I ntrodução: A insuficiência cardíaca é uma síndrome clínica caracterizada por anormalidades da função do ventrículo esquerdo e regulação neurohormonal, associadas a hipertrofia cardíaca (HC). Dentre as vias intracelulares envolvidas na HC, a via dependente de cálcio calcineurina tem se demonstrado importante. O treinamento físico tem sido utilizado como tratamento coadjuvante de pacientes com IC, mas seu papel sobre a atividade da via da calcineurina relacionado a HC na IC ainda não foi estabelecido. Portanto, neste estudo avaliamos o efeito do treinamento físico sobre a via da calcineurina e sobre a HC em um modelo genético de IC induzida por hiperatividade simpática. Métodos: Estudamos camundongos controle (WT) e com inativação gênica para os receptores adrenérgicos 2A e 2C (2A/2CARKO) dos 5 aos 7 meses, que foram divididos nos grupos WT (n=19), 2A/2CARKO (n=26) e 2A/2CARKO treinados (n=31). O treinamento físico aeróbico em esteira foi realizado durante 8 semanas, 5 vezes por semana por 1 hora. Foi avaliada a tolerância ao esforço pela distância total percorrida em um teste máximo até a exaustão em esteira, a função cardíaca pela fração de encurtamento por meio do ecocardiograma, a estrutura cardíaca pela massa cardíaca das câmaras cardíacas, diâmetro transverso dos cardiomiócitos por microscopia óptica, expressão gênica da -MHC por RT-PCR, a expressão das proteínas calcineurina, NFATc3 e GATA-4 nos extratos citoplasmáticos e nucleares por meio do Western blot, e a localização sub-celular das proteínas NFATc3 e GATA-4 por microscopia confocal. Resultados: Os camundongos 2A/2CARKO apresentaram intolerância ao esforço, prejuízo na função cardíaca e alterações estruturais cardíacas observadas pelo aumento na massa do ventrículo esquerdo, do diâmetro transverso dos cardiomiócitos e da expressão gênica da -MHC. Além disso, os camundongos 2A/2CARKO não apresentaram diferenças na expressão da proteína calcineurina, mas apresentaram aumento na expressão das proteínas NFATc3 e GATA-4 nos extratos nucleares, como também um aumento na localização nuclear das proteínas NFATc3 e GATA-4 quando comparados ao grupo WT. Após o treinamento físico, os camundongos 2A/2CARKO apresentaram aumento na tolerância ao esforço e na função cardíaca, reversão parcial das alterações cardíacas observadas que foram acompanhadas por uma redução na expressão das proteínas NFATc3 3 GATA-4 nos extratos nucleares, como também uma redução na localização das proteínas NFATc3 e GATA-4 no núcleo por microscopia confocal. Conclusão: Os resultados sugerem que o treinamento físico é capaz de promover remodelamento cardíaco reverso com redução na participação da via intracelular da calcineurina e um menor agravamento da IC neste modelo genético de IC. / I ntroduction: Heart failure (HF) is a clinical syndrome characterized by cardiac dysfunction associated with neuro-hormonal hyperactivity, which culminates in cardiac hypertrophy (CH). Among the intracellular pathways involved in CH associated with HF, the calcium-dependept calcineurin pathway has been demonstrated to take an important role. Exercise training has been used as adjuvant treatment of patients with IC, but its role on cardiac remodeling related with calcineurin pathway in CH of HF has not yet been studied yet. Therefore, in the present study we evaluated the effect of exercise training on the calcineurin pathway and on CH in a genetic model of sympathetic hyperactivity induced HF. Methods: A cohort of male congenic 2A/2C-ARKO mice in a C57BL6/J genetic background and their wild-type controls (WT) were studied from 5 to 7 months of age, and were randomly assigned into WT (n=19), 2A/2C-ARKO (n=26) and 2A/2C-ARKO trained (n=31) groups. Treadmill aerobic exercise training was performed over 8 wk, 5 times per wk for 1 hour. Exercise tolerance was evaluated by total distance covered in treadmill maximal test until exhaustion, fractional shortening by echocardiogram, cardiac structure by mass of cardiac cardiac mass, and cardiomyocyte cross-sectional diameter by optical microscopy. -MHC mRNA levels were evaluated by RT-PCR, and expression of calcineurin, NFATc3 and GATA-4 in cytoplasmatic and nuclear extracts were evaluated by Western blot. Indeed sub-cellular localization of NFATc3 and GATA-4 proteins were studied by confocal microscopy. Results: 2A/2C-ARKO mice displayed exercise intolerance, cardiac dysfunction and structural cardiac alterations, which included increased left ventricle mass, myocyte crosssectional diameter