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Benefit of exercise training therapy and cardiac resynchronization in heart failure patients (BETTER-HF)
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Resumo(s)
RESUMO: Introdução
A insuficiência cardíaca crónica é conhecida como síndrome complexa, associada a elevada mortalidade e incapacidade, envolvendo múltiplos mecanismos fisiopatológicos, neuro-hormonais, endoteliais e inflamatórios.
Além da terapêutica médica optimizada, a terapêutica não farmacológica, como a ressincronização cardíaca e o treino de exercício, assume um papel fundamental.
Na insuficiência cardíaca avançada, doentes com critérios para terapêutica de ressincronização cardíaca (CRT) têm sido exaustivamente estudados, apesar da maioria dos estudos não se ter dedicado à diversidade de efeitos e mecanismos fisiopatológicos envolvidos, nos doentes mais gravemente sintomáticos.
Nesta população com insuficiência cardíaca avançada tratada com CRT, estudos relativos aos efeitos e mecanismos do treino de exercício, especificamente exercício intervalado de alta intensidade, são ainda poucos e de pequena dimensão.
Hipótese
Hpótese principal formulada:
Existe benefício em associar um programa de treino de exercício de alta intensidade, de longa duração, após ressincronização cardíaca em doentes com insuficiência cardíaca avançada.
Hipótese secundária:
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Estão envolvidos vários mecanismos fisiopatológicos, contribuindo diferentemente para o benefício do treino de exercício após CRT e para o benefício de CRT sem programa de exercício subsequente, em doentes com insuficiência cardíaca avançada.
Objectivos
O objectivo primário desta tese foi determinar os efeitos do programa de exercício intervalado de alta intensidade (HIIT), de longa duração, sobre a classe funcional clínica, qualidade de vida, capacidade funcional de exercício, função cardíaca e remodelagem ventricular, em doentes com insuficiência cardíaca avançada após implante do ressincronizador.
O objectivo secundário pretendeu avaliar o papel potencial de diferentes mecanismos fisiopatológicos nos benefícios do treino de exercício após CRT, HIIT, e após CRT sem exercício subsequente: função endotelial, função do sistema nervoso autónomo, processo inflamatório e apoptose.
Metodologia
Efectuámos um ensaio controlado aleatorizado para determinar os efeitos da intervenção de exercício, HIIT, em doentes com insuficiência cardíaca avançada após CRT.
Os critérios de inclusão foram, doentes com insuficiência cardíaca estável, em classe III-IV (NYHA), sob terapêutica farmacológica optimizada, referenciados para CRT pelas recomendações actuais presentes, etiologia isquémica e não isquémica, com idade superior a 18 anos. Os critérios de exclusão incluiram insuficiência cardíaca instável, doença ortopédica ou muscular incapacitante para exercício e residência geograficamente distante do hospital.
Os doentes que preencheram os critérios de inclusão foram aleatorizados para treino de exercício intervalado de alta intensidade ou para grupo controlo (EXTG e CG, respectivamente).
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A aleatorização, realizada por um investigador independente, foi estratificada, baseada na idade (<65 ou >65 anos), sexo, etiologia (isquémica e não isquémica) e gravidade de disfunção ventricular esquerda (fracção de ejecção ventricular esquerda <20 ou >20%).
Os doentes com os mesmos critérios de inclusão, que não aceitaram a intervenção exercício ou que viviam longe, sem os restantes critérios de exclusão, foram adicionalmente estudados como cohort prospectivo para avaliação dos efeitos e mecanismos da intervenção CRT.
Durante o periodo de Janeiro 2012 a Março 2015, todos os doentes com insuficiência cardíaca e critérios para ressincronização cardíaca elegíveis foram estudados.
O programa de treino de exercício foi iniciado 1 mês após implante de cardioressincronizador e durou 6 meses com frequência bissemanal, consistindo em sessões de 60 minutos, realizadas no hospital, monitorizadas e supervisionadas. Incluiu treino aeróbio intervalado de alta intensidade (HIIT), adaptado a partir do protocolo de Wisloff, e exercícios de resistência, flexibilidade e coordenação.
Os momentos do estudo usados para avaliação das variáveis independentes foram: momento basal, pré implante do ressincronizador (M1), aos 3 meses após exercício, correspondendo a 4 meses após implante (M2) e aos 6 meses após exercício, correspondendo a 7 meses após implante (M3).
