity aerobic interval (AIT) and continuous moderate-intensity exercise (CME) on HR response to exercise and CRF of FH+. Forty-four young FH+ women (25.0 ± 4.4 years) randomized to control (CON; n = 12), AIT (80-90% of VO(2MAX); n = 16), or CME (50-60% of VO(2MAX); n = 16) performed a graded exercise test (GXT) before and after 16 weeks of follow-up to evaluate HR response to exercise and several parameters of CRF. Resting, maximal, and reserve HR did not change after the follow-up in all groups. HR recovery (difference between HR(MAX) and HR at 1 minute of GXT recovery phase) improved only after AIT (11.8 ± 4.9 vs. 20.6 ± 5.8 bpm, p < 0.01). Both exercise programmes were effective for improving CRF parameters, but AIT was more effective than CME for improving oxygen consumption at the respiratory compensation point (VO(2RCP); 22.1% vs. 8.8%, p = 0.008) and maximal effort (VO(2MAX); 15.8% vs. 8.0%, p = 0.036), as well as tolerance time (TT) to reach anaerobic threshold (TT(AT); 62.0 vs. 37.7, p = 0.048), TT(RCP) (49.3 vs. 32.9, p = 0.032), and TT(MAX) (38.9 vs. 29.2, p = 0.042). Exercise intensity was an important factor in improving HR recovery and CRF of FH+women. These findings may have important implications for designing exercise-training programmes for the prevention of an inherited hypertensive disorder.

Glycemia and prognosis of patients with chronic heart failure--subanalysis of the Long-term Prospective Randomized Controlled Study Using Repetitive Education at Six-Month Intervals and Monitoring for Adherence in Heart Failure Outpatients (REMADHE) trial.

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

Can tricuspid annuloplasty of the donor heart reduce valve insufficiency following cardiac transplantation with bicaval anastomosis?

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

Cardiac reinnervation affects cardiorespiratory adaptations to exercise training in individuals with heart transplantation.

PURPOSE: The purpose of this study was to investigate the hemodynamic and cardiorespiratory adaptations to exercise in individuals with heart transplantation with evidence of cardiac reinnervation (cardiac reinnervation group) versus without evidence of cardiac reinnervation (no cardiac reinnervation group). METHODS: Sedentary individuals with heart transplantation (age = 45.5 ± 2.2 years; time elapsed since surgery = 6.7 ± 0.7 years) were divided into the cardiac reinnervation (n = 16) and no cardiac reinnervation (n = 17) groups according to their heart rate response to cardiopulmonary exercise testing. The 24-hour ambulatory blood pressure, carotid-femoral pulse wave velocity, and cardiorespiratory fitness were assessed before and after 12 weeks of a thrice-weekly exercise program (five minutes of warm-up, 30 min of endurance exercise, one set of 10-15 reps in five resistance exercises, and five minutes of cool-down). RESULTS: The cardiac reinnervation group had reduced (p < 0.01) 24-hour systolic/diastolic blood pressure (7/9 mm Hg), daytime systolic/diastolic blood pressure (9/10 mm Hg) and nighttime diastolic blood pressure (6 mm Hg) after training. The no cardiac reinnervation group reduced (p < 0.05) only 24-hour (5 mm Hg), daytime (5 mm Hg) and nighttime (6 mm Hg) diastolic blood pressure after training. Hourly analysis showed that the cardiac reinnervation group reduced systolic/diastolic blood pressure for 10/21 h, while the no cardiac reinnervation group reduced systolic/diastolic blood pressure for only 3/11 h. The cardiac reinnervation group also improved both maximal oxygen consumption (10.8%) and exercise tolerance (13.4%) after training, but the no cardiac reinnervation group improved only exercise tolerance (9.9%). Pulse wave velocity did not change in both groups. CONCLUSION: There were greater improvements in ambulatory blood pressure and maximal oxygen consumption in the cardiac reinnervation than the no cardiac reinnervation group. These results suggest that cardiac reinnervation associates with hemodynamic and cardiorespiratory adaptations to exercise training in individuals with heart transplantation.

Exhaled breath acetone for predicting cardiac and overall mortality in chronic heart failure patients.

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

miRNAs may play a major role in the control of gene expression in key pathobiological processes in Chagas disease cardiomyopathy.

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

Impact of Delayed Whole Blood Processing Time on Plasma Levels of miR- 1 and miR-423-5p up to 24 Hours.

