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.

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).

Mode of death on Chagas heart disease: comparison with other etiologies. a subanalysis of the REMADHE prospective trial.

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

Hypertonic saline solution for prevention of renal dysfunction in patients with decompensated heart failure.

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

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.

Anemia and renal failure as predictors of risk in a mainly non-ischemic heart failure population.

Anemia and renal failure (RF) are related to poor prognosis in chronic heart failure (HF). Anemia appear early in the course of RF and its value as predictor of risk in HF may be overlap by the value of RF. We aimed to establish the prognostic value of anemia and RF in a Brazilian HF population.

Beta-blocker therapy and mortality of patients with Chagas cardiomyopathy: a subanalysis of the REMADHE prospective trial.

BACKGROUND: Peculiar aspects of Chagas cardiomyopathy raise concerns about efficacy and safety of sympathetic blockade. We studied the influence of beta-blockers in patients with Chagas cardiomyopathy. METHODS AND RESULTS: We examined REMADHE trial and grouped patients according to etiology (Chagas versus non-Chagas) and beta-blocker therapy. Primary end point was all-cause mortality or heart transplantation. Altogether 456 patients were studied; 27 (5.9%) were submitted to heart transplantation and 202 (44.3%) died. Chagas etiology was present in 68 (14.9%) patients; they had lower body mass index (24.1+/-4.1 versus 26.3+/-5.1, P=0.001), smaller end-diastolic left ventricle diameter (6.7+/-1.0 mm versus 7.0+/-0.9 mm, P=0.001), smaller proportion of beta-blocker therapy (35.8% versus 68%, P<0.001), and higher proportion of spironolactone therapy (74.6% versus 57.8%, P=0.003). Twenty-four (35.8%) patients with Chagas disease were under beta-blocker therapy and had lower serum sodium (136.6+/-3.1 versus 138.4+/-3.1 mEqs, P=0.05) and lower body mass index (22.5+/-3.3 versus 24.9+/-4.3, P=0.03) compared with those who received beta-blockers. Survival was lower in patients with Chagas heart disease as compared with other etiologies. When only patients under beta-blockers were considered, the survival of patients with Chagas disease was similar to that of other etiologies. The survival of patients with beta-blockers was higher than that of patients without beta-blockers. In Cox regression model, left ventricle end-diastolic diameter (hazard ratio, 1.78; CI, 1.15 to 2.76; P=0.009) and beta-blockers (hazard ratio, 0.37; CI, 0.14 to 0.97; P=0.044) were associated with better survival. CONCLUSIONS: Our study suggests that beta-blockers may have beneficial effects on survival of patients with heart failure and Chagas heart disease and warrants further investigation in a prospective, randomized trial. Clinical Trial Registration- clinicaltrials.gov. Identifier: NCT00505050.

Normalization of right ventricular performance and remodeling evaluated by magnetic resonance imaging at late follow-up of heart transplantation: relationship between function, exercise capacity and pulmonary vascular resistance.

BACKGROUND: Right ventricular (RV) dysfunction remains one of the most prominent complications during the period immediately after heart transplantation (HT); however, late adaptation of the RV has not been well described. The aim of our study was to evaluate RV function and remodeling using magnetic resonance imaging (MRI) and to correlate it with exercise capacity and also with hemodynamic data obtained before HT. METHODS: We prospectively evaluated RV function of 25 heart-transplanted patients, without cardiac allograft vasculopathy, who were documented by negative dobutamine stress echocardiography during late follow-up (Group 1, 6 +/- 4.3 years) using MRI. We then compared Group 1 with a control group consisting of 10 patients, who were < or =1 year post-HT (Group 2), hemodynamically stable, and with the same pre-operative hemodynamic features as Group 1. Their pulmonary arterial systolic blood pressure (PSBP) varied from 17 to 67 mm Hg (43.2 +/- 15.3) and pulmonary vascular resistance (PVR) from 1.0 to 5.4 Wood units (2.5 +/- 1.12). The following parameters were studied: RV end-diastolic volume (EDV) and systolic volume (ESV); stroke volume (SV); ejection fraction (EF); and mass (M). We also evaluated the VO2 peak and slope VE/VCO2 values during a treadmill test. Data were analyzed and correlated with the hemodynamic values of PVR and PSBP obtained pre-HT. RESULTS: In Group 1, treadmill evaluation data showed exercise VO2 peak (19.9 +/- 3.19 ml/kg/min) and slope VE/VCO2 (36.9 +/- 4.5) values comparable to those of sedentary individuals; RV variables according to MRI were within normal ranges, with the following mean values for Groups 1 and 2, respectively: RVEDV, 99.6 +/- 4.0 ml vs 127 +/- 16 ml (p = 0.03); RVESV, 42 +/- 2 ml vs 58.5 +/- 9 ml (p = 0.01); RVSV, 57 +/- 3 ml vs 71 +/- 10 ml (p = 0.1); RVEF, 58 +/- 1.4% vs 54 +/- 3.8% (p = 0.29); and RVM, 43.4 +/- 1.9 g vs 74 +/- 8.8 g (p = 0.001). There was no correlation between hemodynamic pulmonary values before HT or any other index of late RV performance, including RV remodeling and hypertrophy, in our study population (p = not significant). CONCLUSIONS: In contrast to what we would expect for heart transplant patients at late follow-up, the RV may adapt to pulmonary pressure and resistance, with reverse remodeling characterized by volume and mass reduction, leading to normalization of RV function despite abnormal hemodynamic pulmonary values being measured before HT. There was no influence on the low exercise capacity observed in these patients, in the absence of cardiac allograft vasculopathy.