Characteristics of adults with potential refractory chronic cough identified using an algorithm designed for administrative claims databases: A descriptive study.

Objective As population-based studies describing the characteristics of patients with refractory chronic cough (RCC) are sparse, the objective of this descriptive study was to identify and describe such patients using an algorithm developed for administrative claims databases and requiring validation in future. Methods We identified adults with chronic cough (N = 782,121) from Optum Clinformatics™ Data Mart as individuals with a 'cough event' (primary cough event; based on ICD codes/relevant prescriptions) and ≥2 cough events in the 56-180 preceding days. We applied several exclusion criteria to identify potential RCC cases and stratified them into probable, possible, and unlikely RCC cohorts by the number of cough events during 1-year follow up (≥3, 1-2 or 0 events, respectively). Patient characteristics were described during the year before the primary cough event and follow up. Results 16.8% (n = 131,772) of patients with chronic cough were potential RCC cases: 25.8% probable, 35.9% possible and 38.3% unlikely. The majority were female (66.4-70.5%); median age was 53-60 years. The most common comorbidities and cough-associated complications at baseline were: allergic rhinitis (30.7-39.1%), hypertension (37.3-47.7%), gastro-oesophageal reflux disease (23.7-34.3%), asthma (18.1-27.3%), insomnia (6.3-8.3%) and stress incontinence (2.5-3.9%). Among probable RCC cases, use of several medications was higher during follow up versus baseline: 52.7% versus 49.0% (cough treatments), 73.3% versus 69.0% (respiratory drugs), 40.5% versus 34.2% (gastrointestinal drugs) and 58.8% versus 56.1% (psychotherapeutics). Conclusion Our algorithm requires validation but provides a starting point to identify patients with RCC in claims databases in future studies.

Efficacy and Safety of Eliapixant in Refractory Chronic Cough: The Randomized, Placebo-Controlled Phase 2b PAGANINI Study.

INTRODUCTION: The PAGANINI study evaluated the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough (RCC). METHODS: PAGANINI was a randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose-finding, phase 2b study. Adults with RCC lasting ≥ 12 months and cough severity ≥ 40 mm on a visual analog scale at screening were enrolled. Participants were randomized 1:1:1:1 to twice-daily 25 mg, 75 mg, or 150 mg oral eliapixant or placebo for 12 weeks. The primary endpoint was change from baseline in 24-h cough count after 12 weeks of intervention. RESULTS: Overall, 310 participants were randomized to twice-daily eliapixant 25 mg (n = 75), 75 mg (n = 78), 150 mg (n = 80), or placebo (n = 77). A statistically significant dose-response signal with eliapixant was detected for the primary endpoint (all dose-response models, adjusted p < 0.1; one-sided). Adverse events (AEs) were reported in 39 (51%) participants with placebo and 43-51 (57-65%) participants receiving eliapixant. The most common AE was dysgeusia, occurring in 1% (n = 1) of the placebo group and 1-16% (n = 1-13) of the eliapixant groups in a dose-related manner. One case of a moderate drug-induced liver injury occurred in a participant receiving 150 mg twice-daily eliapixant. CONCLUSION: Eliapixant demonstrated efficacy and a favorable taste tolerability profile in RCC. However, a drug-induced liver injury contributed to intensified liver monitoring in clinical trials with eliapixant and discontinuation of the entire development program in all indications by Bayer AG. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04562155; registered September 18, 2020.

Vericiguat: A Randomized, Phase Ib, Placebo-Controlled, Double-Blind, QTc Interval Study in Patients with Chronic Coronary Syndromes.

BACKGROUND: Vericiguat is indicated for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. OBJECTIVE: To investigate the effects of vericiguat on QT interval in patients with chronic coronary syndromes (CCS). METHODS: This was a randomized, phase Ib, placebo-controlled, double-blind, double-dummy, multicenter study. Vericiguat once daily was up-titrated from 2.5 mg to 5 mg and then to 10 mg (treatments A, B, and C) at 14-day intervals. Positive control was moxifloxacin 400 mg (single dose on day 8 or day 50; placebo on other days [treatment D]). We evaluated the placebo-adjusted change from baseline of the Frederica-corrected QTc interval (QTcF), pharmacokinetics, safety, and tolerability of vericiguat. RESULTS: In total, 74 patients with CCS, with mean (standard deviation) age 63.4 (8.0) years, were included and 72 patients completed the study. At each timepoint up to 7 h after administration, mean placebo-corrected change in QTcF from baseline was < 6 ms and the upper limit of the two-sided 90% confidence interval of the mean was below the 10-ms threshold for clinical relevance. Moxifloxacin confirmed the assay sensitivity. Median time of maximum concentration of vericiguat was 4.5 h post-dose. The adverse event profile of vericiguat was consistent with its mechanism of action, and the findings did not indicate any safety concerns. CONCLUSIONS: As part of an integrative risk assessment, this study demonstrated no clinically relevant corrected QT prolongation with vericiguat 10 mg once daily at steady state. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03504982.