BACKGROUND: Circulating cell-free miRNAs hold great promise as a new class of biomarkers due to their high stability in body fluids and association with disease stages. However, even using sensitive and specific methods, technical challenges are associated with miRNA analysis in body fluids. A major source of variation in plasma and serum is the potential cell-derived miRNA contamination from hemolysis. OBJECTIVES: The study aimed to evaluate the effect of the delayed whole blood processing time on the concentrations of miR-1 and -423-5p. METHODS: Ten blood samples were incubated for 0, 3 and 24 hours at room temperature prior to processing into plasma. For each time point, hemolysis was assessed in plasma by UV spectrophotometry at 414nm wavelength (λ414). Circulating levels of miR-1 and -423-5p were measured by RT-qPCR; miR-23a and -451 were also analyzed as controls. RESULTS: A significant hemolysis was observed only after 24h (λ414 0.3 ± 0.02, p < 0.001). However, only small changes in miR-1 and -423-5p levels were observed up to 24h of storage at room temperature (Ct 31.5 ± 0.5 to 31.8 ± 0.6for miR-1, p = 0.989; and 29.01 ± 0.3 to 29.04 ± 0.3, p = 0.614 for - 423-5p). No correlation was observed between hemolysis and the levels of miR-1 and -423-5p. CONCLUSION: Our data indicate that the storage of whole blood samples at room temperature for up to 24h prior to their processing into plasma does not appear to have a significant impact on miR-1 and - 423-5p concentrations.

Archaea Symbiont of T. cruzi Infection May Explain Heart Failure in Chagas Disease.

Background: Archaeal genes present in Trypanosoma cruzi may represent symbionts that would explain development of heart failure in 30% of Chagas disease patients. Extracellular vesicles in peripheral blood, called exosomes (< 0.1 µm) or microvesicles (>0.1 µm), present in larger numbers in heart failure, were analyzed to determine whether they are derived from archaea in heart failure Chagas disease. Methods: Exosomes and microvesicles in serum supernatant from 3 groups were analyzed: heart failure Chagas disease (N = 26), asymptomatic indeterminate form (N = 21) and healthy non-chagasic control (N = 16). Samples were quantified with transmission electron microscopy, flow cytometer immunolabeled with anti-archaemetzincin-1 antibody (AMZ 1, archaea collagenase) and probe anti-archaeal DNA and zymography to determine AMZ1 (Archaeal metalloproteinase) activity. Results: Indeterminate form patients had higher median numbers of exosomes/case vs. heart failure patients (58.5 vs. 25.5, P < 0.001), higher exosome content of AMZ1 antigens (2.0 vs. 0.0; P < 0.001), and lower archaeal DNA content (0.2 vs. 1.5, P = 0.02). A positive correlation between exosomes and AMZ1 content was seen in indeterminate form (r = 0.5, P < 0.001), but not in heart failure patients (r = 0.002, P = 0.98). Higher free archaeal DNA (63.0 vs. 11.1, P < 0.001) in correlation with exosome numbers (r = 0.66, P = 0.01) was seen in heart failure but not in indeterminate form (r = 0.29, P = 0.10). Flow cytometer showed higher numbers of AMZ1 microvesicles in indeterminate form (64 vs. 36, P = 0.02) and higher archaeal DNA microvesicles in heart failure (8.1 vs. 0.9, P < 0.001). Zymography showed strong% collagenase activity in HF group, mild activity in IF compared to non-chagasic healthy group (121 ± 14, 106 ± 13 and 100; P < 0.001). Conclusions: Numerous exosomes, possibly removing and degrading abnormal AMZ1 collagenase, are associated with indeterminate form. Archaeal microvesicles and their exosomes, possibly associated with release of archaeal AMZ1 in heart failure, are future candidates of heart failure biomarkers if confirmed in larger series, and the therapeutic focus in the treatment of Chagas disease.

Systemic effects of controlled exposure to diesel exhaust: a meta-analysis from randomized controlled trials.

