Gilson Soares Feitosa

Resultados iniciais do transplante de células de medula óssea para o miocárdio de pacientes com insuficiência cardíaca de etiologia chagásica

OBJECTIVE To evaluate early effects of bone marrow cell transplantation to the myocardium of patients with heart failure (CHF) due to Chagas disease. METHODS We studied 28 patients (mean age 52.2 +/- 9.9), of whom 24 were male. Despite optimized treatment, 25 patients were in NYHA class III and three patients, in NYHA class IV. The procedure consisted of aspiration of 50 mL of bone marrow, separation of the mononuclear fraction, and intracoronary injection. Effects on left ventricle ejection fraction (LVEF), distance walked in the six-minute walking test, quality-of-life, NYHA class, arrhythmogenic and biochemical parameters, were all evaluated. RESULTS There were no complications directly related to the procedure. Baseline left ventricular ejection fraction was 20.1 +/- 6.8%, and 60 days after transplantation it increased to 23.0 +/- 9.0%, p = 0.02. Significant improvements were observed in the NYHA class (3.1 +/- 0.3 to 1.8 +/- 0.5; p < 0.0001); quality-of-life (50.9 +/- 11.7 to 21.8 +/- 13.4; p < 0.0001); and distance walked in six minutes (355 +/- 136 m to 443 +/- 110 m; p = 0,003). The number of ventricular premature beats in 24 hours tended to increase (5,322 +/- 4,977 to 7,441 +/- 7,955; p = 0,062), but without increase in ventricular tachycardia episodes (61 +/- 127 to 54 +/- 127; p = 0.27). CONCLUSION Our data demonstrate for the first time that intracoronary injection of bone marrow mononuclear cells is feasible and suggest that it may be potentially safe and effective in patients with CHF due to Chagas disease.

Multicenter randomized trial of cell therapy in cardiopathies – MiHeart Study

BackgroundCardiovascular diseases are the major cause of death in the world. Current treatments have not been able to reverse this scenario, creating the need for the development of new therapies. Cell therapies have emerged as an alternative for cardiac diseases of distinct causes in experimental animal studies and more recently in clinical trials.Method/DesignWe have designed clinical trials to test for the efficacy of autologous bone marrow derived mononuclear cell therapies in four different cardiopathies: acute and chronic ischemic heart disease, and Chagasic and dilated cardiomyopathy. All trials are multicenter, randomized, double-blind and placebo controlled. In each trial 300 patients will be enrolled and receive optimized therapy for their specific condition. Additionally, half of the patients will receive the autologous bone marrow cells while the other half will receive placebo (saline with 5% autologous serum). For each trial there are specific inclusion and exclusion criteria and the method for cell delivery is intramyocardial for the chronic ischemic heart disease and intracoronary for all others. Primary endpoint for all studies will be the difference in ejection fraction (determined by Simpsons rule) six and twelve months after intervention in relation to the basal ejection fraction. The main hypothesis of this study is that the patients who receive the autologous bone-marrow stem cell implant will have after a 6 month follow-up a mean increase of 5% in absolute left ventricular ejection fraction in comparison with the control group.DiscussionMany phase I clinical trials using cell therapy for cardiac diseases have already been performed. The few randomized studies have yielded conflicting results, rendering necessary larger well controlled trials to test for efficacy of cell therapies in cardiopathies.The trials registration numbers at the NIH registry are the following: Chagasic cardiomyopathy (NCT00349271), dilated cardiomyopathy (NCT00333827), acute myocardial infarction (NCT00350766) and Chronic Ischemic Heart Disease (NCT00362388).

Cell Therapy in Chagas Cardiomyopathy (Chagas Arm of the Multicenter Randomized Trial of Cell Therapy in Cardiopathies Study) A Multicenter Randomized Trial