As variáveis dependentes estudadas foram: classe functional clínica (NYHA), scores de qualidade de vida (questionário HeartQol), parâmetros de função cardíaca e remodelagem reversa (determinadas por ecocardiografia e doseamento plasmático de péptido natriurético, BNP), de capacidade funcional de exercício (determinadas por prova de esforço cardio-respiratória, CPT), de função do sistema nervoso autonómico, SNA (por cintigrafia cardíaca com 123I-MIBG, prova de esforço cardio-respiratória e análise da variabilidade da frequência cardíaca no Holter-24 horas), de função endotelial e rigidez arterial (determinada por doseamento de NO, óxido nítrico, e por PAT, tonometria arterial periférica), marcadores de inflamação e apoptose (medição de proteína C reactiva de alta sensibilidade, hs-CPR, factor de necrose tumoral alfa, TNF-α, interleucina-6, IL-6, fracção solúvel do cluster de diferenciação 40, sCD40, fracção solúvel do ligando Fas, sFasL) e frequência de eventos major cardiovasculares aos 6 meses de exercício.
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As excepções aos 3 momentos de avaliação foram: 123I-MIBG cintigrafia cardíaca, realizada antes do CRT (M1) e aos 6 meses de exercício (M3), análise de variabilidade da frequência cardíaca por estudo Holter-24horas, realizado apenas basal, pre-CRT (M1) e frequência de eventos, avaliada em M3.
A segurança do treino de exercício HIIT foi avaliada.
A resposta ecocardiográfica foi definida pelo aumento de pelo menos 5% da fracção de ejecção ventricular esquerda (LVEF), em valor absoluto e a resposta clínica como melhoria de pelo menos 1 classe funcional clínica (NYHA). A resposta funcional foi definida como o aumento de pelo menos 1 ml/kg/min de VO2p.
Resultados
A partir de um cohort inicial de 121 doentes com insuficiência cardíaca selecionados para CRT, foram aleatorizados 62 doentes. Realizaram programa de treino de exercício HIIT, 22 doentes (EXTG), idade média 67,5±9,8%, 22,7% do sexo feminino, 40% isquémicos, LVEF basal 26,68±6,21%, enquanto 28 doentes foram incluídos no grupo controlo (CG). As características demográficas e clínicas basais foram idênticas estatisticamente.
No grupo aleatorizado (n=50), todos os doentes tiveram benefício significativo, aos 6 meses após início do exercício, relativamente a: diminuição da classe clínica de NYHA (p <0,001), melhoria do score de qualidade de vida HeartQol (p <0,001), aumento da LVEF, fracção de ejecção ventricular esquerda (p <0,005), diminuição dos volumes ventriculares esquerdos, LVED, tele-diastólico (p < 0,05) e LVES, tele-sistólico (p <0,02). Verificou-se uma diferença significativa da classe funcional clínica (NYHA), nos dois grupos aleatorizados, com maior diminuição no EXTG (p=0,034). Apenas no EXTG, se encontrou um aumento significativo da duração da prova de esforço cardio-respiratória, aos 3 meses (p=0,017) e aos 6 meses (p=0,008). O tempo para o limiar anaeróbio, VAT, aumentou significativamente no EXTG aos 3 meses (p= 0,006) e aos 6 meses (p=0,004), sendo significativamente diferente do CG aos 3 meses (p=0,006) e apresentando uma tendência para significado estatístico aos 6 meses (p=0,064), momento em que a variação foi também significativa no CG. O TNF-α diminuiu significativamente apenas no EXTG, aos 6 meses (p=0,016), com uma diferença estatística significativa em relação ao
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CG (p=0,008). Não se verificaram diferenças significativas nas variações dos parâmetros ecocardiográficos entre os dois grupos aleatorizados. Relativamente ao número de respondedores, no grupo de treino de exercício foram identificados mais respondedores clínicos (95%) e ecocardiográficos (81,8%) que no grupo controlo (78,5% e 72,7%, respectivamente), após 6 meses de exercício. A diferença no número de respondedores entre os 2 grupos aleatorizados, não atingiu contudo significado estatístico (provavelmente pela dimensão da amostra), mas com uma tendência para mais respondedores clínicos no grupo de exercício. A diferença no numero de respondedores funcionais, apesar de em numero tendencialmente superior no grupo de exercício (77,2%) não foi significativa. O programa HIIT mostrou ser seguro, sem eventos major ou minor durante o exercício. Aos 6 meses de exercício (7 meses após implantação do ressincronizador), registaram-se 9% de eventos no grupo exercício e 10,7% no grupo controlo. Verificou-se ocorrência de morte ou internamento hospitalar em 1/22 doentes (4,5%) do grupo de exercício e em 3/28 doentes (10,7%) do grupo controlo. A única morte nos doentes aleatorizados ocorreu no grupo controlo, 1/28 doentes (3,5%).
