Exercise Training Restores Cardiac Protein Quality Control in Heart Failure

Exercise training is a well-known coadjuvant in heart failure treatment; however, the molecular mechanisms underlying its beneficial effects remain elusive. Despite the primary cause, heart failure is often preceded by two distinct phenomena: mitochondria dysfunction and cytosolic protein quality control disruption. The objective of the study was to determine the contribution of exercise training in regulating cardiac mitochondria metabolism and cytosolic protein quality control in a post-myocardial infarction-induced heart failure (MI-HF) animal model. Our data demonstrated that isolated cardiac mitochondria from MI-HF rats displayed decreased oxygen consumption, reduced maximum calcium uptake and elevated H2O2 release. These changes were accompanied by exacerbated cardiac oxidative stress and proteasomal insufficiency. Declined proteasomal activity contributes to cardiac protein quality control disruption in our MI-HF model. Using cultured neonatal cardiomyocytes, we showed that either antimycin A or H2O2 resulted in inactivation of proteasomal peptidase activity, accumulation of oxidized proteins and cell death, recapitulating our in vivo model. Of interest, eight weeks of exercise training improved cardiac function, peak oxygen uptake and exercise tolerance in MI-HF rats. Moreover, exercise training restored mitochondrial oxygen consumption, increased Ca2+-induced permeability transition and reduced H2O2 release in MI-HF rats. These changes were followed by reduced oxidative stress and better cardiac protein quality control. Taken together, our findings uncover the potential contribution of mitochondrial dysfunction and cytosolic protein quality control disruption to heart failure and highlight the positive effects of exercise training in re-establishing cardiac mitochondrial physiology and protein quality control, reinforcing the importance of this intervention as a nonpharmacological tool for heart failure therapy.

The medical management after surgery for advanced heart failure

The aim of the Research of this Ph D Project is to improve the medical management after surgery for advanced heart failure, both after left ventricular assist devices (LVAD) implantation, and after heart transplantation in the long-term. Regarding heart transplantation (HTx), the Research Project is focused on diagnostics, classification, prevention and treatment of cardiac allograft vasculopathy (CAV), and on treatment of post-HTx cancers; the results are presented in the first part of this Thesis. In particular, the main aspect investigated are the prognostic role of information derived from coronary angiography, coronary tomography and intravascular ultrasound, and the different sensitivity of these techniques in predicting outcomes and in diagnosing CAV. Moreover, the role of mTOR inhibitors on CAV prevention or treatment is investigated, both alone and in combination with different anti-CMV prevention strategies, as well as the impact of mTOR inhibitors on clinical outcomes in the long term. Regarding LVAD, the main focus is on the role of transthoracic echocardiography in the management of patients with a continuous-flow, centrifugal, intrapericardial pump (HVAD, Heartware); this section is reported in the second part of this Thesis. The main aspects investigated are the use of echocardiography in patients with HVAD device and its interaction with the information derived from pump curves' analysis in predicting aortic valve opening status, a surrogate of the condition of support provided by the LVAD.

Predictors of readmission and health related quality of life in patients with chronic heart failure: a comparison of different psychosocial aspects

Psychological distress is common in patients with chronic heart failure. The impact of different psychological variables on prognosis has been shown but the comparative effects of these variables remain unclear. This study examines the impact of depression, anxiety, vital exhaustion, Type D personality, and social support on prognosis in chronic heart failure patients. One hundred eleven patients (mean age 57 ± 14 years) having participated in an exercise based ambulatory cardiac rehabilitation program were enrolled in a prospective cohort study. Psychological baseline data were assessed at program entry. Mortality, readmission, and health-related quality of life were assessed at follow up (mean 2.8 ± 1.1 years). After controlling for disease severity none of the psychological variables were associated with mortality, though severe anxiety predicted readmission [HR = 3.21 (95% CI, 1.04-9.93; P = .042)]. Health-related quality of life was independently explained by vital exhaustion, anxiety and either body mass index (physical dimension) or sex (emotional dimension). As psychological variables have a strong impact on health-related quality of life they should be routinely assessed in chronic heart failure patients` treatment.