and increased -MHC expression when compared to WT group. In addition, we observed alteration in calcineurin pathway associated with CH of 2A/2C-ARKO mice, named increased NFATc3 and GATA-4 expression in nuclear extracts paralleled by increased nuclear localization of NFATc3 and GATA-4 by confocal microscopy when compared to WT group. Exercise training in 2A/2CARKO mice improved exercise tolerance and cardiac function with a partial reversion of CH associated with reduced nuclear expression and localization of NFATc3 and GATA-4 when compared with WT mice. Conclusions: These data provide evidences for the anticardiac remodeling effect of exercise training in HF associated with reduced activation of calcineurin intracellular pathway

Introdução: A cardiomiopatia dilatada é uma das principais causas de insuficiência cardíaca com alta morbidade e mortalidade. Alterações genéticas em mais de 29 genes já foram relacionadas com a doença, contudo, elas explicam apenas uma pequena porcentagem dos casos sugerindo haver então outros genes relacionados com a doença. Foram relacionados para o presente projeto quatro genes candidatos, previamente relacionados com outras doenças cardíacas, para verificação de uma possível associação com a cardiomiopatia dilata idiopática. Objetivos: Avaliar a presença e frequência de mutações nos genes ACTC1, CSRP3, FKBP1A e FKBP1B de pacientes com cardiomiopatia dilatada do Instituto do Coração de São Paulo (InCor, FMUSP), investigar se há correlações entre o genótipo e o fenótipo e estudar as alterações funcionais desencadeadas pelas mutações encontradas. Métodos: Amostras de DNA de 186 pacientes com cardiomiopatia dilatada idiopática foram selecionados de um banco de dados do Instituto do Coração e triados geneticamente para alterações nos genes selecionados. Resultados e Discussão: Foram encontradas nove novas variantes genéticas. Cinco delas também estavam presentes no grupo controle, sendo excluídas como causativas da doença. Três delas não estavam presentes no grupo controle, contudo, dados de bioinformática avaliaram as alterações com um risco baixo de serem causativas. Uma alteração no gene CSRP3, que levava a troca de aminoácido, não estava presente no grupo controle e apresentou dados indicativos de mutação causativa da doença. Lâminas cardíacas foram avaliadas para verificação de possíveis dos mecanismos de ação, contudo, houve apenas a exclusão de alguns mecanismos previamente descritos na literatura. Conclusões: Não há evidências de que as alterações nos genes ACTC1, FKBP1A e FKBP1B estariam associadas com o desenvolvimento da doença. A alteração no gene CSRP3 também é capaz de causar cardiomiopatia dilatada idiopática / Introduction: Dilated Cardiomyopathy is one of the leading causes of heart failure with high morbidity e mortality. Already known genetic alterations explain little percentage of cases suggesting that other genes would be related with the disease. Four candidates genes previously related with other cardiac diseases were selected for the project to verify a possible relationship with dilated cardiomyopathy. Objectives: Evaluate the presence and frequency of genetic alterations in ACTC1, FKBP1A, FKBP1B and CSRP3 genes in dilated cardiomyopathy patients of São Paulo Heart Institute (Incor, FMUSP). To investigate for genotype/phenotype correlations and to study functional alterations triggered by the found mutations. Methods: DNA samples from 186 patients with dilated cardiomyopathy were selected from the Incor DNA bank and genetically screened for alterations in the selected genes. Results and Discussion: Nine new genetic variants were found. Five of them were present in the control population, thus being excluded as disease causative. Three of them were not present in the control population; however, bioinformatics analysis evaluated the alterations having a low risk of being causatives. One alteration in CSRP3 gene that resulted in amino-acid change was not present in control population and exhibit indicative data of disease causing mutation. Analysis of patient heart showed no difference from some disease mechanisms described in literature. Conclusions: There are no evidences that alterations in ACTC1, FKBP1A and FKBP1B genes would associated with disease development. Alteration in CSRP3 gene is also capable to cause dilated cardiomyopathy s