Vericiguat is approved for treating worsening heart failure with reduced ejection fraction. As part of the safety evaluation of vericiguat, this study assessed its effect on the QT interval of the electrocardiogram. An electrocardiogram measures electrical activity of the heart. The QT interval is the time from the start of the Q wave to the end of the T wave. A longer than normal QT interval indicates an increased chance for abnormal heart rhythms. Usually, a QT study is conducted at high doses in healthy volunteers. Previous studies indicated that high doses of vericiguat may cause increased changes in blood pressure in healthy volunteers. Therefore, this study was performed in patients at a normal therapeutic dose. Patients with chronic coronary syndromes were enrolled rather than patients with heart failure with reduced ejection fraction, because they have fewer electrocardiogram abnormalities. The starting dose of vericiguat was 2.5 mg once daily, and the dose was increased to 5 mg and then to 10 mg at 14-day intervals. Placebo was tested for comparison and moxifloxacin (400 mg), a drug known to increase the QT interval, was tested to confirm that the study could detect a change in the QT interval. An increase in the QT interval of more than 10 ms was considered clinically relevant. Of 74 patients included, 72 completed the study. At each timepoint (up to 7 h after dosing), the difference between the QT change for vericiguat and placebo was less than 10 ms; therefore, vericiguat does not prolong the QT interval to a clinically relevant extent.

Impact of telemedicine in hospital culture and its consequences on quality of care and safety.

OBJECTIVE: To describe the impact of the telemedicine application on the clinical process of care and its different effects on hospital culture and healthcare practice. METHODS: The concept of telemedicine through real time audio-visual coverage was implemented at two different hospitals in São Paulo: a secondary and public hospital, Hospital Municipal Dr. Moysés Deutsch, and a tertiary and private hospital, Hospital Israelita Albert Einstein. RESULTS: Data were obtained from 257 teleconsultations records over a 12-month period and were compared to a similar period before telemedicine implementation. For 18 patients (7.1%) telemedicine consultation influenced in diagnosis conclusion, and for 239 patients (92.9%), the consultation contributed to clinical management. After telemedicine implementation, stroke thrombolysis protocol was applied in 11% of ischemic stroke patients. Telemedicine approach reduced the need to transfer the patient to another hospital in 25.9% regarding neurological evaluation. Sepsis protocol were adopted and lead to a 30.4% reduction mortality regarding severe sepsis. CONCLUSION: The application is associated with differences in the use of health services: emergency transfers, mortality, implementation of protocols and patient management decisions, especially regarding thrombolysis. These results highlight the role of telemedicine as a vector for transformation of hospital culture impacting on the safety and quality of care.

Impact of telemedicine in hospital culture and its consequences on quality of care and safety / Impacto da telemedicina na cultura hospitalar e suas consequências na qualidade e segurança do cuidado

ABSTRACT Objective To describe the impact of the telemedicine application on the clinical process of care and its different effects on hospital culture and healthcare practice. Methods The concept of telemedicine through real time audio-visual coverage was implemented at two different hospitals in São Paulo: a secondary and public hospital, Hospital Municipal Dr. Moysés Deutsch, and a tertiary and private hospital, Hospital Israelita Albert Einstein. Results Data were obtained from 257 teleconsultations records over a 12-month period and were compared to a similar period before telemedicine implementation. For 18 patients (7.1%) telemedicine consultation influenced in diagnosis conclusion, and for 239 patients (92.9%), the consultation contributed to clinical management. After telemedicine implementation, stroke thrombolysis protocol was applied in 11% of ischemic stroke patients. Telemedicine approach reduced the need to transfer the patient to another hospital in 25.9% regarding neurological evaluation. Sepsis protocol were adopted and lead to a 30.4% reduction mortality regarding severe sepsis. Conclusion The application is associated with differences in the use of health services: emergency transfers, mortality, implementation of protocols and patient management decisions, especially regarding thrombolysis. These results highlight the role of telemedicine as a vector for transformation of hospital culture impacting on the safety and quality of care.

RESUMO Objetivo Analisar o impacto da aplicação de telemedicina no processo clínico de cuidado e seus diferentes efeitos sobre a cultura hospitalar e na prática assistencial. Métodos O conceito de telemedicina, por meio de uma cobertura integral em tempo real, foi implementada em dois hospitais diferentes em São Paulo, um secundário e público, o Hospital Municipal Dr. Moysés Deutsch, e um terciário e privado, o Hospital Israelita Albert Einstein. Resultados Os dados foram obtidos a partir de 257 teleconsultas registradas ao longo de um período de 12 meses e comparados a igual período antes da implementação. Em 18 pacientes (7,1%), a telemedicina influenciou no diagnóstico e, para 239 pacientes (92,9%), a consulta contribuiu para o manejo clínico. Após a implementação da telemedicina, o protocolo de trombólise para acidente vascular cerebral foi aplicado em 11% dos pacientes com acidente vascular cerebral. A introdução da telemedicina reduziu a necessidade de transferir pacientes para avaliação neurológica externa em 25,9%. O protocolo de sepse foi adotado, sendo observada redução da mortalidade em 30,4% nos casos de sepse grave. Conclusão A aplicação da telemedicina está associada com diferenças na utilização dos serviços de saúde: transferências, mortalidade, implementação de protocolos e apoio à decisão médica, especialmente em relação à trombólise. Estes resultados destacam o papel da telemedicina como um vetor de transformação da cultura hospitalar e seu impacto sobre a segurança e na qualidade assistencial.

