Fátima D. Cruz

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 β-blockers in patients with Chagas cardiomyopathy. Methods and Results— We examined REMADHE trial and grouped patients according to etiology (Chagas versus non-Chagas) and β-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 β-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 β-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 β-blockers. Survival was lower in patients with Chagas heart disease as compared with other etiologies. When only patients under β-blockers were considered, the survival of patients with Chagas disease was similar to that of other etiologies. The survival of patients with β-blockers was higher than that of patients without β-blockers. In Cox regression model, left ventricle end-diastolic diameter (hazard ratio, 1.78; CI, 1.15 to 2.76; P =0.009) and β-blockers (hazard ratio, 0.37; CI, 0.14 to 0.97; P =0.044) were associated with better survival. Conclusions— Our study suggests that β-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][1]. Received June 1, 2009; accepted November 11, 2009. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00505050&atom=%2Fcirchf%2F3%2F1%2F82.atomBackground—Peculiar aspects of Chagas cardiomyopathy raise concerns about efficacy and safety of sympathetic blockade. We studied the influence of &bgr;-blockers in patients with Chagas cardiomyopathy. Methods and Results—We examined REMADHE trial and grouped patients according to etiology (Chagas versus non-Chagas) and &bgr;-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 &bgr;-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 &bgr;-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 &bgr;-blockers. Survival was lower in patients with Chagas heart disease as compared with other etiologies. When only patients under &bgr;-blockers were considered, the survival of patients with Chagas disease was similar to that of other etiologies. The survival of patients with &bgr;-blockers was higher than that of patients without &bgr;-blockers. In Cox regression model, left ventricle end-diastolic diameter (hazard ratio, 1.78; CI, 1.15 to 2.76; P=0.009) and &bgr;-blockers (hazard ratio, 0.37; CI, 0.14 to 0.97; P=0.044) were associated with better survival. Conclusions—Our study suggests that &bgr;-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.

Mychophenolate Mofetil Increased Chagas Disease Reactivation in Heart Transplanted Patients: Comparison Between Two Different Protocols

Heart transplantation (HT) remains the treatment of choice for advanced chagasic cardiomyopathy. New immunosuppression protocols have provided better control of rejection (RJ) and cardiac allograft vasculopathy. However, their influence on infection and Chagas disease reactivation (CDR) is not well established. The aim of this study was to compare the CDR rate in patients under two different immunosuppression protocols. We studied 39 chagasic patients who had undergone orthotopic HT between April, 1987 and June, 2004. They were divided into two groups, one taking azathioprine (group 1 = 24 patients) and the other taking mycophenolate mofetil (group 2 = 15 patients), in the standard doses (2 mg/kg/day and 2 g/day, respectively), beside prednisone and cyclosporine, in equivalent doses. The number of CDR and RJ episodes were analyzed in the first and second years after HT. CDR rates were 8%± 5% at 1 year and 12%± 6% at 2 years of follow‐up in group 1. Otherwise, patients in group 2 presented CDR rates of 75%± 10% and 81%± 9% at the same periods, respectively (p < 0.0001, hazard ratio = 6.06). When comparing RJ rates in the first year after HT, both groups had similar behavior under both immunosuppression protocols (p = 0.88). These data show that current prescribed doses of mycophenolate mofetil increase the early risk of CDR without changing RJ incidence in this period.

Granulocyte-colony stimulating factor or granulocyte-colony stimulating factor associated to stem cell intracoronary infusion effects in non ischemic refractory heart failure.

We prospectively studied bone marrow stem cell (BMSC) therapy in 23 patients with non ischemic refractory heart failure(HF) in comparison with a HF control group with 17 patients. BMSC patients randomly underwent granulocyte-colony stimulating factor (G-CSF) administration (14 patients) or G-CSF associated to BMSC intracoronary infusion (eight patients). After the first month all BMSC patients received G-CSF with one-month interval between each one. CD34+ cell peaks (per mm(3)) in BMSC patients were 19+/-12 and in normal control 60+/-20 (p=0.003). In BMSC patients after the 1st G-CSF left ventricular(LV) ejection fraction (EF) increased from 21.4+/-4.7% to 23.6+/-7.7%(p=.048), peak VO(2) (ml/kg/min) from 9.9+/-2.4 to 11.6+/-3 (p=.04), functional class and quality of life improved whereas in the HF control group LVEF, RFEF and functional class were unchanged. Both BMSC subgroups presented improvement of LV function evaluated by DTI velocities. Evaluations after the first month in BMSC patients showed improvements in LVEF (p=.001), right VEF (p=0.01), DTI velocities (p=.009), peak VO(2) (p=0.04), functional class (p<0.001) and quality of life (p<0.001). In conclusion, CD34+ mobilization is impaired in HF. Stem cell therapy can improve HF. Randomized trials should be developed to confirm our results.

β-Blocker Therapy and Mortality of Patients With Chagas CardiomyopathyCLINICAL PERSPECTIVE

Background— Peculiar aspects of Chagas cardiomyopathy raise concerns about efficacy and safety of sympathetic blockade. We studied the influence of β-blockers in patients with Chagas cardiomyopathy. Methods and Results— We examined REMADHE trial and grouped patients according to etiology (Chagas versus non-Chagas) and β-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 β-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 β-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 β-blockers. Survival was lower in patients with Chagas heart disease as compared with other etiologies. When only patients under β-blockers were considered, the survival of patients with Chagas disease was similar to that of other etiologies. The survival of patients with β-blockers was higher than that of patients without β-blockers. In Cox regression model, left ventricle end-diastolic diameter (hazard ratio, 1.78; CI, 1.15 to 2.76; P =0.009) and β-blockers (hazard ratio, 0.37; CI, 0.14 to 0.97; P =0.044) were associated with better survival. Conclusions— Our study suggests that β-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][1]. Received June 1, 2009; accepted November 11, 2009. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00505050&atom=%2Fcirchf%2F3%2F1%2F82.atomBackground—Peculiar aspects of Chagas cardiomyopathy raise concerns about efficacy and safety of sympathetic blockade. We studied the influence of &bgr;-blockers in patients with Chagas cardiomyopathy. Methods and Results—We examined REMADHE trial and grouped patients according to etiology (Chagas versus non-Chagas) and &bgr;-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 &bgr;-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 &bgr;-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 &bgr;-blockers. Survival was lower in patients with Chagas heart disease as compared with other etiologies. When only patients under &bgr;-blockers were considered, the survival of patients with Chagas disease was similar to that of other etiologies. The survival of patients with &bgr;-blockers was higher than that of patients without &bgr;-blockers. In Cox regression model, left ventricle end-diastolic diameter (hazard ratio, 1.78; CI, 1.15 to 2.76; P=0.009) and &bgr;-blockers (hazard ratio, 0.37; CI, 0.14 to 0.97; P=0.044) were associated with better survival. Conclusions—Our study suggests that &bgr;-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.

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 ClinicalTrails.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.

Effect of a sequential education and monitoring programme on quality-of-life components in heart failure

Trials of disease management programmes (DMP) in heart failure (HF) have shown controversial results regarding quality of life. We hypothesized that a DMP applied over the long‐term could produce different effects on each of the quality‐of‐life components.

Left cardiac sympathetic denervation for treatment of symptomatic systolic heart failure patients: a pilot study

To evaluate the feasibility, safety, and potential beneficial effects of left cardiac sympathetic denervation (LCSD) in systolic heart failure (HF) patients.

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.

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.