Multicenter randomized trial of cell therapy in cardiopathies – MiHeart Study

Abstract Background: Cardiovascular 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/Design: We 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 Simpson's 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. Discussion: Many 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).

Metabolic, hemodynamic and structural adjustments to low intensity exercise training in a metabolic syndrome model

Background The increase in fructose consumption is paralleled by a higher incidence of metabolic syndrome, and consequently, cardiovascular disease mortality. We examined the effects of 8 weeks of low intensity exercise training (LET) on metabolic, hemodynamic, ventricular and vascular morphological changes induced by fructose drinking in male rats. Methods Male Wistar rats were divided into (n = 8 each) control (C), sedentary fructose (F) and ET fructose (FT) groups. Fructose-drinking rats received D-fructose (100 g/l). FT rats were assigned to a treadmill training protocol at low intensity (30% of maximal running speed) during 1 h/day, 5 days/week for 8 weeks. Measurements of triglyceride concentrations, white adipose tissue (WAT) and glycemia were carried out together with insulin tolerance test to evaluate metabolic profile. Arterial pressure (AP) signals were directly recorded. Baroreflex sensitivity (BS) was evaluated by the tachycardic and bradycardic responses. Right atria, left ventricle (LV) and ascending aorta were prepared to morphoquantitative analysis. Results LET reduced WAT (−37.7%), triglyceride levels (−33%), systolic AP (−6%), heart weight/body weight (−20.5%), LV (−36%) and aortic (−76%) collagen fibers, aortic intima-media thickness and circumferential wall tension in FT when compared to F rats. Additionally, FT group presented improve of BS, numerical density of atrial natriuretic peptide granules (+42%) and LV capillaries (+25%), as well as the number of elastic lamellae in aorta compared with F group. Conclusions Our data suggest that LET, a widely recommended practice, seems to be particularly effective for preventing metabolic, hemodynamic and morphological disorders triggered by MS.

Long-term cardiac changes in patients with systemic lupus erythematosus

Abstract Background The aim of this study was evaluate the late-onset repercussions of heart alterations of patients with systemic lupus erythematosus (SLE) after a 13-year follow up. Methods A historical prospective study was carried out involving the analysis of data from the charts of patients with a confirmed diagnosis of lupus in follow up since 1998. The 13-year evolution was systematically reviewed and tabulated to facilitate the interpretation of the data. Results Forty-eight patient charts were analyzed. Mean patient age was 34.5 ± 10.8 years at the time of diagnosis and 41.0 ± 10.3 years at the time of the study (45 women and 3 men). Eight deaths occurred in the follow-up period (two due to heart problems). Among the alterations found on the complementary exams, 46.2% of cases demonstrated worsening at reevaluation and four patients required a heart catheterization. In these cases, coronary angioplasty was performed due to the severity of the obstructions and one case required a further catheterization, culminating in the need for surgical myocardial revascularization. Conclusion The analysis demonstrated progressive heart impairment, with high rates of alterations on conventional complementary exams, including the need for angioplasty or revascularization surgery in four patients. These findings indicate the need for rigorous cardiac follow up in patients with systemic lupus erythematosus.

A behavioral intervention in a cohort of Japanese-Brazilians at high cardiometabolic risk

OBJECTIVE: To assess the effect of a health promotion program on cardiometabolic risk profile in Japanese-Brazilians. METHODS: A total of 466 subjects from a study on diabetes prevalence conducted in the city of Bauru, southeastern Brazil, in 2000 completed a 1-year intervention program (2005-2006) based on healthy diet counseling and physical activity. Changes in blood pressure and metabolic parameters in the 2005-2006 period were compared with annual changes in these same variables in the 2000-2005 period. RESULTS: During the intervention, there were greater annual reductions in mean (SD) waist circumference [-0.5(3.8) vs. 1.2(1.2) cm per year, p<0.001], systolic blood pressure [-4.6(17.9) vs. 1.8(4.3) mmHg per year, p<0.001], 2-hour plasma glucose [-1.2(2.1) vs. -0.2(0.6) mmol/L per year, p<0.001], LDL-cholesterol [-0.3(0.9) vs. -0.1(0.2) mmol/L per year, p<0.001] and Framingham coronary heart disease risk score [-0.25(3.03) vs. 0.11(0.66) per year, p=0.02] but not in triglycerides [0.2(1.6) vs. 0.1(0.42) mmol/L per year, p<0.001], and fasting insulin level [1.2(5.8) vs. -0.7(2.2) IU/mL per year, p<0.001] compared with the pre-intervention period. Significant reductions in the prevalence of impaired fasting glucose/impaired glucose tolerance and diabetes were seen during the intervention (from 58.4% to 35.4%, p<0.001; and from 30.1% to 21.7%, p= 0.004, respectively). CONCLUSIONS: A one-year community-based health promotion program brings cardiometabolic benefits in a high-risk population of Japanese-Brazilians.