Heart transplantation: review.

Heart transplantation is currently the definitive gold standard surgical approach in the treatment of refractory heart failure. However, the shortage of donors limits the achievement of a greater number of heart transplants, in which the use of mechanical circulatory support devices is increasing. With well-established indications and contraindications, as well as diagnosis and treatment of rejection through defined protocols of immunosuppression, the outcomes of heart transplantation are very favorable. Among early complications that can impact survival are primary graft failure, right ventricular dysfunction, rejection, and infections, whereas late complications include cardiac allograft vasculopathy and neoplasms. Despite the difficulties for heart transplantation, in particular, the shortage of donors and high mortality while on the waiting list, in Brazil, there is a great potential for both increasing effective donors and using circulatory assist devices, which can positively impact the number and outcomes of heart transplants.

Heart transplantation: review / Transplante cardíaco: revisão

ABSTRACT Heart transplantation is currently the definitive gold standard surgical approach in the treatment of refractory heart failure. However, the shortage of donors limits the achievement of a greater number of heart transplants, in which the use of mechanical circulatory support devices is increasing. With well-established indications and contraindications, as well as diagnosis and treatment of rejection through defined protocols of immunosuppression, the outcomes of heart transplantation are very favorable. Among early complications that can impact survival are primary graft failure, right ventricular dysfunction, rejection, and infections, whereas late complications include cardiac allograft vasculopathy and neoplasms. Despite the difficulties for heart transplantation, in particular, the shortage of donors and high mortality while on the waiting list, in Brazil, there is a great potential for both increasing effective donors and using circulatory assist devices, which can positively impact the number and outcomes of heart transplants.

RESUMO O transplante cardíaco é atualmente a abordagem cirúrgica definitiva padrão-ouro no tratamento da insuficiência cardíaca refratária. No entanto, a escassez de doadores limita a realização de um número maior de transplantes cardíacos, situação em que vem aumentando a utilização de dispositivos de assistência circulatória mecânica. Com indicações e contraindicações bem estabelecidas, além de diagnóstico e tratamento de rejeição, por meio de protocolos definidos de imunossupressão, os resultados do transplante cardíaco são muito favoráveis. Dentre as complicações precoces que podem impactar a sobrevida, destacamos a disfunção primária do enxerto, a disfunção do ventrículo direito, rejeição e infecções; já as complicações tardias incluem a doença vascular do enxerto e as neoplasias. Apesar das dificuldades para realização do transplante cardíaco, em especial pela escassez de doadores e pela elevada mortalidade em fila de espera, no Brasil, existe um grande potencial, tanto no aumento de doadores efetivos, quanto na utilização de dispositivos de assistência circulatória, o que pode vir a impactar positivamente no número e nos resultados do transplante cardíaco.

Agreement of BNP and NT-proBNP and the influence of clinical and laboratory variables.

OBJECTIVE: To correlate the serum levels of B type natriuretic peptide and the N-terminal fraction of the pro-B type natriuretic peptide, as well as to analyze the influence of age, obesity, renal failure, left ventricle ejection fraction, diastolic dysfunction, and anemia on serum levels of both markers. METHODS: An observational study in which the agreement was compared between these markers in consecutive samples of 138 patients. For the correlation, Pearson's test was used, and p<0.05 was considered statistically significant. RESULTS: A linear association was observed between the B type natriuretic peptide and N-terminal fraction of the pro-B type natriuretic peptide (r=0.907; p<0.001). When evaluating the categorized measurements as normal and altered, there was good agreement, with 90.6% of agreement classifications (p<0.001) in which altered values of the N-terminal fraction of the pro-B type natriuretic peptide and normal values of the B type natriuretic peptide represented 8.7% of the total; the opposite situation represented 1% of the total. Assessment of the influence of the clinical and laboratorial factors on the levels of natriuretic peptides showed that they rise according to age, but that they fall as the ejection fraction increases. Patients with anemia (p<0.001) or with renal failure (p=0.007) had higher values of both markers. There was no association between obesity and the B type natriuretic peptide. CONCLUSION: There was satisfactory agreement between the B type natriuretic peptide and the N-terminal fraction of the pro-B type natriuretic peptide. Age, creatinine levels, and hemoglobin, as well as ventricular function, influence the serum levels of both natriuretic peptides.

Decompensated heart failure.