INTRODUCTION: Ambient air pollution is associated with adverse cardiovascular events. This meta-analysis aimed to investigate the short-term association between air pollution and cardiovascular effects on healthy volunteers. METHODS: We searched databases to identify randomized trials with controlled human exposures to either of two models for studying ambient particulate matter: diesel-exhaust or concentrated ambient particles. Estimates of size effect were performed using standardized mean difference (SMD). Heterogeneity was assessed with I2 statistics. Outcomes were vascular function estimated by forearm blood flow (FBF), blood pressure, heart rate, and blood analysis. RESULTS: Database searches yielded 17 articles (n = 342) with sufficient information for meta-analyses. High levels of heterogeneity for the some outcomes were analyzed using random-effects model. The pooled effect estimate showed that short-term exposure to air pollution impaired FBF response from 2.7 to 2.5 mL/100 mL tissue/min (SMD 0.404; p = .006). There was an increase in 5000 platelet/mm3 following pollution exposure (SMD 0.390; p = .050) but no significant differences for other outcomes. CONCLUSION: Controlled human exposures to air pollution are associated with the surrogates of vascular dysfunction and increase in platelet count, which might be related to adverse cardiovascular events. Given the worldwide prevalence of exposure to air pollution, these findings are relevant for public health. KEY MESSAGES Controlled exposure to air pollution impairs vasomotor response, which is a surrogate for adverse cardiovascular events. This is the first meta-analysis from randomized clinical trials showing short-term association between air pollution and cardiovascular effects on healthy volunteers. Given the worldwide prevalence of exposure to air pollution, this finding is important for public health.

Inflammatory biomarkers and effect of exercise on functional capacity in patients with heart failure: Insights from a randomized clinical trial.

Background In patients with heart failure, inflammation has been associated with worse functional capacity, but it is uncertain whether it could affect their response to exercise training. We evaluated whether inflammatory biomarkers are related to differential effect of exercise on the peak oxygen uptake (V˙O2) among patients with heart failure. Design Open, parallel group, randomized controlled trial. Methods Patients with heart failure and ejection fraction ≤0.4 were randomized into exercise training or control for 12 weeks. Patients were classified according to: 1) inflammatory biomarkers blood levels, defined as 'low' if both interleukin-6 and tumor necrosis factor-alpha blood levels were below median, and 'high' otherwise; and 2) galectin-3 blood levels, which also reflect pro-fibrotic processes. Results Forty-four participants (50 ± 7 years old, 55% men, 25% ischemic) were allocated to exercise training ( n = 28) or control ( n = 16). Exercise significantly improved peak V˙O2 among participants with 'low' inflammatory biomarkers (3.5 ± 0.9 vs. -0.7 ± 1.1 ml/kg per min, p = 0.006), as compared with control, but not among those with 'high' inflammatory biomarkers (0.4 ± 0.6 vs. -0.2 ± 0.7 ml/kg per min, p = 0.54, p for interaction = 0.009). Similarly, exercise improved peak V˙O2 among participants with below median (2.4 ± 0.8 vs. -0.3 ± 0.9 ml/kg per min, p = 0.032), but not among those with above median galectin-3 blood levels (0.3 ± 0.7 vs. -0.7 ± 1.0 ml/kg per min, p = 0.41, p for interaction = 0.053). Conclusion In patients with heart failure, levels of biomarkers that reflect pro-inflammatory and pro-fibrotic processes were associated with differential effect of exercise on functional capacity. Further studies should evaluate whether exercise training can improve clinical outcomes in patients with heart failure and low levels of these biomarkers.

Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients.

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

Effects of reducing exposure to air pollution on submaximal cardiopulmonary test in patients with heart failure: Analysis of the randomized, double-blind and controlled FILTER-HF trial.

BACKGROUND: Air pollution exposure could mitigate the health benefits of exercise in patients with heart failure (HF). We tested the effects of a respiratory filter on HF patients exposed to air pollution during exercise. METHODS AND RESULTS: Ancillary analysis of the FILTER-HF trial, focused on the exercise outcomes. In a randomized, double-blind, 3-way crossover design, 26 HF patients and 15 control volunteers were exposed to clean air, unfiltered dilute diesel engine exhaust (DE), or filtered DE for 6min during a submaximal cardiopulmonary testing in a controlled-exposure facility. Prospectively collected data included six-minute walking test [6mwt], VO2, VE/VCO2 Slope, O2Pulse, pulmonary ventilation [VE], tidal volume, VD/Vt, oxyhemoglobin saturation and CO2-rebreathing. Compared to clean air, DE adversely affected VO2 (11.0±3.9 vs. 8.4±2.8ml/kg/min; p<0.001); 6mwt (243.3±13.0 vs. 220.8±13.7m; p=0.030); and O2Pulse (8.9±1.0 vs. 7.8±0.7ml/beat; p<0.001) in HF patients. Compared to DE, filtration reduced the particulate concentration from 325±31 to 25±6µg/m(3), and was associated with an increase in VO2 (10.4±3.8ml/kg/min; p<0.001 vs. DE) and O2Pulse (9.7±1.1ml/beat; p<0.001 vs. DE) in patients with HF. Filtration was associated with higher VE and CO2-rebreathing in both groups. VE/VCO2 Slope was higher among patients with HF. CONCLUSION: DE adversely affects exercise capacity in patients with HF. A simple respiratory filter can reduce the adverse effects of pollution on VO2 and O2Pulse. Given the worldwide prevalence of exposure to traffic-related air pollution, these findings are relevant for public health especially in this highly susceptible population. The filter intervention holds great promise that needs to be tested in future studies.