Impact of urban atmospheric environment on hospital admissions in the elderly

OBJECTIVE: To analyze the impact of intra-urban atmospheric conditions on circulatory and respiratory diseases in elder adults. METHODS: Cross-sectional study based on data from 33,212 hospital admissions in adults over 60 years in the city of São Paulo, southeastern Brazil, from 2003 to 2007. The association between atmospheric variables from Congonhas airport and bioclimatic index, Physiological Equivalent Temperature, was analyzed according to the district's socioenvironmental profile. Descriptive statistical analysis and regression models were used. RESULTS: There was an increase in hospital admissions due to circulatory diseases as average and lowest temperatures decreased. The likelihood of being admitted to the hospital increased by 12% with 1ºC decrease in the bioclimatic index and with 1ºC increase in the highest temperatures in the group with lower socioenvironmental conditions. The risk of admission due to respiratory diseases increased with inadequate air quality in districts with higher socioenvironmental conditions. CONCLUSIONS: The associations between morbidity and climate variables and the comfort index varied in different groups and diseases. Lower and higher temperatures increased the risk of hospital admission in the elderly. Districts with lower socioenvironmental conditions showed greater adverse health impacts.

Doenças crônicas não transmissíveis no Brasil: prioridade para enfrentamento e investigação

As Doenças Crônicas Não Transmissíveis representam a maior carga de morbimortalidade no Brasil. Em 2011, o Ministério da Saúde lançou seu Plano de Ações Estratégicas para o Enfrentamento das Doenças Crônicas Não Transmissíveis, enfatizando ações populacionais para controlar as doenças cardiovasculares, diabetes, câncer e doença respiratória crônica, predominantemente pelo controle do fumo, inatividade física, alimentação inadequada e uso prejudicial de álcool. Apesar da produção científica significativa sobre essas doenças e seus fatores de risco no Brasil, poucos são os estudos de coorte nessa temática. Nesse contexto, o Estudo Longitudinal da Saúde do Adulto (ELSA-Brasil) acompanha 15.105 servidores públicos do País. Seus dados espelham a realidade brasileira de altas prevalências de diabetes e hipertensão e dos fatores de risco. A diversidade das informações produzidas permitirá aprofundar o entendimento causal dessas doenças e subsidiar políticas públicas para seu enfrentamento.

Validação da versão curta do questionário Rose de angina no Brasil

FUNDAMENTO: A angina pectoris estável é uma condição grave com poucos estudos epidemiológicos no Brasil. OBJETIVO: Validar a versão curta do questionário Rose de angina em português do Brasil para seu uso em pesquisas e estudos longitudinais. MÉTODOS: Foi recrutado um total de 116 pacientes consecutivos de uma clínica ambulatorial sem histórico de infarto do miocárdio e/ou revascularização coronariana para a aplicação de três questões do questionário Rose, abordando dor no peito após esforço. Utilizamos como padrão-ouro o teste em esteira ergométrica com o protocolo Ellestad. RESULTADOS: A versão curta do questionário Rose de angina dos 116 indivíduos submetidos ao teste de esforço em esteira ergométrica mostrou 89,7% de acurácia, 25% de sensibilidade, 92% de especificidade, 10% de valor preditivo positivo, 97,2% de valor preditivo negativo e 3,1 de razão de probabilidade positiva e 0,82 de razão de probabilidade negativa. CONCLUSÃO: A versão em português com os três itens do questionário Rose de angina é adequada para objetivos epidemiológicos.

Percepção do médico sobre pagamento por desempenho no gerenciamento de doenças cardiovasculares: o caso de uma operadora de plano de saúde

Desde os anos 50, os fatores de risco para as doenças cardiovasculares passaram a ser valorizados. O gerenciamento de doenças cardiovasculares (PGC) busca a construção da autonomia e melhoria da qualidade de vida dos pacientes. Em alguns países, para alcançar esses objetivos, tem sido apontada a utilização de programas de pagamento por desempenho (PPP) aos médicos como um dos elementos de melhoria nos processos e nos resultados dos pacientes e na condição de remuneração. O objetivo deste estudo é analisar o ponto de vista dos médicos sobre a implantação dos pagamentos por desempenho vinculados ao PGC em uma operadora de plano de saúde. Trata-se de investigação de caráter qualitativo, do tipo estudo de caso, apresentando entrevistas semiestruturadas com médicos participantes ou não do PGC, em setembro de 2009, tendo como referência as ações implantadas em 2008. Foram entrevistados 23 médicos (14 homens e 09 mulheres). Como resultado foi observado que o incentivo financeiro é reconhecido pelos médicos como importante, mas não determinante da inclusão de pacientes no PGC. O principal motivo apresentado foi a organização do cuidado, no qual o paciente é mais bem acompanhado e controlado, e o trabalho médico, avaliado segundo parâmetros preestabelecidos. O PGC e o PPP têm potencial de transformação do cuidado em saúde. O trabalho multidisciplinar e a maior produtividade nos atendimentos no consultório foram os principais efeitos positivos identificados. Outros estudos são necessários para acompanhar a evolução e os efeitos do pagamento por desempenho no trabalho médico.