Heart failure is a disease with high incidence and prevalence in the population. The costs with hospitalization for decompensated heart failure reach approximately 60% of the total cost with heart failure treatment, and mortality during hospitalization varies according to the studied population, and could achieve values of 10%. In patients with decompensated heart failure, history and physical examination are of great value for the diagnosis of the syndrome, and also can help the physician to identify the beginning of symptoms, and give information about etiology, causes and prognosis of the disease. The initial objective of decompensated heart failure treatment is the hemodynamic and symptomatic improvement preservation and/or improvement of renal function, prevention of myocardial damage, modulation of the neurohormonal and/or inflammatory activation and control of comorbidities that can cause or contribute to progression of the syndrome. According to the clinical-hemodynamic profile, it is possible to establish a rational for the treatment of decompensated heart failure, individualizing the proceedings to be held, leading to reduction in the period of hospitalization and consequently reducing overall mortality.

Comparação entre BNP e NT-proBNP quanto à concordância e quanto à influência das variáveis clínicas e laboratoriais / Agreement of BNP and NT-proBNP and the influence of clinical and laboratory variables

OBJETIVO: Correlacionar os níveis séricos do peptídeo natriurético tipo B e da fração N-terminal do pró-peptídeo natriurético tipo B, além de analisar a influência de idade, obesidade, insuficiência renal, fração da ejeção do ventrículo esquerdo, disfunção diastólica e anemia nos níveis séricos de ambos os marcadores. MÉTODOS: Estudo observacional, no qual se comparou a concordância entre esses marcadores em amostras consecutivas de 138 pacientes. Para a correlação, utilizou-se o teste de Pearson e foi considerado estatisticamente significante p<0,05. RESULTADOS: Observou-se associação linear entre peptídeo natriurético tipo B e fração N-terminal do pró-peptídeo natriurético tipo B (r=0,907; p<0,001). Ao se avaliarem as medidas categorizadas como normais e alteradas, encontrou-se boa concordância, com 90,6% de classificações concordantes (p<0,001), sendo que valores alterados da fração N-terminal do pró-peptídeo natriurético tipo B e normais de peptídeo natriurético tipo B representaram 8,7% do total, e o contrário representou 1% do total. A avaliação da influência dos fatores clínicos e laboratoriais nos níveis dos peptídeos natriuréticos mostrou que eles se elevam de acordo com a idade, mas que diminuem conforme aumenta a fração de ejeção. Pacientes com anemia (p<0,001) ou com insuficiência renal (p=0,007) apresentaram valores maiores de ambos os marcadores. Não houve associação entre obesidade e peptídeo natriurético tipo B. CONCLUSÃO: Houve concordância satisfatória entre peptídeo natriurético tipo B e a fração N-terminal do pró-peptídeo natriurético tipo B. Idade, níveis de creatinina e hemoglobina, assim como função ventricular, influenciam os níveis séricos de ambos os peptídeos natriuréticos.

OBJECTIVE: To correlate the serum levels of B type natriuretic peptide and the N-terminal fraction of the pro-B type natriuretic peptide, as well as to analyze the influence of age, obesity, renal failure, left ventricle ejection fraction, diastolic dysfunction, and anemia on serum levels of both markers. METHODS: An observational study in which the agreement was compared between these markers in consecutive samples of 138 patients. For the correlation, Pearson's test was used, and p<0.05 was considered statistically significant. RESULTS: A linear association was observed between the B type natriuretic peptide and N-terminal fraction of the pro-B type natriuretic peptide (r=0.907; p<0.001). When evaluating the categorized measurements as normal and altered, there was good agreement, with 90.6% of agreement classifications (p<0.001) in which altered values of the N-terminal fraction of the pro-B type natriuretic peptide and normal values of the B type natriuretic peptide represented 8.7% of the total; the opposite situation represented 1% of the total. Assessment of the influence of the clinical and laboratorial factors on the levels of natriuretic peptides showed that they rise according to age, but that they fall as the ejection fraction increases. Patients with anemia (p<0.001) or with renal failure (p=0.007) had higher values of both markers. There was no association between obesity and the B type natriuretic peptide. CONCLUSION: There was satisfactory agreement between the B type natriuretic peptide and the N-terminal fraction of the pro-B type natriuretic peptide. Age, creatinine levels, and hemoglobin, as well as ventricular function, influence the serum levels of both natriuretic peptides.

Insuficiência cardíaca descompensada / Decompensated heart failure

A insuficiência cardíaca apresenta elevada incidência e prevalência em todo mundo. Os custos com internação por insuficiência cardíaca descompensada chegam a aproximadamente 60% do custo total do tratamento da insuficiência cardíaca, e a mortalidade durante a internação varia conforme a população estudada, podendo chegar a 10%. Em pacientes com insuficiência cardíaca descompensada, os achados de história e exame físico são de grande valor por fornecerem, além do diagnóstico da síndrome, o tempo de início dos sintomas, as informações sobre etiologia, as causas de descompensação e o prognóstico. O objetivo inicial do tratamento da insuficiência cardíaca descompensada é a melhora hemodinâmica e sintomática. Além disso, outros alvos devem ser buscados, incluindo preservação e/ou melhora da função renal, prevenção de lesão miocárdica, modulação da ativação neuro-hormonal e/ou inflamatória, e manejo de comorbidades que podem causar ou contribuir para progressão da síndrome. Com base nos perfis clínico-hemodinâmicos, é possível estabelecer um racional para o tratamento da insuficiência cardíaca descompensada, individualizando o procedimento a ser instituído e objetivando redução de tempo de internação e de mortalidade.