No total do cohort de doentes com CRT verificou-se um benefício significativo após 7 meses de implantação: redução da classe funcional NYHA (p <0,001), aumento do score HeartQol (p <0,001), aumento da LVEF (p < 0,001), diminuição do volume tele-sistólico ventricular esquerdo (p=0,001), aumento do valor absoluto de GLS, strain global longitudinal, (p=0,003), relação E/e’, rácio entre onda E do fluxo de câmara de entrada do ventrículo esquerdo e e’ médio de doppler tecidular do anel mitral, (p=0,009), redução da massa ventricular esquerda (p=0,026), redução do VE/VCO2 slope, declive da razão entre ventilação minuto e produção de CO2, (p=0,003), aumento da duração do teste cardiopulmonar (p=0,002), aumento do tempo para VAT, limiar anaeróbio (p=0,001), redução do HRR1 (frequência cardíaca de recuperação ao primeiro minuto), (p=0,015), redução do HRR6 (frequência cardíaca de recuperação ao 6º minuto), (p=0,033) e aumento do VO2p, consumo de oxigénio pico, (p=0,04). Na amostra total dos doentes insuficientes cardíacos com CRT (incluindo 18% dos doentes submetidos a exercício) 75,6% foram respondedores clínicos, 63,9% respondedores ecocardiográficos e 62,8% respondedores funcionais. Os respondedores ecocardiográficos ao CRT tinham diferenças significativas nos parâmetros de base e na variação de alguns parâmetros: M1, menores volumes ventriculares esquerdos, maior TAPSE, maior SDNN (standard
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deviation NN interval), maior heart-mediastinum ratio precoce (HMRe) e tardio (HMRl); M3-M1, maior aumento de LVEF, maior redução de volume LVES, maior aumento do valor absoluto de GLS e tendência para maior aumento de VO2p. Os respondedores tiveram menor número de eventos major registados em M3.
Analizando todos os doentes com CRT, valores de 123MIBG HMRl>1,5 identificaram mais respondedores ecocardiográficos (probabilidade 2 vezes superior), apenas em não isquemicos.
Os eventos aos 7 meses após CRT, M3, morte ou admissão hospitalar ou arritmia ocorreram em 14,8% da população total e em 16,1% dos doentes não submetidos a exercício.A morte ocorreu em 4,9% no grupo total e em 6% do grupo não submetido a exercício.
Conclusão
No presente ensaio aleatorizado e controlado, realizado numa amostra de doentes com insuficiência cardíaca avançada, referenciada para CRT, o exercício HIIT após implante do ressincronizador provou ser benéfico e seguro, associado a um maior número de respondedores ecocardiográficos e clínicos, acompanhado de uma melhoria clínica mais significativa, evidenciando o benefício adicional ao CRT. A melhoria do componente periférico da insuficiência cardíaca condicionada pelo exercício foi demonstrada pelo aumento significativo da capacidade funcional ao esforço e do tempo para VAT, acompanhada de maior número de respondedores funcionais, tendo-se verificado um efeito modulatório sobre a inflamação que poderá ter contribuído para este efeito. Não foram demonstrados benefícios do exercício na função endotelial, no sistema nervoso autonómico e na apoptose. Ocorreram menos eventos major aos 6 meses em doentes submetidos a HIIT.
A avaliação adicional dos doentes com CRT no estudo observacional demonstrou melhoria clínica, de qualidade de vida e de função ventricular sistólica e diastólica significativa, mesmo excluindo aqueles que fizeram treino de exercício. O efeito central do CRT na remodelagem cardíaca demonstrou ser crucial, com melhoria das diversas variáveis ecocardiográficas. Contrariamente, não se demonstraram efeitos periféricos benéficos do CRT, VO2p, duração CPT ou tempo VAT, aos 7 meses, uma vez excluídos os
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doentes que fizeram programa de exercício. O sistema nervoso autónomo demonstrou ser um mecanismo relevante na resposta ao CRT, mas apenas em insuficientes cardíacos não isquémicos. Não foram demonstrados efeitos benéficos do CRT na função endotelial, inflamação ou apoptose. Registaram-se mais eventos em doentes sem terapêutica de exercício.
