Le réseau lymphatique permet le drainage des liquides interstitiels, le transport des cellules immunitaires et intervient dans le métabolisme lipidique. La dérégulation de ce système est impliquée dans de nombreuses pathologies comme les lymphœdèmes, le rejet de greffe ou encore l'échappement tumoral. Le cœur est pourvu d'un réseau lymphatique abondant dont l'importance n'est apparue que très récemment dans les pathologies ischémiques. En effet, suite à un infarctus du myocarde, la dysfonction lymphatique observée favorise l'œdème et l'inflammation tissulaire, révélant le réseau lymphatique comme un acteur majeur du développement de cette pathologie. Les processus régulant la formation de vaisseaux lymphatiques chez l'adulte sont largement dépendants de facteurs de croissance aux effets pro- ou anti- lymphangiogéniques. Les cellules immunes et plus particulièrement les macrophages sécrètent un grand nombre de ces facteurs et leur importance dans la réponse lymphangiogénique a été montrée dans différentes conditions physio-pathologiques, telles que la lymphangiogenèse tumorale et inflammatoire. Il a longtemps été admis que les macrophages tissulaires provenaient exclusivement de la différenciation de monocytes sanguins. Cependant, l'existence de macrophages provenant de progéniteurs embryonnaires a été récemment mise en évidence. Dorénavant, les macrophages tissulaires résidents sont perçus comme des populations hétérogènes pouvant prétendre à des différences fonctionnelles. A ce jour, les modifications du réseau lymphatique et les mécanismes permettant sa régulation, au cours de pathologies non ischémiques, n'ont pas été abordées. Ainsi, nous avons entrepris d'identifier et de caractériser les différentes populations de macrophages cardiaques participant à la régulation du réseau lymphatique suite à une surcharge barométrique. Nos résultats ont montré une diminution précoce du réseau lymphatique cardiaque dans le cœur murin hypertrophié au cours d'une surcharge de pression induite par constriction de l'aorte transverse. Cette réduction du réseau est associée à la perte d'une population majoritaire de macrophages cardiaques portant le récepteur 1 à l'acide hyaluronique (Lyve-1). Cette population résidente diminue dans le cœur insuffisant, au profit de macrophages infiltrants dérivés de monocytes sanguins. Par ailleurs, en plus d'être corrélée à la baisse du réseau lymphatique cardiaque, la diminution du nombre de macrophages Lyve-1 est proportionnelle à la détérioration de la fonction cardiaque. La prévention de l'infiltration monocytaire a permis de maintenir le pool de macrophages exprimant Lyve-1, le réseau lymphatique et la fonction cardiaques lors d'une surcharge de pression. La caractérisation par RT-PCR des différentes populations de macrophages récupérés par tri cellulaire nous a permis de montrer que les macrophages Lyve-1 présentent des caractéristiques particulières, avec une forte expression de VEGFR3 et NRP2, molécules de signalisation lymphangiogène. De plus, ces macrophages Lyve-1 à la polarisation mixte et à l'activité phagocytaire importante, expriment de nombreux facteurs pro-lymphangiogéniques (VEGFc, VEGFd, IGF1). Ils ont montré une activité pro-lymphangiogène in vitro sur des explants de canal thoracique et sur des cellules endothéliales lymphatiques et in vivo avec la formation de vaisseaux lymphatiques naissants lors de l'injection de ces macrophages Lyve-1 dans le cœur. Leur localisation à proximité des vaisseaux lymphatiques et leur capacité pro-lymphangiogène leurs confèrent un rôle évident dans le maintien du réseau lymphatique lors d'un remodelage cardiaque de surcharge de pression. Ces travaux ont permis l'identification d'une population originale de macrophages cardiaques pouvant entrer dans la régulation du système lymphatique au cours d'une surcharge de pression. / The lymphatic system has recently emerged as an important regulator of the cardiac interstitial fluid compartment and function. Experimental obstruction of lymphatic vessel leads to cardiac œdema, myocardial stiffness, fibrosis and ventricle dysfunction. Following myocardial infarction, stimulation of lymphangiogenesis was found to reduce fibrosis and inflammation and to improve cardiac function. Macrophages have been largely described as important contributors of lymphangiogenesis in inflammatory situations such as cancer. Recently, genetic fate mapping demonstrated that distinct populations of macrophages coexist in the adult heart. In addition to monocyte derived-macrophages that massively colonize injured heart, a subpopulation of tissue-resident macrophages that originates from embryonic precursors persists into adulthood by means of local self- renewal. To date the distinct involvement of cardiac macrophage subpopulations in cardiac lymphatic remodeling and heart failure progression induced by pressure overload is largely unknown. In our study, we observed