Heart failure is a disease with high incidence and prevalence in the population. The costs with hospitalization for decompensated heart failure reach approximately 60% of the total cost with heart failure treatment, and mortality during hospitalization varies according to the studied population, and could achieve values of 10%. In patients with decompensated heart failure, history and physical examination are of great value for the diagnosis of the syndrome, and also can help the physician to identify the beginning of symptoms, and give information about etiology, causes and prognosis of the disease. The initial objective of decompensated heart failure treatment is the hemodynamic and symptomatic improvement preservation and/or improvement of renal function, prevention of myocardial damage, modulation of the neurohormonal and/or inflammatory activation and control of comorbidities that can cause or contribute to progression of the syndrome. According to the clinical-hemodynamic profile, it is possible to establish a rational for the treatment of decompensated heart failure, individualizing the proceedings to be held, leading to reduction in the period of hospitalization and consequently reducing overall mortality.

Quimiossensibilidade durante exercício na insuficiência cardíaca: respostas ventilatórias, cronotrópicas e neurohormonais / Exercise chemosensitivity in heart failure: ventilatory, chronotropic and neurohormonal responses / Quimiosensibilidad durante ejercicio en la insuficiencia cardíaca: respuestas ventilatorias, cronotrópicas y neurohormonales

FUNDAMENTO: Insuficiência cardíaca (IC) está associada com aumento da quimio-sensibilidade periférica e central em repouso, que pode estar correlacionada com um aumento na resposta ventilatória durante exercício. Entretanto, SUS sensibilidade na IC durante o exercício ainda não foi reportada. OBJETIVO: Testar se o estímulo dos quimiorreceptores centrais e periféricos em pacientes com IC pode modular respostas ventilatórias, cronotrópicas e neurohormonais durante exercício submáximo. MÉTODOS: Investigamos a quimio-sensibilidade central e periférica em 15 pacientes com insuficiência cardíaca (IC) e 7 controles normais (C), comparando a resposta durante 3 testes de caminhada de 6 minutos (TC6M), realizado em esteira ergométrica com: ar ambiente, em hipóxia e em hipercapnia (em ordem randômica). RESULTADOS: FR em ar ambiente nos grupos C e IC foi 17±2 e 22±2 (p<,0001); em hipóxia, foi 17±1 e 23±2 (p<,02); com CO25 por cento foi 20±2 e 22±5 (p<,02). Volume tidal (VT) ou corrente em ar ambiente foi 1,25±0,17 e 1,08±0,19 (p<,01); em hipóxia 1,65±0,34 e 1,2±0,2(p<,0001); com CO25 por cento 1,55±0,46 e 1,29±0,39 (p<,0001). Em repouso, o aumento na IC foi maior para VE (C 33±40 por cento, IC 62±94 por cento, p<,01), FC(C 7±10 por cento, IC 10±10 por cento, p<0,05) em repouso. Durante a hipóxia, o aumento durante o exercício na IC foi maior para FR (C 1±4, IC 11±6,p<,05), FC (C 12±2, IC 14±3, p<,05), VE/VO2 (C -4±18 por cento, IC 24±21 por cento, p<,01), FC/VO2 (C -26±11 por cento, IC 11±5 por cento, p<,01), VE/DC (C 36±10 por cento, 46±14, p<,05 por cento ) and FC/DC (C 18±8 por cento, HF 29±11, p<,01). Durante exercício em hipóxia no grupo IC, o NO diminuiu e os níveis de IL-6 e aldosterona aumentaram. Os níveis neurohormonais permaneceram inalterados no grupo C. CONCLUSÃO: A quimio-sensibilidade central e a periférica durante o exercício estão aumentadas na IC e podem modular padrões respiratórios, cronotrópicos cardíacos e atividade neurohormonal durante exercício.

BACKGROUND: Heart failure (HF) is associated with resting increased peripheral and central chemosensitivity which may correlate with an increased ventilatory response to exercise. However, its sensitivity in HF during exercise was never really reported. OBJECTIVE: We tested if stimulation of central and peripheral chemoreceptors in HF patients could modulate ventilatory, chronotropic, and neurohormonal response during submaximal exercise. METHODS: We investigated central and peripheral chemosensitivity in 15 HF and 7 control (C) comparing response through three 6 minute walking tests conducted in a treadmill with : room air, hypoxia, and hypercapnia (in a randomic order). RESULTS: RR at room air C and HF was 17±2 and 22±2 (p<.0001); at hypoxia 17±1 and 23±2 (p<.02); at CO25 percent was 20±2 and 22±5 (p<.02). Tidal volume (TV) at room air was 1.25±0.17 and 1.08±0.19 (p<.01); at hypoxia 1.65±0.34 and 1.2±0.2 (p<.0001); at CO25 percent 1.55±0.46 and 1.29±0.39 (p<.0001). At rest the increment in HF was higher for VE (C 33±40 percent, HF 62±94 percent, p<.01), HR(C 7±10 percent, HF 10±10 percent, p<0.05) at rest. During hypoxia exercise increment in HF was higher for RR (C 1±4, HF 11±6,p<.05), HR (C 12±2, HF 14±3, p<.05), VE/VO2 (C -4±18 percent, HF 24±21 percent, p<.01), HR/VO2 (C -26±11 percent, HF 11±5 percent, p<.01), VE/WD (C 36±10 percent, 46±14, p<.05 percent) and HR/WD (C 18±8 percent, HF 29±11, p<.01). During HF hypoxia exercise NO reduced, and IL-6, aldosterone levels increased. Neurohormonal levels unchanged in C. CONCLUSION: Exercise peripheral and central chemosensitivity are increased in HF and may modulate respiratory pattern, cardiac chronotropic, and neurohormonal activity during exercise.