La Galanine est un peptide ubiquitaire de 29 acides aminés chez les mammifères (30 chez l'homme) qui contrôle de nombreuses fonctions biologiques: (I) secrétions endocrines (insuline, somatostatine, glucagon); (II) comportement (prise alimentaire, nociception, apprentissage, mémoire); (III) tonicité musculaire dans le tractus digestif. Ce peptide a particulièrement été étudié dans le système nerveux central où il joue un rôle dans l'évolution de certaines maladies neurodégénératives telles que les maladies de Parkinson et d'Alzheimer. La galanine agit en se fixant sur 3 récepteurs connus, GalR1-2-3 qui appartient à la grande famille des récepteurs couplés aux protéines G (GPCR). Bien que la Galanine et ses trois récepteurs soient fortement exprimés au niveau périphérique, leur rôle dans les effets périphériques et leur implication en pathologie ont été très peu étudié. L'objectif de mon travail de thèse a été d'identifier le rôle de la galanine dans le remodelage myocardique, qui constitue un déterminant majeur dans la progression de l'insuffisance cardiaque. Dans un premier temps, nous avons démontré que la galanine possède des propriétés anti-apoptotiques et anti-oxydantes in vitro dans les cardiomyocytes. En effet, le traitement de cellules par la galanine entraîne une diminution de l'apoptose et de la production de radicaux libres oxygénés en réponse à l'hypoxie. En accord avec ces effets bénéfiques au niveau cellulaire, les études in vivo réalisées dans un modèle d'ischémie-reperfusion cardiaque, ont montré que le traitement à la galanine dans la phase précoce de reperfusion réduit l'apoptose et la nécrose myocardique. De plus, nous avons confirmé in vivo l'importance de la galanine dans la défense contre le stress oxydant associé aux lésions mitochondriales post-ischémiques. Dans un deuxième temps, nous avons mis en évidence le rôle important de la galanine dans le contrôle de l'activité des fibroblastes cardiaques in vitro. Nous avons montré que la galanine inhibe des étapes clés d'activation de la cascade pro-fibrotique dans les fibroblastes cardiaques. Les propriétés anti-fibrotiques de la galanine ont également été confirmées in vivo dans un modèle de surcharge en pression par constriction aortique chez la souris. Dans ce modèle, nos résultats montrent que le traitement chronique à la galanine s'accompagne d'une amélioration de la fonction cardiaque. Ces données nous ont permis de démontrer que la galanine joue un rôle clé dans le remodelage cardiaque et de proposer la galanine comme un candidat potentiel dans le traitement de l'insuffisance cardiaque. / Galanin is an ubiquitous 29 amino acid peptide in mammals (30 in humans) that controls many biological functions: (I) endocrine secretions (insulin, somatostatin, glucagon); (II) behavior control (food intake, nociception, learning, memory, pain); (III) muscle tonicity in the digestive tract. This peptide has been particularly studied in the central nervous system where it plays a role in the evolution of neurodegenerative diseases such as Parkinson's and Alzheimer's. Although Galanin and its three receptors (GalR1, GalR2, GalR3) are strongly expressed at the peripheral level, their role in peripheral effects and their involvement in the pathology have been poorly studied. The objective of my thesis work was to identify the role of galanin in myocardial remodeling, which is a major determinant in the progression of heart failure. Firstly, we demonstrated that galanin has anti-apoptotic and anti-oxidant properties in vitro in cardiomyocytes. Indeed, the treatment of cells with galanin causes a dose-dependent decrease in apoptosis and reactive oxygen species in response to hypoxia. In line with these beneficial effects at the cellular level, using in vivo model of cardiac ischaemia-reperfusion we showed that galanin treatment reduces apoptosis and necrosis in the early phase of reperfusion. In addition, we confirmed in vivo the importance of galanin in the defense against oxidative stress associated with post-ischemic mitochondrial lesions. Secondly, we demonstrated the important role of galanin in controlling the activity of cardiac fibroblasts. Using in vitro models, we have shown that galanin inhibits activation of key steps of the pro-fibrotic cascade in cardiac fibroblasts. The anti-fibrotic properties of galanin were also confirmed in vivo in a mouse model of pressure overload-induced heart failure. This observation is accompanied by an improvement of cardiac function. These data reveal that galanin plays a key role in cardiac remodeling and suggest galanin as a potential candidate in the treatment of heart failure.