Respiratory Filter Reduces the Cardiovascular Effects Associated With Diesel Exhaust Exposure: A Randomized, Prospective, Double-Blind, Controlled Study of Heart Failure: The FILTER-HF Trial.

OBJECTIVES: The goal of this study was to test the effects of a respiratory filter intervention (filter) during controlled pollution exposure. BACKGROUND: Air pollution is considered a risk factor for heart failure (HF) decompensation and mortality. METHODS: This study was a double-blind, randomized to order, controlled, 3-way crossover, single-center clinical trial. It enrolled 26 patients with HF and 15 control volunteers. Participants were exposed in 3 separate sessions to clean air, unfiltered diesel exhaust exposure (DE), or filtered DE. Endpoints were endothelial function assessed by using the reactive hyperemia index (RHi), arterial stiffness, serum biomarkers, 6-min walking distance, and heart rate variability. RESULTS: In patients with HF, DE was associated with a worsening in RHi from 2.17 (interquartile range [IQR]: 1.8 to 2.5) to 1.72 (IQR: 1.5 to 2.2; p = 0.002) and an increase in B-type natriuretic peptide (BNP) from 47.0 pg/ml (IQR: 17.3 to 118.0 pg/ml) to 66.5 pg/ml (IQR: 26.5 to 155.5 pg/ml; p = 0.004). Filtration reduced the particulate concentration (325 ± 31 µg/m(3) vs. 25 ± 6 µg/m(3); p < 0.001); in the group with HF, filter was associated with an improvement in RHi from 1.72 (IQR: 1.5 to 2.2) to 2.06 (IQR: 1.5 to 2.6; p = 0.019) and a decrease in BNP from 66.5 pg/ml (IQR: 26.5 to 155.5 pg/ml) to 44.0 pg/ml (IQR: 20.0 to 110.0 pg/ml; p = 0.015) compared with DE. In both groups, DE decreased the 6-min walking distance and arterial stiffness, although filter did not change these responses. DE had no effect on heart rate variability or exercise testing. CONCLUSIONS: To our knowledge, this trial is the first to show that a filter can reduce both endothelial dysfunction and BNP increases in patients with HF during DE. Given these potential benefits, the widespread use of filters in patients with HF exposed to traffic-derived air pollution may have beneficial public health effects and reduce the burden of HF. (Effects of Air Pollution Exposure Reduction by Filter Mask on Heart Failure; NCT01960920).

Sleep-Disordered Breathing Exacerbates Muscle Vasoconstriction and Sympathetic Neural Activation in Patients with Systolic Heart Failure.

BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with heart failure (HF), and hypoxia and hypercapnia episodes activate chemoreceptors stimulating autonomic reflex responses. We tested the hypothesis that muscle vasoconstriction and muscle sympathetic nerve activity (MSNA) in response to hypoxia and hypercapnia would be more pronounced in patients with HF and SDB than in patients with HF without SDB (NoSBD). METHODS AND RESULTS: Ninety consecutive patients with HF, New York Heart Association functional class II-III, and left ventricular ejection fraction ≤40% were screened for the study. Forty-one patients were enrolled: NoSDB (n=13, 46 [39-53] years) and SDB (n=28, 57 [54-61] years). SDB was characterized by apnea-hypopnea index ≥15 events per hour (polysomnography). Peripheral (10% O2 and 90% N2, with CO2 titrated) and central (7% CO2 and 93% O2) chemoreceptors were stimulated for 3 minutes. Forearm and calf blood flow were evaluated by venous occlusion plethysmography, MSNA by microneurography, and blood pressure by beat-to-beat noninvasive technique. Baseline forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance were similar between groups. MSNA was higher in the SDB group. During hypoxia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group (P<0.01 to all comparisons). Similarly, during hypercapnia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group (P<0.001 to all comparisons). MSNA were higher in response to hypoxia (P=0.024) and tended to be higher to hypercapnia (P=0.066) in the SDB group. CONCLUSIONS: Patients with HF and SDB have more severe muscle vasoconstriction during hypoxia and hypercapnia than HF patients without SDB, which seems to be associated with endothelial dysfunction and, in part, increased MSNA response.

Impact of Exhaled Breath Acetone in the Prognosis of Patients with Heart Failure with Reduced Ejection Fraction (HFrEF). One Year of Clinical Follow-up.

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