Obesidade induzida por consumo de dieta: modelo em roedores para o estudo dos distúrbios relacionados com a obesidade

A obesidade vem aumentando significativamente em todo o mundo, e os fatores ambientais, como o consumo excessivo de alimentos e o sedentarismo, são os principais fatores relacionados com a gênese dessa doença. Em animais de laboratório, a gênese da obesidade está relacionada, em sua maioria, com mutações genéticas, porém esse modelo é muito distante do encontrado nos humanos. A adoção de dietas hipercalóricas ou hiperlipídicas vem sendo utilizada como modelo de indução da obesidade em animais, devido à sua semelhança com a gênese e às respostas metabólicas decorrentes da obesidade em humanos. Assim, o objetivo dessa revisão de literatura é apresentar os diferentes tipos de dietas utilizadas para a indução da obesidade em roedores, as modificações metabólicas induzidas e identificar alguns cuidados que devem ser tomados para que esse modelo seja eficaz para o estudo das complicações relacionadas com a obesidade. Realizou-se busca na base de dados PubMed utilizando as expressões: 1-"hipercaloric diet" AND "rodent", 2- "hiperlipidic diet" AND "rodent", sendo selecionadas aquelas consideradas mais relevantes a partir dos critérios: data de publicação (1995-2011), a utilização de animais wild type, a descrição detalhada sobre a dieta utilizada e a análise de parâmetros bioquímicos e vasculares de interesse. Foram inseridas referências para introduzir assuntos como o aumento da prevalência da obesidade e questões relacionadas com a gênese da obesidade em humanos. Podemos considerar eficiente o modelo de obesidade induzida por dieta em roedores quando o objetivo é o estudo da fisiopatologia das complicações metabólicas e vasculares associadas à obesidade.

The renin–angiotensin system plays a major role in voiding dysfunction of ovariectomized rats

Aims: The renin–angiotensin system (RAS) plays a major role in cardiovascular diseases in postmenopausal women, but little is known about its importance to lower urinary tract symptoms. In this study we have used the model of ovariectomized (OVX) estrogen-deficient rats to investigate the role of RAS in functional and molecular alterations in the urethra and bladder. Main methods: Responses to contractile and relaxant agents in isolated urethra and bladder, as well as cystometry were evaluated in 4-month OVX Sprague–Dawley rats. Angiotensin-converting enzyme activity and Western blotting for AT1/AT2 receptors were examined. Key findings: Cystometric evaluations in OVX rats showed increases in basal pressure, capacity and micturition frequency, as well as decreased voiding pressure. Angiotensin II and phenylephrine produced greater urethral contractions in OVX compared with Sham group. Carbachol-induced bladder contractions were significantly reduced in OVX group. Relaxations of urethra and bladder to sodium nitroprusside and BAY 41-2272 were unaffected by OVX. Angiotensin-converting enzyme activity was 2.6-fold greater (p < 0.05) in urethral tissue of OVX group,whereas enzyme activity in plasma and bladder remained unchanged. Expressions of AT1 and AT2 receptors in the urethra were markedly higher in OVX group. In bladder, AT1 receptors were not detected, whereas AT2 receptor expression was unchanged between groups. 17β-Estradiol replacement (0.1 mg/kg, weekly) or losartan (30 mg/kg/day) largely attenuated most of the alterations seen in OVX group. Significance: Prolonged estrogen deprivation leads to voiding dysfunction and urethral hypercontractility that are associated with increased ACE activity and up-regulation of angiotensin AT1/AT2 receptor in the urethral tissue.

Targeting aldehyde dehydrogenase 2: new therapeutic opportunities

A family of detoxifying enzymes called aldehyde dehydrogenases (ALDHs) has been a subject of recent interest, as its role in detoxifying aldehydes that accumulate through metabolism and to which we are exposed from the environment has been elucidated. Although the human genome has 19 ALDH genes, one ALDH emerges as a particularly important enzyme in a variety of human pathologies. This ALDH, ALDH2, is located in the mitochondrial matrix with much known about its role in ethanol metabolism. Less known is a new body of research to be discussed in this review, suggesting that ALDH2 dysfunction may contribute to a variety of human diseases including cardiovascular diseases, diabetes, neurodegenerative diseases, stroke, and cancer. Recent studies suggest that ALDH2 dysfunction is also associated with Fanconi anemia, pain, osteoporosis, and the process of aging. Furthermore, an ALDH2 inactivating mutation (termed ALDH2*2) is the most common single point mutation in humans, and epidemiological studies suggest a correlation between this inactivating mutation and increased propensity for common human pathologies. These data together with studies in animal models and the use of new pharmacological tools that activate ALDH2 depict a new picture related to ALDH2 as a critical health-promoting enzyme.