that expression of Lyve-1 identifies a resident macrophage subset abundant in mouse heart. This Lyve-1 positive macrophage subset decreased rapidly in cardiac remodeling induced by chronic pressure overload. In addition, the number of cells found in heart was positively correlated with the preservation of cardiac lymphatic network and function after transverse aortic constriction (TAC). Blocking recruitment of monocyte derived macrophages expanded Lyve-1 positive macrophages, attenuated cardiac lymphatic remodeling and contractile dysfunction of pressure overloaded heart. Lyve-1 positive macrophages express pro-lymphangiogenic factors and sustain lymphangiogenesis in vitro and in vivo. In conclusion, resident macrophage subset expressing the Lyve-1 receptor participates to maintain cardiac function after chronic pressure overload by mechanisms that may involve the preservation of cardiac lymphatic system. These results provide insight into the regulation of lymphatic homeostasis by tissue resident macrophage during heart failure induced by pressure overload.

Heart failure is a chronic disease and a common cause of hospitalizations and readmissions within 30-days of discharge. To decrease the cost of care for patients with heart failure, the Centers for Medicare and Medicaid Services initiated the Readmissions Reduction Program that reduces payment to hospitals with preventable readmissions. Among the causes for readmissions of patients with heart failure are concurrent behavioral health issues that can lead to decreased medication compliance and increased risk for disease progression. The prevalence of comorbid depression is as high as 77% among patients with heart failure and may be an important factor in readmissions. Although cardiac nurses in the emergency room, intensive care unit, and the progressive care units at a community hospital were perceived by managers to be in optimal settings to assess for behavioral health issues and make referrals as appropriate, assessments were not being conducted. The purpose of the project was to determine the barriers nurses faced in completing the assessments. Four audiotaped focus groups with a total of 18 cardiac nurses were held and the data were transcribed for analysis. Using Kalcaba's comfort contexts (physical, psychospiritual, social, and environmental), the barriers identified by the nurses were categorized into a fishbone diagram and a Pareto chart. The nurses identified lack of a standardized screening tool, lack of priority given to behavioral health assessments, lack of time to conduct the assessments, and lack of a clear facility policy related to the assessments as barriers. A positive social change resulting from the project is an initiative to address the barriers and ensure that patients with heart failure are cared for in a holistic manner that addresses physical and behavioral health issues.

Background: Heart failure (HF) is a leading cause of hospitalization, readmissions, and death in the United States. Patients hospitalized for HF are at risk for readmission, in- hospital mortality, and early post-discharge death. In the United States, inpatient care has been estimated to cost $83,980 over the lifetime of each patient with HF. The majority of patients with HF depend on caregiver support for successful HF self-care, which is essential for optimal patient outcomes. Support from caregivers is thought to be important for better self-care, and lower readmission and mortality rates. Yet, there are few studies considering the influence of caregivers on HF patient self-care, readmission, and mortality. Objective: The purpose of my dissertation was to determine the influence of HF caregivers on patient self-care, readmission, and mortality. The specific aims of this dissertation were to: (1) to determine if caregiver depressive symptoms mediate the relationship between family functioning and caregiver quality of life, (2) to determine if there is an association between living arrangements (living with someone vs. living alone) and all-cause readmission and death in patients with HF, and (3) to determine the efficacy of an in-hospital, multi-session, educational intervention for caregivers on heart failure patients’ self-care and 30 day readmission rate, and to evaluate the efficacy of the intervention on caregivers’ knowledge, self-efficacy and perceived control. Methods: Specific aim one was addressed by a secondary analysis of data from one- hundred and forty-three HF caregivers recruited from an outpatient clinic. Multiple regression with mediation analysis was used to determine whether depressive symptoms mediated the relationship between family functioning as measured using the three scales of the Family Assessment Device (i.e., general, problem-solving, communication) and caregiver quality of life. Specific aim two was addressed by a retrospective chart review of all 398 patients with a