Effects of a comprehensive rehabilitation program on quality of life in patients with chronic heart failure

This evaluation was performed to assess the effects of a new, comprehensive outpatient rehabilitation program on generic and disease-specific quality of life related to exercise tolerance in stable chronic heart failure patients. Fifty-one patients (aged 59+/-11 years; 84% men) were treated for 12 weeks. Patients underwent optimized drug treatment, exercise training, and counseling and education. At baseline and at the end of the program, functional status, exercise capacity, and quality of life were assessed using the Medical Outcomes Study 36-item Short-Form Health Survey and the Minnesota Living with Heart Failure Questionnaire. Left ventricular ejection fraction and New York Heart Association functional class, as well as measures of physical fitness and walking distance covered in 6 minutes, improved significantly (by 11%-20% and by 58% on average, respectively). Physical functioning (effect size, 0.38; p<0.0001), role functioning (effect size, 0.17; p<0.05), and mental component score (effect size, 0.47; p<0.0001) on the questionnaire improved significantly. Disease-specific quality of life improved in sum score (effect size, 0.24; p<0.0001) and physical component score (effect size, 0.35; p<0.0001). The latter was inversely correlated to improvement in peak power output (r= -0.31; p<0.05). In patients with stable chronic heart failure, significant improvements in both generic and disease-specific quality of life related to improved exercise tolerance can be achieved within 12 weeks of comprehensive rehabilitation.

Psychometric properties of the MacNew heart disease health-related quality of life instrument in patients with heart failure

RATIONALE, AIMS AND OBJECTIVES: Heart failure (HF) is a severe chronic disease and impairs health-related quality of life (HRQL). While validated specific HRQL instruments are required for evaluation of treatment and rehabilitation in patients with HF, a single validated measure to document changes in HRQL for patients with different heart disease diagnoses would be invaluable. The purpose of this analysis was the psychometric analysis of the German MacNew Heart Disease Questionnaire (MacNew) in HF patients, which has previously been shown to be reliable and valid in patients with myocardial infarction, angina pectoris and arrhythmia. METHODS: We recruited 89 patients (61.7+/-11.5 years; 84.3% male) in two Austrian and one Swiss cardiology department with documented HF (effect sizes 28.9+/-10.1%). The self-administered MacNew, the Short Form-36 (SF-36) and the Hospital Anxiety and Depression Scale were completed. Internal consistency reliability (Cronbach's alpha), discriminative and evaluative validity were assessed. RESULTS: Cronbach's alpha exceeded 0.80. Each MacNew scale differentiated between patients with and without anxiety (3.9+/-1.0 vs. 5.3+/-0.8, all P<0.001), with and without depression (4.2+/-1.2 vs. 5.2+/-0.9 all P<0.03) and by the SF-36 health transition item (deteriorate=4.39, no change=4.95, improve=5.45, all P<0.02). Evaluative validity was demonstrated with effect sizes >0.70 for a subsample attending a 12-week outpatient rehabilitation programme. CONCLUSIONS: The German language version of the MacNew demonstrates consistently acceptable psychometric properties of reliability, validity and responsiveness in patients with documented HF. Together with previous documentation of reliability, validity and responsive, these findings strengthen the argument for the MacNew as a potential 'core' HRQL measure, at least in the German language.

Relation of heart rate recovery to psychological distress and quality of life in patients with chronic heart failure

BACKGROUND: Psychological distress, poor disease-specific quality of life (QoL), and reduction in vagally mediated early heart rate recovery (HRR) after exercise, all previously predicted morbidity and mortality in patients with chronic heart failure (CHF). We hypothesized lower HRR with greater psychological distress and poorer QoL in CHF. DESIGN: All assessments were made at the beginning of a comprehensive cardiac outpatient rehabilitation intervention program. METHODS: Fifty-six CHF patients (mean 58+/-12 years, 84% men) completed the Hospital Anxiety and Depression Scale and the Minnesota Living With Heart Failure Questionnaire. HRR was determined as the difference between HR at the end of exercise and 1 min after exercise termination (HRR-1). RESULTS: Elevated levels of anxiety symptoms (P=0.005) as well as decreased levels of the Minnesota Living With Heart Failure Questionnaire total (P = 0.025), physical (P=0.026), and emotional (P=0.017) QoL were independently associated with blunted HRR-1. Anxiety, total, physical, and emotional QoL explained 11.4, 8, 7.8, and 9.0%, respectively, of the variance after controlling for covariates. Depressed mood was not associated with HRR-1 (P=0.20). CONCLUSION: Increased psychological distress with regard to elevated anxiety symptoms and impaired QoL were independent correlates of reduced HRR-1 in patients with CHF. Reduced vagal tone might explain part of the adverse clinical outcome previously observed in CHF patients in relation to psychological distress and poor disease-specific QoL.