Myocardial infarction (MI) induced heart failure (HF) is a leading cause of morbidity and mortality over the world. Regular exercise improves quality of life and decreases hospitalization and mortality of patients with HF. In animals, exercise post MI attenuates progressive cardiac remodeling and cardiac dysfunction, and decreases neuronal activity in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM), which are key brain nuclei contributing to sympathetic hyperactivity post MI. The peripheral and central molecular mechanisms underlying these beneficial effects of exercise are not well understood. We studied one possible mechanism, brain-derived neurotrophic factor (BDNF), an exercise-induced factor, which via binding to its receptor tropomyosin-related kinase B (TrkB) may contribute to improvement of cardiac function post MI. In the brain, the ratio between two isoforms of the TrkB receptor, full-length and truncated forms (TrkB.FL/TrkB.T1) determines the extent of intracellular responses to mature BDNF (mBDNF; an active form of BDNF) and a decrease in this ratio may reflect down-regulation of BDNF-TrkB.FL signaling. Ca2+/calmodulin-dependent kinase II (CaMKII) and protein kinase B (Akt) are intracellular factors of BDNF-TrkB signaling in hippocampal/cortical neurons. Activation of cardiac BDNF-TrkB signaling may increase cardiomyocyte survival and myocardial contractility. In hypertensive rats, the role of BDNF-TrkB signaling in the PVN and RVLM appears opposite with activation of this axis in the PVN increasing, but in the RVLM decreasing sympathetic nerve activity (SNA). However, activation of CaMKII and Akt in the PVN and RVLM both mediate increase in SNA. The specific role of BDNF-TrkB signaling in the PVN and RVLM of rats with HF post MI has not yet been studied. We hypothesized that exercise training post MI enhances BDNF-TrkB signaling pathways in the left ventricle (LV) and RVLM, but inhibits in the PVN, and thereby preserves cardiac structure and function post MI. We evaluated changes in BDNF-TrkB axis and intracellular factors CaMKII and Akt in the non-infarct area of the LV, PVN and RVLM in sedentary and exercising rats with MI. The impact of systemic blockade of BDNF-TrkB signaling was assessed with ANA-12, a selective non-competitive antagonist of TrkB receptors. In the infarct area of the LV, mBDNF protein decreased and TrkB.T1 protein increased. In the non-infarct area, mBDNF tended to be decreased without change in TrkB.T1 expression. The activities of CaMKII and Akt were decreased in the non-infarct area of the LV. In the PVN and RVLM, the TrkB.FL/TrkB.T1 ratio was decreased but without changes in mBDNF and downstream factors except for decrease in Akt activity in the RVLM. Exercise training improved ejection fraction (EF), cardiac index and LV end-diastolic pressure, but only the exercise-induced improvement of EF was blocked by ANA-12. In the non-infarct area of the LV, exercise prevented decreases in mBDNF, CaMKII and Akt, and these effects were prevented by ANA-12. In the PVN, exercise increased mBDNF and decreased Akt activity, whereas in the RVLM, exercise had no effect on mBDNF but decreased CaMKII activity. The exercise-induced increase mBDNF in the PVN and decrease in p-CaMKIIβ expression in the RVLM were prevented by ANA-12. Our findings suggest that down-regulation of BDNF-TrkB signaling post MI is prominent in the LV with decreases in mBDNF protein in the infarct area and intracellular factors CaMKII and Akt in the non-infarct area. Increases in mBDNF, CaMKII and Akt in the LV by exercise may contribute to improvement of EF. In the PVN and RVLM, despite a decrease in the ratio of TrkB.FL/TrkB.T1 in both brain nuclei, only Akt activity decreased in the RVLM post MI. Exercise-induced decreases in activities of CaMKII in the RVLM and Akt in the PVN may both contribute to reduction in sympathetic hyperactivity post MI.