FUNDAMENTO: La insuficiencia cardíaca (IC) está asociada con aumento de la quimiosensibilidad periférica y central en reposo, que puede estar correlacionada con un aumento en la respuesta ventilatoria durante ejercicio. Mientras tanto, SUS sensibilidad en la IC durante el ejercicio aun no fue reportada. OBJETIVO: Verificar si el estímulo de los quimiorreceptores centrales y periféricos en pacientes con IC puede modular respuestas ventilatorias, cronotrópicas y neurohormonales durante ejercicio submáximo. MÉTODOS: Investigamos la quimiosensibilidad central y periférica en 15 pacientes con insuficiencia cardíaca (IC) y 7 controles normales (C), comparando la respuesta durante 3 tests de caminata de 6 minutos (TC6M), realizado en cinta ergométrica con: aire ambiente, en hipoxia y en hipercapnia (en orden randómico). RESULTADOS: FR en aire ambiente en los grupos C y IC fue 17±2 y 22±2 (p<,0001); en hipoxia, fue 17±1 y 23±2 (p<.02); con CO25 por ciento fue 20±2 y 22±5 (p<,02). Volumen tidal (VT) o corriente en aire ambiente fue 1,25±0,17 y 1,08±0,19 (p<,01); en hipoxia 1,65±0,34 y 1,2±0,2 (p<,0001); con CO25 por ciento 1,55±0,46 y 1,29±0,39 (p<,0001). En reposo, el aumento en la IC fue mayor para VI (C 33±40 por ciento, IC 62±94 por ciento, p<,01), FC(C 7±10 por ciento, IC 10±10 por ciento, p<0,05) en reposo. Durante la hipoxia, el aumento durante el ejercicio en la IC fue mayor para FR (C 1±4, IC 11±6, p<.05), FC (C 12±2, IC 14±3, p<.05), VI/VO2 (C -4±18 por ciento, IC 24±21 por ciento, p<.01), FC/VO2 (C -26±11 por ciento, IC 11±5 por ciento, p<.01), VI/DC (C 36±10 por ciento, 46±14, p<.05 por ciento) y FC/DC (C 18±8 por ciento, HF 29±11, p<.01). Durante ejercicio en hipoxia en el grupo IC, el NO disminuyó y los niveles de IL-6 y aldosterona aumentaron. Los niveles neurohormonales permanecieron inalterados en el grupo C. CONCLUSIÓN: La quimiosensibilidad central y la periférica durante el ejercicio están aumentadas en la IC y pueden modular estándares respiratorios, cronotrópicos cardíacos y actividad neurohormonal durante ejercicio.

Exercise chemosensitivity in heart failure: ventilatory, chronotropic and neurohormonal responses.

BACKGROUND: Heart failure (HF) is associated with resting increased peripheral and central chemosensitivity which may correlate with an increased ventilatory response to exercise. However, its sensitivity in HF during exercise was never really reported. OBJECTIVE: We tested if stimulation of central and peripheral chemoreceptors in HF patients could modulate ventilatory, chronotropic, and neurohormonal response during submaximal exercise. METHODS: We investigated central and peripheral chemosensitivity in 15 HF and 7 control (C) comparing response through three 6 minute walking tests conducted in a treadmill with : room air, hypoxia, and hypercapnia (in a randomic order). RESULTS: RR at room air C and HF was 17±2 and 22±2 (p<.0001); at hypoxia 17±1 and 23±2 (p<.02); at CO25% was 20±2 and 22±5 (p<.02). Tidal volume (TV) at room air was 1.25±0.17 and 1.08±0.19 (p<.01); at hypoxia 1.65±0.34 and 1.2±0.2 (p<.0001); at CO25% 1.55±0.46 and 1.29±0.39 (p<.0001). At rest the increment in HF was higher for VE (C 33±40%, HF 62±94%, p<.01), HR(C 7±10%, HF 10±10%, p<0.05) at rest. During hypoxia exercise increment in HF was higher for RR (C 1±4, HF 11±6,p<.05), HR (C 12±2, HF 14±3, p<.05), VE/VO2 (C -4±18%, HF 24±21%, p<.01), HR/VO2 (C -26±11%, HF 11±5%, p<.01), VE/WD (C 36±10%, 46±14, p<.05%) and HR/WD (C 18±8%, HF 29±11, p<.01). During HF hypoxia exercise NO reduced, and IL-6, aldosterone levels increased. Neurohormonal levels unchanged in C. CONCLUSION: Exercise peripheral and central chemosensitivity are increased in HF and may modulate respiratory pattern, cardiac chronotropic, and neurohormonal activity during exercise.