An ICT-based closed-loop model to improve care for heart failure patients

Durante las últimas décadas se ha producido un fenómeno global de envejecimiento en la población. Esta tendencia se puede observar prácticamente en todos los países del mundo y se debe principalmente a los avances en la medicina, y a los descensos en las tasas de fertilidad y mortalidad. El envejecimiento de la población tiene un gran impacto en la salud de los ciudadanos, y a menudo es la causa de aparición de enfermedades crónicas. Este tipo de enfermedades supone una amenaza y una carga importantes para la sociedad, especialmente en aspectos como la mortalidad o los gastos en los sistemas sanitarios. Entre las enfermedades cardiovasculares, la insuficiencia cardíaca es probablemente la condición con mayor prevalencia y afecta a 23-26 millones de personas en todo el mundo. Normalmente, la insuficiencia cardíaca presenta un mal pronóstico y una tasa de supervivencia bajas, en algunos casos peores que algún tipo de cáncer. Además, suele ser la causa de hospitalizaciones frecuentes y es una de las enfermedades más costosas para los sistemas sanitarios. La tendencia al envejecimiento de la población y la creciente incidencia de las enfermedades crónicas están llevando a una situación en la que los sistemas de salud no son capaces de hacer frente a la demanda de la sociedad. Los servicios de salud existentes tendrán que adaptarse para ser efectivos y sostenibles en el futuro. Es necesario identificar nuevos paradigmas de cuidado de pacientes, así como mecanismos para la provisión de servicios que ayuden a transformar estos sistemas sanitarios. En este contexto, esta tesis se plantea la búsqueda de soluciones, basadas en las Tecnologías de la Información y la Comunicación (TIC), que contribuyan a realizar la transformación en los sistemas sanitarios. En concreto, la tesis se centra en abordar los problemas de una de las enfermedades con mayor impacto en estos sistemas: la insuficiencia cardíaca. Las siguientes hipótesis constituyen la base para la realización de este trabajo de investigación: 1. Es posible definir un modelo basado en el paradigma de lazo cerrado y herramientas TIC que formalice el diseño de mejores servicios para pacientes con insuficiencia cardíaca. 2. El modelo de lazo cerrado definido se puede utilizar para definir un servicio real que ayude a gestionar la insuficiencia cardíaca crónica. 3. La introducción, la adopción y el uso de un servicio basado en el modelo definido se traducirá en mejoras en el estado de salud de los pacientes que sufren insuficiencia cardíaca. a. La utilización de un sistema basado en el modelo de lazo cerrado definido mejorará la experiencia del usuario de los pacientes. La definición del modelo planteado se ha basado en el estándar ISO / EN 13940- Sistema de conceptos para dar soporte a la continuidad de la asistencia. Comprende un conjunto de conceptos, procesos, flujos de trabajo, y servicios como componentes principales, y representa una formalización de los servicios para los pacientes con insuficiencia cardíaca. Para evaluar el modelo definido se ha definido un servicio real basado en el mismo, además de la implementación de un sistema de apoyo a dicho servicio. El diseño e implementación de dicho sistema se realizó siguiendo la metodología de Diseño Orientado a Objetivos. El objetivo de la evaluación consistía en investigar el efecto que tiene un servicio basado en el modelo de lazo cerrado sobre el estado de salud de los pacientes con insuficiencia cardíaca. La evaluación se realizó en el marco de un estudio clínico observacional. El análisis de los resultados ha comprendido métodos de análisis cuantitativos y cualitativos. El análisis cuantitativo se ha centrado en determinar el estado de salud de los pacientes en base a datos objetivos (obtenidos en pruebas de laboratorio o exámenes médicos). Para realizar este análisis se definieron dos índices específicos: el índice de estabilidad y el índice de la evolución del estado de salud. El análisis cualitativo ha evaluado la autopercepción del estado de salud de los pacientes en términos de calidad de vida, auto-cuidado, el conocimiento, la ansiedad y la depresión, así como niveles de conocimiento. Se ha basado en los datos recogidos mediante varios cuestionarios o instrumentos estándar (i.e. EQ-5D, la Escala de Ansiedad y Depresión (HADS), el Cuestionario de Cardiomiopatía de Kansas City (KCCQ), la Escala Holandesa de Conocimiento de Insuficiencia Cardíaca (DHFKS), y la Escala Europea de Autocuidado en Insuficiencia Cardíaca (EHFScBS), así como cuestionarios dedicados no estandarizados de experiencia de usuario. Los resultados obtenidos en ambos análisis, cuantitativo y cualitativo, se compararon con el fin de evaluar la correlación entre el estado de salud objetivo y subjetivo