Heart failure (HF) is one of the top causes of mortality in the United States and globally. In order to combat the high mortality rates of this disease, medical technology, including internal cardioverter defibrillators (ICD) and left ventricular assist devices (LVAD), have become one of the most common treatments. Over the past 10 years the utilization of these cardiac devices has increased exponentially, which has created a new phenomenon of how we discuss death with patients who have one of these devices. The purpose of this dissertation is to increase understanding of the end-of-life decision making processes and current experiences that patients with a cardiac device are having. This dissertation includes four original manuscripts that focus on patients with a cardiac device and their experiences with decision-making at the end-of-life. The first paper is a data-based paper that examines experiences of patients with an ICD and what factors are associated with having a conversation with their providers about end-of-life. The second paper is an integrative review of the literature regarding what is currently known about end-of-life with an LVAD. The third paper is a psychometric evaluation of the Control Attitudes Scale-Revised (CAS-R) for patients with an LVAD. The fourth paper is a data-based manuscript that looks at patients with an LVAD and their attitudes and experiences with end-of-life conversations with providers and next-of-kin and the impact of cognition on these attitudes and experiences. The findings of this dissertation will hopefully inform providers of patients with cardiac devices about their patients end-of-life decision making processes. It will also demonstrate the gaps that are currently in practice, and ideally be able expand on how to assist patients and providers on improving communication about end-of-life decision making.

In the United States, congestive heart failure (CHF) is a cardiac condition with increasing hospitalization and rehospitalization burden to patients, families, and the healthcare system. This chronic condition is expected to affect more than 8 million people by 2030; however, not much is known about the relationship between risk factors and hospital readmissions once CHF patients are discharged to a skilled nursing facility (SNF). Applying a systems theory unbounded systems thinking, coupled with a systems-thinking approach the purpose of this quantitative, retrospective cohort study was to examine CHF hospital readmissions from SNFs within a 90-day period using a secondary data set of gender, age, race, SNF geographic location, length of SNF stay, and home health use risk factors. A binary logistic regression analysis revealed that out of 238 episodes, 99 patients were readmitted; however, no statistically significant relationship between the risk factors and readmission was found. Findings suggest that CHF readmissions from the SNF are not attributed to only quantifiable risk factors. Based on these findings, further research can support social change through multifaceted quantitative and qualitative systemic analyses to identify and inform how healthcare organizations can better assist the elderly population with CHF and improve future post-acute community-based health education and prevention programs.

More than 5 million Americans have heart failure, with approximately 5% of those affected being veterans. As the number of patients with CHF continues to rise, new treatment options are needed to improve the quality of care. Current studies show Telehealth is one treatment option. The purpose of this scholarly project was to determine if veterans diagnosed with CHF were able to maintain optimal weight and blood pressure following participation in Care Coordination Home Telehealth (CCHT) program. The CCHT program provides care to veterans, through the use of monitoring devices placed in their home. Bandura's self-efficacy theory was used as a guide to develop veterans' self-management skills. A retrospective chart review was conducted on 26 veterans with CHF enrolled in the CCHT program. Post participation weight and blood pressure were analyzed at 16 weeks to determine whether there was a difference from the pre-participation measures. There was no change in systolic blood pressure, diastolic blood pressure, or weight levels during the 16-week period. Limitations of this project were the small sample size (n = 26), attrition rate (n = 43), no data on nurse interaction, and a short follow-up period. Implications for nursing practice and enhancing the program's efficacy are recommended. This scholarly project has the potential to support social change by expanding veteran's access to care.