Transplantation for Chagas' disease: an overview of immunosuppression and reactivation in the last two decades.

Over the last 20 yr, the immunosuppression protocols in chagasic heart-transplanted patients have gone through three phases, and we have identified several changes and discoveries about Chagas' disease reactivation, mortality, and neoplasia development. The first phase was especially important because until that time, Chagas' disease was an absolute contraindication for transplantation. The second phase started when an adjustment was made to the immunosuppression protocol, a lower dosage being adopted to avoid adverse effects, especially neoplasias and reactivation episodes. Currently, strategies to change the immunosuppression, especially replacement of mycophenolate mofetil by azathioprine or low doses of mycophenolate in this special situation, have been shown to be effective in reducing Chagas' disease reactivation. Cardiac transplantation for Chagas' disease is a reality. Although patients with Chagas' disease may experience particular complications when undergoing transplantation compared with transplantation for other etiologies, these difficulties are well known, and treatment and preventive strategies are also better established. In other organs and tissues, transplantation in patients with Chagas' disease also has good outcomes. Blood monitoring for parasitemias is mandatory as is the institution of therapy in the case of a reactivation diagnosis. Acute Chagas' disease may occur in patients who received organs from donors with Chagas' disease.

Heart failure treatment profile at the beta blockers era.

OBJECTIVES: The inhibition of the rennin-angiotensin-aldosterone system (RAAS) and sympathetic autonomous nervous system has increased the perspective of survival in these patients, as well as allowing the improvement of the quality of life. The aim of this study was to evaluate the reality of the treatment employed and its impact on the disease in patients followed at a specialized heart failure (HF) outpatient clinic. METHODS: A sample of 96 patients followed at the HF and Transplant Outpatient Clinic of Heart Institute of the University of São Paulo School of Medicine (InCor -HCFMUSP) were evaluated. The data were collected during the ambulatory consultation from the medical files and through physical examination. Patients were randomly selected for the study. RESULTS: Most of the patients were Functional Class II (42.3%) and evolution stage C (94.9%). The medical prescription given to the patients was quite similar to the one recommended by the directives. Approximately 95% of them received RAAS inhibitors (ACE inhibitor--enalapril and captopril--or angiotensin receptor antagonist--losartan), whereas 85% of the patients additionally received beta blockers (carvedilol). The mean dose prescribed was also similar to the one used in large studies and reached more than 60% of the maximum dose for each medication. The hemodynamic data show that patients were stable, despite the intensity of the dysfunction and ventricular remodeling observed in these patients. CONCLUSION: Patients with HF followed by a specialized medical team receive a medical prescription that is closer to the recommended one. These patients, despite the marked characteristics of disease severity, achieve hemodynamic and clinical stability with an adequate therapeutic optimization.

Perfil do tratamento da insuficiência cardíaca na era dos betabloqueadores / Heart failure treatment profile at the beta blockers era

OBJETIVOS: A inibição dos sistemas renina-angiotensina-aldosterona (SRAA) e sistema nervoso autônomo simpático aumentou a perspectiva de sobrevida desses pacientes, além de permitir substancial melhora na qualidade de vida. O objetivo deste trabalho foi avaliar a realidade do tratamento aplicado e seu impacto sobre a doença em pacientes acompanhados em um ambulatório especializado em insuficiência cardíaca(IC). MÉTODOS: Foram estudados 96 pacientes acompanhados no ambulatório de Insuficiência Cardíaca e Transplante do Instituto do Coração, do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP). Os dados foram coletados durante a consulta ambulatorial a partir de prontuário médico e exame clínico. A escolha dos pacientes foi aleatória. RESULTADOS: A maior parte dos pacientes encontrava-se em classe funcional II (42,3 por cento) e em estágio C de evolução (94,9 por cento). A prescrição médica para os pacientes foi bastante próxima do preconizado pelas diretrizes. Aproximadamente 95 por cento recebem inibidores do SRAA (inibidor de ECA - enalapril e captopril - ou antagonista dos receptores de angiotensina-losartan), enquanto 85 por cento dos pacientes recebem, além desses, agentes betabloqueadores (carvedilol). A dose média prescrita também se aproxima das utilizadas nos grandes estudos, e atinge mais de 60 por cento da dose máxima de cada medicação. Os dados hemodinâmicos encontrados mostram pacientes estáveis, apesar da intensidade da disfunção e do remodelamento ventricular destes. CONCLUSÃO: Pacientes portadores de IC acompanhados por equipe médica especializada têm prescrição médica mais próxima do preconizado. Esses pacientes, embora com características marcadas de gravidade da doença, conseguem estabilidade hemodinâmica e clínica com a otimização terapêutica adequada.