de los pacientes. Los resultados de la validación demostraron que el modelo propuesto tiene efectos positivos en el cuidado de los pacientes con insuficiencia cardíaca y contribuye a mejorar su estado de salud. Asimismo, ratificaron al modelo como instrumento válido para la definición de servicios mejorados para la gestión de esta enfermedad. ABSTRACT During the last decades we have witnessed a global aging phenomenon in the population. This can be observed in practically every country in the world, and it is mainly caused by the advances in medicine, and the decrease of mortality and fertility rates. Population aging has an important impact on citizens’ health and it is often the cause for chronic diseases, which constitute global burden and threat to the society in terms of mortality and healthcare expenditure. Among chronic diseases, Chronic Heart Failure (CHF) or Heart Failure (HF) is probably the one with highest prevalence, affecting between 23 and 26 million people worldwide. Heart failure is a chronic, long-term and serious condition with very poor prognosis and worse survival rates than some type of cancers. Additionally, it is often the cause of frequent hospitalizations and one of the most expensive conditions for the healthcare systems. The aging trends in the population and the increasing incidence of chronic diseases are leading to a situation where healthcare systems are not able to cope with the society demand. Current healthcare services will have to be adapted and redefined in order to be effective and sustainable in the future. There is a need to find new paradigms for patients’ care, and to identify new mechanisms for services’ provision that help to transform the healthcare systems. In this context, this thesis aims to explore new solutions, based on ICT, that contribute to achieve the needed transformation within the healthcare systems. In particular, it focuses on addressing the problems of one of the diseases with higher impact within these systems: Heart Failure. The following hypotheses represent the basis to the elaboration of this research: 1. It is possible to define a model based on a closed-loop paradigm and ICT tools that formalises the design of enhanced healthcare services for chronic heart failure patients. 2. The described closed-loop model can be exemplified in a real service that supports the management of chronic heart failure disease. 3. The introduction, adoption and use of a service based on the outlined model will result in improvements in the health status of patients suffering heart failure. 4. The user experience of patients when utilizing a system based on the defined closed-loop model will be enhanced. The definition of the closed-loop model for health care support of heart failure patients have been based on the standard ISO/EN 13940 System of concepts to support continuity of care. It includes a set of concept, processes and workflows, and services as main components, and it represent a formalization of services for heart failure patients. In order to be validated, the proposed closed-loop model has been instantiated into a real service and a supporting IT system. The design and implementation of the system followed the user centred design methodology Goal Oriented Design. The validation, that included an observational clinical study, aimed to investigate the effect that a service based on the closed-loop model had on heart failure patients’ health status. The analysis of results comprised quantitative and qualitative analysis methods. The quantitative analysis was focused on determining the health status of patients based on objective data (obtained in lab tests or physical examinations). Two specific indexes where defined and considered in this analysis: the stability index and the health status evolution index. The qualitative analysis assessed the self-perception of patients’ health status in terms of quality of life, self-care, knowledge, anxiety and depression, as well as knowledge levels. It was based on the data gathered through several standard instruments (i.e. EQ-5D, the Hospital Anxiety and Depression Scale, the Kansas City Cardiomyopathy Questionnaire, the Dutch Heart Failure Knowledge Scale, and the European Heart Failure Self-care Behaviour Scale) as well as dedicated non-standardized user experience questionnaires. The results obtained in both analyses, quantitative and qualitative, were compared in order to assess the correlation between the objective and subjective health status of patients. The results of the validation showed that the proposed model contributed to improve the health status of the patients and had a positive effect on the patients’ care. It also proved that the model is a valid instrument for designing enhanced healthcare services for heart failure patients.