Dos resultados desta tese, que verificam as hipóteses colocadas, podemos salientar que em doentes com insuficiência cardíaca avançada a intervenção de treino de exercício intervalado de alta intensidade, supervisionado, , após implantação de ressincronizador cardíaco é uma terapêutica não farmacológica segura e tem benefício adicional demonstrado relativo à CRT, resultando em menor número de doentes não respondedores. Esta intervenção não teve efeito deletério sobre a remodelagem reversa e alguns resultados apontam para potencial benefício. Os mecanismos envolvidos estão ligados particularmente ao componente periférico da insuficiência cardíaca, resultando em diminuição da gravidade dos sintomas clínicos, melhoria da capacidade funcional e modulação positiva da resposta fisiopatológica inflamatória.
ABSTRACT: Introduction Chronic heart failure is known to be a complex syndrome, associated to high mortality and disability, involving multiple pathophysiologic mechanisms, neuro-hormonal, endothelial and inflammatory. Besides optimized medication, the nonpharmacologic therapy, like cardiac resynchronization and exercise training, plays a fundamental role. In advanced heart failure, patients with criteria for cardiac resynchronization therapy (CRT) have been studied extensively, though most of the studies were not dedicated to the diversity of effects and involved pathophysiologic mechanisms, in most severely symptomatic patients. In this advanced heart failure population treated with CRT, studies regarding exercise training effects and mechanisms, specifically high intensity interval exercise, are still few and small-sized. 8 Hypothesis Main hypothesis formulated: It is beneficial to associate a high intensity interval training exercise program, long duration, after cardiac resynchronization in advanced Heart Failure Patients. Secondary hypothesis: Several pathophysiologic mechanisms are involved, contributing differently to the exercise training benefit after CRT and to the benefit of CRT without subsequent exercise program in advanced HF patients. Aims The primary aim of this thesis was to determine the effects of a long-term High Intensity Interval Exercise Training (HIIT) program on clinical functional class, quality of life, exercise functional capacity, cardiac function and remodeling, in advanced heart failure patients after cardiac resynchronizer implant. Secondary aim intends to evaluate the potential role of different pathophysiologic mechanisms in the benefits of exercise training after CRT, HIIT, and of CRT without subsequent exercise: endothelial function, autonomic nervous system function, inflammatory process and apoptosis. Methodology A randomized controlled trial was performed to determine the effects of exercise intervention, HIIT, in advanced heart failure patients after CRT. The inclusion criteria considered patients with stable heart failure, class III-IV (NYHA), receiving optimal pharmacologic therapy, assigned to CRT by present guidelines, ischemic and non ischemic etiology, older than 18 years. Exclusion criteria included unstable HF patients, exercise incapacitating orthopedic or muscular disease and geographically long distance living. 9 Patients who fulfilled the inclusion criteria were randomized for long duration high intensity interval exercise training or for control group (EXTG and CG, respectively). Randomization, performed by an independent investigator, was stratified, based on age (<or≥65 years), gender, etiology (ischemic and non ischemic) and severity of left ventricular dysfunction (left ventricular ejection fraction <20% or ≥20%). Patients with the same inclusion criteria, who did not accept exercise intervention or living far, without other exclusion criteria were additionally studied as a prospective cohort for evaluation of CRT intervention effects and mechanisms. During the period from January 2012 to March 2015, all patients with chronic heart failure and criteria for cardiac resynchronization were evaluated. The exercise training program started 1 month after cardiac resynchronizer implant and lasted 6 months, twice a week, consisting of 60 minutes hospital-based, monitored, supervised sessions, starting at 1 month after CRT onset. It included aerobic high intensity interval training (HIIT), adapted from Wisloff protocol, and exercises of resistance, flexibility and coordination. Moments of the study used for the evaluation of independent variables were baseline, before cardioresynchronizer implant (M1), at 3 months of exercise, corresponding to 4 months after CRT (M2) and at 6 months (M3) after exercise, corresponding to 4 months (M2) and 7 months, corresponding to 7 months after CRT (M3). Dependent variables studied were: clinical functional class (NYHA), quality of life scores (HeartQol questionnaire), parameters of cardiac function and reverse remodeling (determined by echocardiography and BNP, plasmatic brain natriuretic peptide, measurement), of functional exercise capacity (determined by cardiopulmonary exercise testing, CPT), of autonomic nervous system function, ANS (determined by 123I-MIBG cardiac scintigraphy, cardiopulmonary exercise testing and 24-hours-holter heart rate variability analysis), of endothelial function and arterial stiffness (determined by NO, plasmatic Nitric Oxide measurement and PAT, peripheral arterial tonometry), inflammation and apoptosis (by measurement of high sensitivity C reactive protein, hs-CPR, Tumor Necrosis Factor alpha, TNF-α, Interleukin-6, IL-6, soluble cluster of differentiation 40, sCD40, soluble ligand of Fas, sFasL) and frequency of major cardiac events identification at 6 months of exercise. 