People living with heart failure (PLHF) should be screened for symptoms at every healthcare visit since they are 3 times more likely to experience ventricular arrhythmias. This quality improvement project (QIP) compared 3 self-administered HF symptoms questionnaires to determine the best screening tool for a tertiary hospital arrhythmia devices clinic. The instruments included the Minnesota Living with Heart Failure Questionnaire (MLHFQ), the Kansas City Cardiomyopathy Questionnaire (KCCQ), and the Self-Reported Heart Failure Symptoms (SHEFS) questionnaire. For a 30-day period, 76 people were eligible to participate in the QIP, with 55 participants included in the final analysis (72.5% participation). The questionnaires were compared and assessed with the gold standard laboratory test for HF (NT-proBNP) for sensitivity and specificity. For HF, the SHEFS was the most sensitive (83%) compared to the NT-proBNP, but the MLHFQ was most specific (89%). When compared to the MLHFQ as the standard, SHEFS was 71% sensitive, and 73% specific for HF. Similarly, when compared to the KCCQ, the SHEFS was both, 75% specific and sensitive in identifying HF. However, the rate of correlation to a positive or negative NT-proBNP test results was the highest for the SHEFS (87%). All 3 questionnaires were statistically significant in predicting admission to hospital for HF in the past 6 months (p = 0.02 to 0.03). Finally, given the shortest length and simplicity of use, the SHEFS was selected by the stakeholders to be the standard screening tool for the clinic. This project contributes to positive social change by providing the first reported comparison in the literature to implement questionnaires in a clinic to assess symptoms for PLHF attending an arrhythmia devices clinic.

Information from anecdotal interviews at a practicum site indicated a lack of training for advanced practice providers (APPs) in core competencies critical for effective practice in a heart failure (HF) unit. The goal of this project was to assess the APPs' verbal reports and develop HF unit-specific training for APPs. The practice-focused question examined whether unit-specific training for HF APPs improved knowledge and skills in HF management. The Johns Hopkins nursing evidence-based practice model and Knowles's adult learning theory were used to create a survey, a focus group, and a pre/posttest assessment of knowledge and skills gap. Descriptive and inferential statistics could be used to analyze pre/post survey data, and thematic analysis could be used to analyze focus group data. Assessment data could be used to develop a targeted HF program based on identified skill deficiencies. The implications of this project related to social change are the potential to increase APPs' knowledge, job engagement, and retention. The program could affect length of stay and 30-day readmission of patients in the HF unit.

With more than 700,000 new diagnoses annually, congestive heart failure (CHF) is a chronic condition that affects the chambers of the heart. When not managed correctly, the disease rapidly progresses to substantial fluid volume overload that impacts activities of daily living and the overall quality of life. The financial implications for poor CHF management cost a mean annual medical expenditure of $33,427 per patient per year. The need for a diagnostic and prognostic at-home protocol is needed in the medical community, as there is currently no such tool on the market. Donabedian's framework was used to guide the formulation and interpretation of this research. The purpose of this project was to design a CHF protocol using evidence-based research for clinicians making home visits to homebound patients with a primary diagnosis of CHF with an individualized protocol focusing on disease management, in home support system, knowledge base and financial factors for homebound patients. The protocol was released through a snowballing campaign to clinicians who work with CHF, transitional care, or homecare who then evaluated the protocol on its perceived efficacy if integrated into practice. Findings were analyzed using simple descriptive statistics by 32 nurses and other health care professionals who responded work in home care, cardiology, medical surgical nursing hospitalists, or skilled nursing facilities. Thirty-one of the 32 respondents deemed the protocol useful and stated a clinical need of protocol as evidenced by completed the AGREE II Questionnaire. The findings demonstrate that the CHF Practice Protocol provides clinicians with an evidence-based guidance to manage homebound patients with CHF on a small scale.