Cost-effectiveness of Transcatheter Mitral Valve Leaflet Repair for the Treatment of Mitral Regurgitation in Heart Failure

Contexte: La régurgitation mitrale (RM) est une maladie valvulaire nécessitant une intervention dans les cas les plus grave. Une réparation percutanée de la valve mitrale avec le dispositif MitraClip est un traitement sécuritaire et efficace pour les patients à haut risque chirurgical. Nous voulons évaluer les résultats cliniques et l'impact économique de cette thérapie par rapport à la gestion médicale des patients en insuffisance cardiaque avec insuffisance mitrale symptomatique. Méthodes: L'étude a été composée de deux phases; une étude d'observation de patients souffrant d'insuffisance cardiaque et de régurgitation mitrale traitée avec une thérapie médicale ou le MitraClip, et un modèle économique. Les résultats de l'étude observationnelle ont été utilisés pour estimer les paramètres du modèle de décision, qui a estimé les coûts et les avantages d'une cohorte hypothétique de patients atteints d'insuffisance cardiaque et insuffisance mitrale sévère traitée avec soit un traitement médical standard ou MitraClip. Résultats: La cohorte de patients traités avec le système MitraClip était appariée par score de propension à une population de patients atteints d'insuffisance cardiaque, et leurs résultats ont été comparés. Avec un suivi moyen de 22 mois, la mortalité était de 21% dans la cohorte MitraClip et de 42% dans la cohorte de gestion médicale (p = 0,007). Le modèle de décision a démontré que MitraClip augmente l'espérance de vie de 1,87 à 3,60 années et des années de vie pondérées par la qualité (QALY) de 1,13 à 2,76 ans. Le coût marginal était 52.500 $ dollars canadiens, correspondant à un rapport coût-efficacité différentiel (RCED) de 32,300.00 $ par QALY gagné. Les résultats étaient sensibles à l'avantage de survie. Conclusion: Dans cette cohorte de patients atteints d'insuffisance cardiaque symptomatique et d insuffisance mitrale significative, la thérapie avec le MitraClip est associée à une survie supérieure et est rentable par rapport au traitement médical.

Multidisciplinary strategies for the management of heart failure patients at high risk for admission - A systematic review of randomized trials

OBJECTIVES The aim of this study was to determine whether multidisciplinary strategies improve outcomes for heart failure (HF) patients. BACKGROUND Because the prognosis of HF remains poor despite pharmacotherapy, there is increasing interest in alternative models of care delivery for these patients. METHODS Randomized trials of multidisciplinary management programs in HF were identified by searching electronic databases and bibliographies and via contact with experts. RESULTS Twenty-nine trials (5,039 patients) were identified but were not pooled, because of considerable heterogeneity. A priori, we divided the interventions into homogeneous groups that were suitable for pooling. Strategies that incorporated follow-up by a specialized multidisciplinary team (either in a clinic or a non-clinic setting) reduced mortality (risk ratio [RR] 0.75, 95% confidence interval [CI] 0.59 to 0.96), HF hospitalizations (RR 0.74, 95% CI 0.63 to 0.87), and all-cause hospitalizations (RR 0.81, 95% CI 0.71 to 0.92). Programs that focused on enhancing patient self-care activities reduced HF hospitalizations (RR 0.66, 95% CI 0.52 to 0.83) and all-cause hospitalizations (RR 0.73, 95% CI 0.57 to 0.93) but had no effect on mortality (RR 1.14, 95% CI 0.67 to 1.94). Strategies that employed telephone contact and advised patients to attend their primary care physician in the event of deterioration reduced HF hospitalizations (RR 0.75, 95% CI 0.57 to 0.99) but not mortality (RR 0.91, 95% CI 0.67 to 1.29) or all-cause hospitalizations (RR 0.98, 95% CI 0.80 to 1.20). In 15 of 18 trials that evaluated cost, multidisciplinary strategies were cost-saving. CONCLUSIONS Multidisciplinary strategies for the management of patients with HF reduce HF hospitalizations. Those programs that involve specialized follow-up by a multidisciplinary team also reduce mortality and all-cause hospitalizations. (C) 2004 by the American College of Cardiology Foundation.

Guidelines for the prevention, detection and management of people with chronic heart failure in Australia 2006

* Chronic heart failure (CHF) is found in 1.5%–2.0% of Australians. Considered rare in people aged less than 45 years, its prevalence increases to over 10% in people aged ≥ 65 years. * CHF is one of the most common reasons for hospital admission and general practitioner consultation in the elderly (≥ 70 years). * Common causes of CHF are ischaemic heart disease (present in > 50% of new cases), hypertension (about two-thirds of cases) and idiopathic dilated cardiomyopathy (around 5%–10% of cases). * Diagnosis is based on clinical features, chest x-ray and objective measurement of ventricular function (eg, echocardiography). Plasma levels of B-type natriuretic peptide (BNP) may have a role in diagnosis, primarily as a test for exclusion. Diagnosis may be strengthened by a beneficial clinical response to treatment(s) directed towards amelioration of symptoms. * Management involves prevention, early detection, amelioration of disease progression, relief of symptoms, minimisation of exacerbations, and prolongation of survival.