10 Exceptions to the 3 moments were, 123I-MIBG cardiac scintigraphy, which was performed before CRT (M1) and at 6 months after exercise (M3), 24hours-holter heart rate variability study, performed only baseline, pre-CRT (M1) and cardiac events evaluation at M3. The safety of HIIT exercise was evaluated. CRT echocardiographic response was defined by the increase of at least 5% of left ventricular ejection fraction (absolute value) and clinical response was defined as the improvement of at least 1 clinical functional class (NYHA). Functional response was defined as the increase of at least 1 mg/kg/min VO2p. Results From the initial cohort sample of 121 heart failure patients selected for CRT, 62 patients were ramdomized. Exercise training program HIIT was performed by 22 patients (EXTG), mean age 67.5+9.8 years old, 22.7% female, 40% ischemic, baseline LVEF 26.68+6.21%, while 28 patients were assigned to the control group (CG). Demographic and baseline clinical characteristics were statistically identical. In the randomized sample (n=50), all patients had significant benefit, at 6 months after exercise onset (M3), regarding: NYHA, New York Heart Association, decrease (p< 0.001), HeartQol score improvement (p<0.001), LVEF, left ventricular ejection fraction increase (p<0.005), LVED, left ventricular end-diastolic volume (p< 0.05) and LVES, left ventricular end-systolic volume decrease (p<0.02). There was a significant difference in the decrease of clinical functional class of NYHA in the two randomized groups, greater in EXTG (p=0.034). Only in EXTG, there was a significant CPT (cardiopulmonary testing) duration increase at 3 months (p=0.017) and at 6 months (p=0.008). VATtime (time to ventilatory anaerobic threshold) significantly increased in EXTG at 3 months (p=0.006) and at 6 months (p=0.004), being significantly different regarding the CG at 3 months (p=0.006) and showing a tendency to statistical significance at 6 months (p=0.064), when variation was also significant in CG. TNF-α decreased significantly, only in EXTG, at 6 months (p=0.016) with a statistical difference from CG (p=0.008). There were no significant differences in echocardiographic parameters between the two randomized groups. Regarding the 11 number of CRT responders, in the exercise group, there were more CRT clinical (95%) , echocardiographic (81.8%) and functional (77.2%) responders than in the control group (78.5%, 72.7% and 53.8%, respectively), after 6 months of exercise. The difference in the number of responders in the two randomized groups, however, did not reach statistical significance (probably because of the sample size), but revealed a tendency for greater number of clinical and functional responders in the exercise group. HIIT program turned out to be safe, without any major or minor events during exercise. At 6 months after exercise (7 months after CRT device implant), death or hospital cardiac admission occurred in 1/22 patients (4.5%) of the exercise group and in 3/28 patients (10.7%) of the control group. The only death in the randomized patients occurred in the control group, 1/28 patients (3.5%). In the total CRT patients cohort there was a significant benefit after cardiac resynchronizer implant, at 7 months: functional NYHA decrease (p<0.001), HeartQol score increase (p<0.001), LVEF increase (p<0.001), LVES volume decrease (p=0.001), GLS (left ventricular global longitudinal strain) absolute value increase (p=0.003), E/e’ (ratio between E wave from pulsed Doppler left ventricular inflow wave and tissue Doppler mitral annular mean e’ decrease (p=0.009), LVM, left ventricular mass decrease (p=0.026), VE/VCO2 slope, minute ventilation to carbon dioxide production ratio slope decrease (p=0.003), cardiopulmonary testing duration increase (p=0.002), VATtime increase (p=0.001), HRR1, Heart Rate Recovery at 1st minute decrease (p=0.015), HRR6, Heart rate recovery at 6th minutes decrease (p=0.033) and VO2p, peak oxygen consumption increase (p=0.04). In total HF patients sample, after CRT (including 18% of the patients submitted to exercise), 75.6% were clinical responders, 63.9% were echocardiographic responders and 62.8% were functional responders. CRT echocardiographic responders had significant differences in baseline parameters and in the variation of some parameters: M1, smaller left ventricular volumes, greater TAPSE, greater SDNN (standard deviation NN interval), greater heart-mediastinum ratio, early (HMRe) and late (HMRl); M3-M1, greater increase of LVEF, greater reduction of LVES volume, greater increase in GLS absolute value and tendency for greater increase in VO2p. Responders had less major events registered at M3. 