Background —Previous studies suggested that transplantation of autologous bone marrow derived mononuclear cells (BMNC) improves heart function in chronic chagasic cardiomyopathy (CCC). We report the results of the first randomized trial of BMNC therapy in CCC. Methods and Results —Patients aged 18-75 years with CCC, NYHA class III or IV, LVEF less than 35%, and optimized therapy were randomized to intracoronary injection of autologous BMNC or placebo. Primary endpoint was the difference in LVEF from baseline to 6 and 12 months after treatment between groups. Analysis was by intention to treat and powered to detect an absolute between-group difference of 5%. Between July 2005 and October 2009 234 patients were enrolled. Two abandoned the study and 49 were excluded due to protocol violation. The remaining 183 patients, 93 in the placebo group and 90 in the BMNC group, had trimmed mean age of 52.4 years (50.8 to 54.0) and LVEF of 26.1% (25.1 to 27.1) at baseline. Median number of injected BMNCs was 2.20 x 108 (1.40-3.50 x 108). Change in LVEF did not differ significantly between treatment groups: trimmed mean ΔEF= 3.0 (1.3 to 4.8) for BMNC and 2.5 (0.6 to 4.5) for placebo (p=0.519) at 6 months; ΔEF= 3.5 (1.5 to 5.5) for BMNC and ΔEF= 3.7 (1.5 to 6.0) for placebo (p=0.850) at 12 months. Left ventricular systolic and diastolic volumes, NYHA class, Minnesota life quality questionnaire, BNP concentrations, and 6-min walking test did also not differ between groups. Conclusions —Intracoronary injection of autologous BMNCs does not improve left ventricular function or quality of life in patients with CCC. Clinical Trial Registration Information —ClinicalTrials.gov; Identifier: [NCT00349271][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00349271&atom=%2Fcirculationaha%2Fearly%2F2012%2F04%2F19%2FCIRCULATIONAHA.111.067785.atomBackground— Previous studies suggested that transplantation of autologous bone marrow–derived mononuclear cells (BMNCs) improves heart function in chronic chagasic cardiomyopathy. We report the results of the first randomized trial of BMNC therapy in chronic chagasic cardiomyopathy. Methods and Results— Patients 18 to 75 years of age with chronic chagasic cardiomyopathy, New York Heart Association class II to IV heart failure, left ventricular ejection fraction (LVEF) <35, and optimized therapy were randomized to intracoronary injection of autologous BMNCs or placebo. The primary end point was the difference in LVEF from baseline to 6 and 12 months after treatment between groups. Analysis was by intention to treat and powered to detect an absolute between-group difference of 5. Between July 2005 and October 2009, 234 patients were enrolled. Two patients abandoned the study and 49 were excluded because of protocol violation. The remaining 183 patients, 93 in the placebo group and 90 in the BMNC group, had a trimmed mean age of 52.4 years (range, 50.8–54.0 years) and LVEF of 26.1 (range, 25.1–27.1) at baseline. Median number of injected BMNCs was 2.20×108 (range, 1.40–3.50×108). Change in LVEF did not differ significantly between treatment groups: trimmed mean change in LVEF at 6 months, 3.0 (1.3–4.8) for BMNCs and 2.5 (0.6–4.5) for placebo (P=0.519); change in LVEF at 12 months, 3.5 (1.5–5.5) for BMNCs and 3.7 (1.5–6.0) for placebo (P=0.850). Left ventricular systolic and diastolic volumes, New York Heart Association functional class, Minnesota quality-of-life questionnaire, brain natriuretic peptide concentrations, and 6-minute walking test did also not differ between groups. Conclusion— Intracoronary injection of autologous BMNCs does not improve left ventricular function or quality of life in patients with chronic chagasic cardiomyopathy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00349271.

Prognostic factors of rheumatic mitral stenosis during pregnancy and puerperium

OBJECTIVE To identify characteristics associated with complications during pregnancy and puerperium in patients with rheumatic mitral stenosis. METHODS Forty-one pregnant women (forty-five pregnancies) with mitral stenosis, followed-up from 1991 to 1999 were retrospectively evaluated. PREDICTOR VARIABLES the mitral valve area (MVA), measured by echocardiogram, and functional class (FC) before pregnancy (NYHA criteria). Maternal events: progression of heart failure, need for cardiac surgery or balloon mitral valvulotomy, death, and thromboembolism. Fetal/neonatal events: abortion, fetal or neonatal death, prematurity or low birth weight (<2,500 g), and extended stay in the nursery or hospitalization in newborn ICU. RESULTS The mean +/- SD of age of the patients was 28.8+/-4.6 years. The eventful and uneventful patients were similar in age and percentage of first pregnancies. As compared with the level 1 MVA, the relative risk (RR) of maternal events was 5.5 (95% confidence interval (CI) =0.8-39.7) for level 2 MVA and 11.4 (95% CI=1.7-74.5) for level 3 MVA. The prepregnancy FC (FC > or = II and III versus I) was also associated with risk for maternal events (RR=2.7; 95% CI=1.4-5.3).MVA and FC were not importantly associated with these events, although a smaller frequency of fetal/neonatal events was observed in patients who had undergone balloon valvulotomy. CONCLUSION In pregnant women with mitral stenosis, the MVA and the FC are strongly associated with maternal complications but are not associated with fetal/neonatal events. Balloon mitral valvulotomy could have contributed to reducing the risks of fetal/neonatal events in the more symptomatic patients who had to undergo this procedure during pregnancy.