OBJECTIVES: The inhibition of the rennin-angiotensin-aldosterone system (RAAS) and sympathetic autonomous nervous system has increased the perspective of survival in these patients, as well as allowing the improvement of the quality of life. The aim of this study was to evaluate the reality of the treatment employed and its impact on the disease in patients followed at a specialized heart failure (HF) outpatient clinic. METHODS: A sample of 96 patients followed at the HF and Transplant Outpatient Clinic of Heart Institute of the University of São Paulo School of Medicine (InCor -HCFMUSP) were evaluated. The data were collected during the ambulatory consultation from the medical files and through physical examination. Patients were randomly selected for the study. RESULTS: Most of the patients were Functional Class II (42.3 percent) and evolution stage C (94.9 percent). The medical prescription given to the patients was quite similar to the one recommended by the directives. Approximately 95 percent of them received RAAS inhibitors (ACE inhibitor - enalapril and captopril - or angiotensin receptor antagonist - losartan), whereas 85 percent of the patients additionally received beta blockers (carvedilol). The mean dose prescribed was also similar to the one used in large studies and reached more than 60 percent of the maximum dose for each medication. The hemodynamic data show that patients were stable, despite the intensity of the dysfunction and ventricular remodeling observed in these patients. CONCLUSION: Patients with HF followed by a specialized medical team receive a medical prescription that is closer to the recommended one. These patients, despite the marked characteristics of disease severity, achieve hemodynamic and clinical stability with an adequate therapeutic optimization.

The importance of amiodarone pulmonary toxicity in the differential diagnosis of a patient with dyspnea awaiting a heart transplant.

Amiodarone is a class III antiarrhythmic medication used extensively to treat ventricular arrhythmias. It is pharmacologically classified as a cationic amphiphilic drug due to its polar and apolar components. During the past few years, amiodarone has proved to be an effective treatment therapy for patients with ventricular dysfunctions, regardless of the etiology, and in particular ventricular arrhythmia associated with Chagas disease. Nevertheless, despite its hemodynamic and electrophysiological benefits, amiodarone produces serious collateral effects such as a bluish skin discoloration, photosensitivity, thyroid dysfunction, corneal deposit, peripheral neuropathy, bone marrow suppression, hepatitis, heart blocks, pneumonitis, among others. The objective of this case report is to discuss one of the most serious complications related to amiodarone, pulmonary toxicity, which is described as a differential diagnosis for a chagasic patient that was on the waiting list for a heart transplant. Amiodarone pneumonitis is a relevant differential diagnosis for heart failure (HF) patients using amiodarone that are admitted to the emergency ward with dyspnea.

Importância da toxicidade pulmonar pela amiodarona no diagnóstico diferencial de paciente com dispnéia em fila para transplante cardíaco / The importance of amiodarone pulmonary toxicity in the differential diagnosis of a patient with dyspnea awaiting a heart transplant / The importance of amiodarone pulmonary toxicity in the differential diagnosis of a patient with dyspnea awaiting a heart transplant

A amiodarona é um antiarrítmico da classe III, amplamente utilizado em arritmias ventriculares¹. Farmacologicamente é classificado como uma drogra ampifílica catiônica, pelos seus constituintes polares e apolares. Nos últimos anos, a amiodarona obteve destaque pelo seu uso em portadores de disfunção ventricular por qualquer etiologia, em especial a chagásica, quando ocorrem arritmias ventriculares². Entretanto, a despeito de seus benefícios hemodinâmicos e eletrofisiológicos, a amiodarona produz efeitos colaterais relevantes, como coloração azulada da pele, fotossensibilidade, disfunção tireoidiana, depósito corneal, neuropatia periférica, supressão da medula óssea, hepatite, bloqueios cardíacos, pneumonites e outros³. Este relato de caso se propõe a abordar uma de suas mais sérias complicações, a toxicidade pulmonar, aqui especialmente descrita como diagnóstico diferencial em um paciente chagásico que aguardava em fila de transplante cardíaco. Pneumonite por amiodarona constitui-se em um importante diagnóstico diferencial entre os pacientes que se apresentam na sala de emergência com dispnéia, quando estes são portadores de insuficiência cardíaca (IC) e estão em uso dessa droga.

Amiodarone is a class III antiarrhythmic medication used extensively to treat ventricular arrhythmias¹. It is pharmacologically classified as a cationic amphiphilic drug due to its polar and apolar components. During the past few years, amiodarone has proved to be an effective treatment therapy for patients with ventricular dysfunctions, regardless of the etiology, and in particular ventricular arrhythmia associated with Chagas disease². Nevertheless, despite its hemodynamic and electrophysiological benefits, amiodarone produces serious collateral effects such as a bluish skin discoloration, photosensitivity, thyroid dysfunction, corneal deposit, peripheral neuropathy, bone marrow suppression, hepatitis, heart blocks, pneumonitis, among others³. The objective of this case report is to discuss one of the most serious complications related to amiodarone, pulmonary toxicity, which is described as a differential diagnosis for a chagasic patient that was on the waiting list for a heart transplant. Amiodarone pneumonitis is a relevant differential diagnosis for heart failure (HF) patients using amiodarone that are admitted to the emergency ward with dyspnea.

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.

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.