12 Analyzing the total HF-CRT patients, values of HMR late>1.5 identified more CRT echocardiographic responders (2-fold probability), only in nonischemic. Events at 7 months after CRT, M3, cardiac death or hospital admission or arrhythmia occurred in 14.8% of total population and in 16.2% of nonrandomized patients. Death occurred in 4.9% in total group and in 6% in nonrandomized group. Conclusion In this controlled randomized trial, performed in a sample of advanced HF patients referred to CRT, HIIT exercise after cardiac resynchronizer implant proved to be beneficial and safe, associated to an increased number of clinical and echocardiographic responders and with more significant clinical improvement, suggesting an additional benefit to CRT. The improvement of the peripheral component of heart failure caused by exercise was demonstrated by CPT duration and time to VAT significant increase, associated with more functional responders, along with positive modulation of inflammation, which might have contributed to this effect. No significant effects were demonstrated in endothelial or autonomic nervous system function. Less major events occurred in the HIIT group after the 6 months of training. The additional evaluation of CRT patients in the observational study of the total HF sample, showed a beneficial effect on symptoms severity, quality of life and systolic and diastolic LV function, even excluding those who performed exercise. Central effect of CRT on cardiac remodeling demonstrated to be crucial, with echocardiographic improvement of several variables. Once EXTG patients were excluded, the restant CRT patients did not show significant improvement at 7 months of VO2p, CPT duration or time to VAT, meaning CRT had no effect on HF peripheral component. Autonomic nervous system demonstrated to be a relevant mechanism for CRT response, but only in nonischemic HF. No beneficial effects of CRT were noticed in endothelial function, inflammation or apoptosis. More events were registered in patients who did not exercise. From these thesis results, we may accept, in advanced heart failure patients, exercise (HIIT) as safe and beneficial nonpharmacologic therapy with demonstrated additional benefit, regarding CRT, resulting in fewer patients with CRT nonresponse. This 13 intervention had no deleterious effect on reverse remodeling and some results point out to a potential benefit. The involved mechanism especially regards the peripheral component of HF, manifested by the decrease in clinical symptoms severity, improvement in functional capacity and positive modulation of pathophysiologic inflammatory response.
ABSTRACT: Introduction Chronic heart failure is known to be a complex syndrome, associated to high mortality and disability, involving multiple pathophysiologic mechanisms, neuro-hormonal, endothelial and inflammatory. Besides optimized medication, the nonpharmacologic therapy, like cardiac resynchronization and exercise training, plays a fundamental role. In advanced heart failure, patients with criteria for cardiac resynchronization therapy (CRT) have been studied extensively, though most of the studies were not dedicated to the diversity of effects and involved pathophysiologic mechanisms, in most severely symptomatic patients. In this advanced heart failure population treated with CRT, studies regarding exercise training effects and mechanisms, specifically high intensity interval exercise, are still few and small-sized. 8 Hypothesis Main hypothesis formulated: It is beneficial to associate a high intensity interval training exercise program, long duration, after cardiac resynchronization in advanced Heart Failure Patients. Secondary hypothesis: Several pathophysiologic mechanisms are involved, contributing differently to the exercise training benefit after CRT and to the benefit of CRT without subsequent exercise program in advanced HF patients. Aims The primary aim of this thesis was to determine the effects of a long-term High Intensity Interval Exercise Training (HIIT) program on clinical functional class, quality of life, exercise functional capacity, cardiac function and remodeling, in advanced heart failure patients after cardiac resynchronizer implant. Secondary aim intends to evaluate the potential role of different pathophysiologic mechanisms in the benefits of exercise training after CRT, HIIT, and of CRT without subsequent exercise: endothelial function, autonomic nervous system function, inflammatory process and apoptosis. Methodology A randomized controlled trial was performed to determine the effects of exercise intervention, HIIT, in advanced heart failure patients after CRT. The inclusion criteria considered patients with stable heart failure, class III-IV (NYHA), receiving optimal pharmacologic therapy, assigned to CRT by present guidelines, ischemic and non ischemic etiology, older than 18 years. Exclusion criteria included unstable HF patients, exercise incapacitating orthopedic or muscular disease and geographically long distance living. 