Bone marrow cell transplantation in chagas' disease heart failure: report of the first human experience

FUNDAMENTO: Insuficiencia cardiaca (IC) causada por Doenca de Chagas (DC) e uma cardiomiopatia inflamatoria progressiva que afeta milhoes de pessoas na America Latina. Estudos com modelos de camundongo de IC devido a DC indicam que o transplante de celulas mononucleares derivadas da medula ossea (TCDMO) pode reduzir a inflamacao, fibrose e melhorar a funcao miocardica. OBJETIVO: O proposito desse estudo foi avaliar, pela primeira vez em seres humanos, a seguranca e a eficacia de TCDMO no miocardio de pacientes com IC devido a DC. METODOS: Um total de 28 pacientes com IC devido a DC (media de idade de 52,2 ± 9,9 anos) com classe funcional NYHA III e IV foram submetidos a TCDMO atraves de injecao coronariana. Os efeitos na fracao de ejecao do ventriculo esquerdo (FEVE), capacidade funcional, qualidade de vida, arritmias e parâmetros bioquimicos, imunologicos e neuro-humorais foram avaliados. RESULTADOS: Nao houve complicacoes diretamente relacionadas ao procedimento. A FEVE foi 20,1 ± 6,8% e 28,3 ± 7,9%, p < 0,03 a nivel basal e 180 dias apos o procedimento, respectivamente. No mesmo periodo, melhoras significantes foram observadas na classe funcional NYHA (3,1 ± 0,3 para 1,8 ± 0,5; p < 0,001), qualidade de vida (50,9 ± 11,7 para 25,1 ± 15,9; p < 0,001), e no teste de caminhada de seis minutos (355 ± 136 m para 437 ± 94 m; p < 0,01). Nao houve alteracoes nos marcadores de ativacao imune ou neurohormonais. Nenhuma complicacao foi registrada. CONCLUSAO: Nossos dados sugerem que a injecao intracoronariana de celulas derivadas da medula ossea e segura e potencialmente efetiva em pacientes com IC devido a DC. A extensao do beneficio, entretanto, parece ser discreta e precisa ser confirmada em estudos clinicos maiores, randomizados, duplo-cegos, controlados com placebo.

Transplante de células da medula óssea na insuficiência cardíaca chagásica: relato da primeira experiência humana

FUNDAMENTO: Insuficiencia cardiaca (IC) causada por Doenca de Chagas (DC) e uma cardiomiopatia inflamatoria progressiva que afeta milhoes de pessoas na America Latina. Estudos com modelos de camundongo de IC devido a DC indicam que o transplante de celulas mononucleares derivadas da medula ossea (TCDMO) pode reduzir a inflamacao, fibrose e melhorar a funcao miocardica. OBJETIVO: O proposito desse estudo foi avaliar, pela primeira vez em seres humanos, a seguranca e a eficacia de TCDMO no miocardio de pacientes com IC devido a DC. METODOS: Um total de 28 pacientes com IC devido a DC (media de idade de 52,2 ± 9,9 anos) com classe funcional NYHA III e IV foram submetidos a TCDMO atraves de injecao coronariana. Os efeitos na fracao de ejecao do ventriculo esquerdo (FEVE), capacidade funcional, qualidade de vida, arritmias e parâmetros bioquimicos, imunologicos e neuro-humorais foram avaliados. RESULTADOS: Nao houve complicacoes diretamente relacionadas ao procedimento. A FEVE foi 20,1 ± 6,8% e 28,3 ± 7,9%, p < 0,03 a nivel basal e 180 dias apos o procedimento, respectivamente. No mesmo periodo, melhoras significantes foram observadas na classe funcional NYHA (3,1 ± 0,3 para 1,8 ± 0,5; p < 0,001), qualidade de vida (50,9 ± 11,7 para 25,1 ± 15,9; p < 0,001), e no teste de caminhada de seis minutos (355 ± 136 m para 437 ± 94 m; p < 0,01). Nao houve alteracoes nos marcadores de ativacao imune ou neurohormonais. Nenhuma complicacao foi registrada. CONCLUSAO: Nossos dados sugerem que a injecao intracoronariana de celulas derivadas da medula ossea e segura e potencialmente efetiva em pacientes com IC devido a DC. A extensao do beneficio, entretanto, parece ser discreta e precisa ser confirmada em estudos clinicos maiores, randomizados, duplo-cegos, controlados com placebo.

Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment)

The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5–50 mg QD) or clonidine (0.1–0.3 mg BID). The primary end point was BP control during office (<140/90 mm Hg) and 24-h ambulatory (<130/80 mm Hg) BP monitoring. Secondary end points included BP control from each method and absolute BP reduction. From 1597 patients recruited, 11.7% (187 patients) fulfilled the resistant hypertension criteria. Compared with the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary end point (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55–1.88]; P=1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01643434.

Cardiopulmonary exercise and 6-min walk tests as predictors of quality of life and long-term mortality among patients with heart failure due to Chagas disease

long-term mortality among patients with heart failure due to Chagas disease☆ Luiz Eduardo Ritt , Antonio Carlos Carvalho , Gilson Soares Feitosa , Joel A. Pinho-Filho , Marcus Vinicius Santos Andrade , Gilson Soares Feitosa-Filho , L. Kristin Newby , Renato D. Lopes a,c,d,⁎ a Cardiology Division, Sao Paulo Federal University, Sao Paulo, Brazil b Cardiology Division, Santa Izabel Hospital, Bahia, Brazil c Brazilian Clinical Research Institute, Sao Paulo, Brazil d Duke Clinical Research Institute, Durham, NC, USA

Cell Therapy in Chagas Cardiomyopathy (Chagas Arm of the MiHeart Study): A Multicenter Randomized Trial

Background —Previous studies suggested that transplantation of autologous bone marrow derived mononuclear cells (BMNC) improves heart function in chronic chagasic cardiomyopathy (CCC). We report the results of the first randomized trial of BMNC therapy in CCC. Methods and Results —Patients aged 18-75 years with CCC, NYHA class III or IV, LVEF less than 35%, and optimized therapy were randomized to intracoronary injection of autologous BMNC or placebo. Primary endpoint was the difference in LVEF from baseline to 6 and 12 months after treatment between groups. Analysis was by intention to treat and powered to detect an absolute between-group difference of 5%. Between July 2005 and October 2009 234 patients were enrolled. Two abandoned the study and 49 were excluded due to protocol violation. The remaining 183 patients, 93 in the placebo group and 90 in the BMNC group, had trimmed mean age of 52.4 years (50.8 to 54.0) and LVEF of 26.1% (25.1 to 27.1) at baseline. Median number of injected BMNCs was 2.20 x 108 (1.40-3.50 x 108). Change in LVEF did not differ significantly between treatment groups: trimmed mean ΔEF= 3.0 (1.3 to 4.8) for BMNC and 2.5 (0.6 to 4.5) for placebo (p=0.519) at 6 months; ΔEF= 3.5 (1.5 to 5.5) for BMNC and ΔEF= 3.7 (1.5 to 6.0) for placebo (p=0.850) at 12 months. Left ventricular systolic and diastolic volumes, NYHA class, Minnesota life quality questionnaire, BNP concentrations, and 6-min walking test did also not differ between groups. Conclusions —Intracoronary injection of autologous BMNCs does not improve left ventricular function or quality of life in patients with CCC. Clinical Trial Registration Information —ClinicalTrials.gov; Identifier: [NCT00349271][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00349271&atom=%2Fcirculationaha%2Fearly%2F2012%2F04%2F19%2FCIRCULATIONAHA.111.067785.atomBackground— Previous studies suggested that transplantation of autologous bone marrow–derived mononuclear cells (BMNCs) improves heart function in chronic chagasic cardiomyopathy. We report the results of the first randomized trial of BMNC therapy in chronic chagasic cardiomyopathy. Methods and Results— Patients 18 to 75 years of age with chronic chagasic cardiomyopathy, New York Heart Association class II to IV heart failure, left ventricular ejection fraction (LVEF) <35, and optimized therapy were randomized to intracoronary injection of autologous BMNCs or placebo. The primary end point was the difference in LVEF from baseline to 6 and 12 months after treatment between groups. Analysis was by intention to treat and powered to detect an absolute between-group difference of 5. Between July 2005 and October 2009, 234 patients were enrolled. Two patients abandoned the study and 49 were excluded because of protocol violation. The remaining 183 patients, 93 in the placebo group and 90 in the BMNC group, had a trimmed mean age of 52.4 years (range, 50.8–54.0 years) and LVEF of 26.1 (range, 25.1–27.1) at baseline. Median number of injected BMNCs was 2.20×108 (range, 1.40–3.50×108). Change in LVEF did not differ significantly between treatment groups: trimmed mean change in LVEF at 6 months, 3.0 (1.3–4.8) for BMNCs and 2.5 (0.6–4.5) for placebo (P=0.519); change in LVEF at 12 months, 3.5 (1.5–5.5) for BMNCs and 3.7 (1.5–6.0) for placebo (P=0.850). Left ventricular systolic and diastolic volumes, New York Heart Association functional class, Minnesota quality-of-life questionnaire, brain natriuretic peptide concentrations, and 6-minute walking test did also not differ between groups. Conclusion— Intracoronary injection of autologous BMNCs does not improve left ventricular function or quality of life in patients with chronic chagasic cardiomyopathy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00349271.