9 Patients who fulfilled the inclusion criteria were randomized for long duration high intensity interval exercise training or for control group (EXTG and CG, respectively). Randomization, performed by an independent investigator, was stratified, based on age (<or≥65 years), gender, etiology (ischemic and non ischemic) and severity of left ventricular dysfunction (left ventricular ejection fraction <20% or ≥20%). Patients with the same inclusion criteria, who did not accept exercise intervention or living far, without other exclusion criteria were additionally studied as a prospective cohort for evaluation of CRT intervention effects and mechanisms. During the period from January 2012 to March 2015, all patients with chronic heart failure and criteria for cardiac resynchronization were evaluated. The exercise training program started 1 month after cardiac resynchronizer implant and lasted 6 months, twice a week, consisting of 60 minutes hospital-based, monitored, supervised sessions, starting at 1 month after CRT onset. It included aerobic high intensity interval training (HIIT), adapted from Wisloff protocol, and exercises of resistance, flexibility and coordination. Moments of the study used for the evaluation of independent variables were baseline, before cardioresynchronizer implant (M1), at 3 months of exercise, corresponding to 4 months after CRT (M2) and at 6 months (M3) after exercise, corresponding to 4 months (M2) and 7 months, corresponding to 7 months after CRT (M3). Dependent variables studied were: clinical functional class (NYHA), quality of life scores (HeartQol questionnaire), parameters of cardiac function and reverse remodeling (determined by echocardiography and BNP, plasmatic brain natriuretic peptide, measurement), of functional exercise capacity (determined by cardiopulmonary exercise testing, CPT), of autonomic nervous system function, ANS (determined by 123I-MIBG cardiac scintigraphy, cardiopulmonary exercise testing and 24-hours-holter heart rate variability analysis), of endothelial function and arterial stiffness (determined by NO, plasmatic Nitric Oxide measurement and PAT, peripheral arterial tonometry), inflammation and apoptosis (by measurement of high sensitivity C reactive protein, hs-CPR, Tumor Necrosis Factor alpha, TNF-α, Interleukin-6, IL-6, soluble cluster of differentiation 40, sCD40, soluble ligand of Fas, sFasL) and frequency of major cardiac events identification at 6 months of exercise. 10 Exceptions to the 3 moments were, 123I-MIBG cardiac scintigraphy, which was performed before CRT (M1) and at 6 months after exercise (M3), 24hours-holter heart rate variability study, performed only baseline, pre-CRT (M1) and cardiac events evaluation at M3. The safety of HIIT exercise was evaluated. CRT echocardiographic response was defined by the increase of at least 5% of left ventricular ejection fraction (absolute value) and clinical response was defined as the improvement of at least 1 clinical functional class (NYHA). Functional response was defined as the increase of at least 1 mg/kg/min VO2p. Results From the initial cohort sample of 121 heart failure patients selected for CRT, 62 patients were ramdomized. Exercise training program HIIT was performed by 22 patients (EXTG), mean age 67.5+9.8 years old, 22.7% female, 40% ischemic, baseline LVEF 26.68+6.21%, while 28 patients were assigned to the control group (CG). Demographic and baseline clinical characteristics were statistically identical. In the randomized sample (n=50), all patients had significant benefit, at 6 months after exercise onset (M3), regarding: NYHA, New York Heart Association, decrease (p< 0.001), HeartQol score improvement (p<0.001), LVEF, left ventricular ejection fraction increase (p<0.005), LVED, left ventricular end-diastolic volume (p< 0.05) and LVES, left ventricular end-systolic volume decrease (p<0.02). There was a significant difference in the decrease of clinical functional class of NYHA in the two randomized groups, greater in EXTG (p=0.034). Only in EXTG, there was a significant CPT (cardiopulmonary testing) duration increase at 3 months (p=0.017) and at 6 months (p=0.008). VATtime (time to ventilatory anaerobic threshold) significantly increased in EXTG at 3 months (p=0.006) and at 6 months (p=0.004), being significantly different regarding the CG at 3 months (p=0.006) and showing a tendency to statistical significance at 6 months (p=0.064), when variation was also significant in CG. TNF-α decreased significantly, only in EXTG, at 6 months (p=0.016) with a statistical difference from CG (p=0.008). There were no significant differences in echocardiographic parameters between the two randomized groups. Regarding the 11 number of CRT responders, in the exercise group, there were more CRT clinical (95%) , echocardiographic (81.8%) and functional (77.2%) responders than in the control group (78.5%, 72.7% and 53.8%, respectively), after 6 months of exercise. The difference in the number of responders in the two randomized groups, however, did not reach statistical significance (probably because of the sample size), but revealed a tendency for greater number of clinical and functional responders in the exercise group. HIIT program turned out to be safe, without any major or minor events during exercise. At 6 months after exercise (7 months after CRT device implant), death or hospital cardiac admission occurred in 1/22 patients (4.5%) of the exercise group and in 3/28 patients (10.7%) of the control group. The only death in the randomized patients occurred in the control group, 1/28 patients (3.5%). In the total CRT patients cohort there was a significant benefit after cardiac resynchronizer implant, at 7 months: functional NYHA decrease (p<0.001), HeartQol score increase (p<0.001), LVEF increase (p<0.001), LVES volume decrease (p=0.001), GLS (left ventricular global longitudinal strain) absolute value increase (p=0.003), E/e’ (ratio between E wave from pulsed Doppler left ventricular inflow wave and tissue Doppler mitral annular mean e’ decrease (p=0.009), LVM, left ventricular mass decrease (p=0.026), VE/VCO2 slope, minute ventilation to carbon dioxide production ratio slope decrease (p=0.003), cardiopulmonary testing duration increase (p=0.002), VATtime increase (p=0.001), HRR1, Heart Rate Recovery at 1st minute decrease (p=0.015), HRR6, Heart rate recovery at 6th minutes decrease (p=0.033) and VO2p, peak oxygen consumption increase (p=0.04). In total HF patients sample, after CRT (including 18% of the patients submitted to exercise), 75.6% were clinical responders, 63.9% were echocardiographic responders and 62.8% were functional responders. CRT echocardiographic responders had significant differences in baseline parameters and in the variation of some parameters: M1, smaller left ventricular volumes, greater TAPSE, greater SDNN (standard deviation NN interval), greater heart-mediastinum ratio, early (HMRe) and late (HMRl); M3-M1, greater increase of LVEF, greater reduction of LVES volume, greater increase in GLS absolute value and tendency for greater increase in VO2p. Responders had less major events registered at M3. 12 Analyzing the total HF-CRT patients, values of HMR late>1.5 identified more CRT echocardiographic responders (2-fold probability), only in nonischemic. Events at 7 months after CRT, M3, cardiac death or hospital admission or arrhythmia occurred in 14.8% of total population and in 16.2% of nonrandomized patients. Death occurred in 4.9% in total group and in 6% in nonrandomized group. Conclusion In this controlled randomized trial, performed in a sample of advanced HF patients referred to CRT, HIIT exercise after cardiac resynchronizer implant proved to be beneficial and safe, associated to an increased number of clinical and echocardiographic responders and with more significant clinical improvement, suggesting an additional benefit to CRT. The improvement of the peripheral component of heart failure caused by exercise was demonstrated by CPT duration and time to VAT significant increase, associated with more functional responders, along with positive modulation of inflammation, which might have contributed to this effect. No significant effects were demonstrated in endothelial or autonomic nervous system function. Less major events occurred in the HIIT group after the 6 months of training. The additional evaluation of CRT patients in the observational study of the total HF sample, showed a beneficial effect on symptoms severity, quality of life and systolic and diastolic LV function, even excluding those who performed exercise. Central effect of CRT on cardiac remodeling demonstrated to be crucial, with echocardiographic improvement of several variables. Once EXTG patients were excluded, the restant CRT patients did not show significant improvement at 7 months of VO2p, CPT duration or time to VAT, meaning CRT had no effect on HF peripheral component. Autonomic nervous system demonstrated to be a relevant mechanism for CRT response, but only in nonischemic HF. No beneficial effects of CRT were noticed in endothelial function, inflammation or apoptosis. More events were registered in patients who did not exercise. From these thesis results, we may accept, in advanced heart failure patients, exercise (HIIT) as safe and beneficial nonpharmacologic therapy with demonstrated additional benefit, regarding CRT, resulting in fewer patients with CRT nonresponse. This 13 intervention had no deleterious effect on reverse remodeling and some results point out to a potential benefit. The involved mechanism especially regards the peripheral component of HF, manifested by the decrease in clinical symptoms severity, improvement in functional capacity and positive modulation of pathophysiologic inflammatory response.
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Insuficiência cardíaca crónica Terapêutica não farmacológica Ressincronização cardíaca Treino de exercício Chronic heart failure Nonpharmacologic therapy Cardiac resynchronization Exercise training