Eficácia e tolerabilidade da associação bisoprolol/hidroclorotiazida na hipertensão arterial

PURPOSE Multicenter, open and non-controlled study to evaluated the efficacy and the tolerability of a low-dose combination of two anti-hypertensive agents: a cardioselective beta-blocker, bisoprolol (2.5 and 5.0 mg) with 6.25 mg of hydrochlorothiazide. METHODS One hundred and six patients in the stage I and stage II of the systemic hypertension (mild to moderate) were given the bisoprolol/hydrochlorothiazide combination once daily and the diastolic and systolic blood pressures were monitored during the 8-week trial. RESULTS The bisoprolol/hydrochlorothiazide combination reduced the initial mean values of systolic and diastolic blood pressures, respectively, from the 157.4 mmHg and 98.8 mmHg to 137.3 mmHg and 87.4 mmHg. At the end of the treatment period, 61% of the patients normalized blood pressure values (< 90 mmHg) and 22.9% of them had responded to the treatment, resulting in a total response rate (normalized + responsive) of 83.9% of cases. Adverse events were described only in 18.9% of the patients and dizziness and headache were the most common. There were no clinically significant changes on plasma levels of potassium, uric acid, glucose, or in the lipid profile. CONCLUSION The combination of low dosages of bisoprolol and hydrochlorothiazide may be considered an effective, well tolerated and rational alternative for the initial treatment of the patients with mild to moderate hypertension.PURPOSE: Multicenter, open and non-controlled study to evaluated the efficacy and the tolerability of a low-dose combination of two anti-hypertensive agents: a cardioselective beta-blocker, bisoprolol (2.5 and 5.0mg) with 6.25mg of hydrochlorothiazide. METHODS: One hundred and six patients in the stage I and stage II of the systemic hypertension (mild to moderate) were given the bisoprolol/hydrochlorothiazide combination once daily and the diastolic and systolic blood pressures were monitored during the 8-week trial. RESULTS: The bisoprolol/hydrochlorothiazide combination reduced the initial mean values of systolic and diastolic blood pressures, respectively, from the 157.4mmHg and 98.8mmHg to 137.3mmHg and 87.4mmHg. At the end of the treatment period, 61% of the patients normalized blood pressure values (<90mmHg) and 22.9% of them had responded to the treatment, resulting in a total response rate (normalized + responsive) of 83.9% of cases. Adverse events were described only in 18.9% of the patients and dizziness and headache were the most common. There were no clinically significant changes on plasma levels of potassium, uric acid, glucose, or in the lipid profile. CONCLUSION: The combination of low dosages of bisoprolol and hydrochlorothiazide may be considered an effective, well tolerated and rational alternative for the initial treatment of the patients with mild to moderate hypertension.