primary diagnosis of HF admitted to an academic medical center in one year. We collected data on patient sociodemographic, clinical characteristics, and patient living condition. The independent association of living alone with all-cause readmission or all-cause death was evaluated using Cox proportional hazards modeling adjusting for covariates. Specific aim three was addressed using a two-group (educational intervention for caregivers of patients with heart failure vs. usual educational care), prospective, repeated measures randomized controlled trial of 37 patient and caregiver dyads in which caregivers only received in-hospital HF education. Outcome measures included patient self-care, and patient all-cause readmission or all- cause death, as well as caregiver self-efficacy, knowledge, and perceived control. Patient self-care, and caregiver self-efficacy, knowledge, and perceived control were assessed at baseline (in hospital), at discharge, 7 and 30-days after patient discharge. Patient readmissions and death were assessed by a phone call at 30-days follow-up. The intervention directed only at caregivers consisted of three in-hospital, educational sessions with telephone follow-up. The educational sessions were designed to deliver HF information and skills to caregivers, thereby providing them with the resources needed to improve their self-efficacy, perceived control and HF knowledge thus improving patient self-care and readmission rates. Results: Specific aim one: The three subscales of the Family Assessment Device predicted depressive symptoms (p < 0.001) and caregiver quality of life (p < 0.001). Depressive symptoms also predicting caregiver quality of life (p < 0.001). The inclusion of depressive symptoms in the final model with each subscale of the Family Assessment Device (i.e., general family functioning, problem-solving, communication) decreased the significance of family functioning as a predictor of caregiver quality of life indicating mediation by depressive symptoms. Specific aim two: Heart failure patients living with someone experienced a significantly longer time to rehospitalization than those living alone (290 vs. 201 days, p=0.005). In a Cox regression hazard regression model, adjusting for covariates, patients who lived alone were 1.42 times more likely to be rehospitalized one year after discharge than those who lived with someone (p=0.013). The relationship between living alone and all-cause death was not significant after adjustment for covariates. Specific aim three: A linear mixed-model analysis revealed that patients whose caregiver was in the intervention group had significantly better self- care maintenance (p < 0.001) and self-care management (p < 0.001) across time. Cox survival analysis demonstrated that patients whose caregiver did not receive the educational intervention were 11 times more likely (p=0.002) to experience cardiac readmission than patients whose caregiver did receive the educational intervention. Caregivers who received the educational intervention had higher perceived control (p < 0.001) for up to 30-days post-intervention versus the control group, however, there were no differences between caregiver groups in self-efficacy and HF knowledge. Conclusion: In this dissertation, we found caregivers to play an important part in improving patient outcomes of self-care and readmission after discharge from a hospitalization for HF. Future large-scale studies are needed to develop and test interventions focused on caregivers to improve both patient and caregiver outcomes. Such studies will assist clinicians in understanding how better to support caregivers in their ability to positively influence HF self-care and readmission rates in patients with HF.

Heart failure is a major public health issue, with its prevalence estimated to be 6.5 million adults in the USA. Of the hospitalized heart failure (HF) cases, 50% are characterized by preserved ejection function (HFpEF). In HFpEF, the heart pumps a normal proportion of blood that enters it. However, thickening of the ventricular walls inhibits the chamber filling to normal volume. The direct basis of HFpEF is a slowed elongation of the cardiac muscle during the diastolic phase of the cardiac cycle. Elucidation of mechanisms that mediate relaxation of cardiac muscle could help understand the pathogenic mechanisms in HFpEF. Myocardial contraction and relaxation are tightly controlled processes that involve thick and thin filament regulatory proteins. β-Adrenergic signaling pathway is a major regulator of myocardial contraction and relaxation via the activation of protein kinase A (PKA). Two key myofilament proteins, troponin I (TnI) and myosin binding protein-C (MyBPC), are phosphorylated by PKA following β-adrenergic stimulation. The purpose of this thesis is to develop a liquid chromatography-mass spectrometry (LC-MS) method for the quantification of phosphorylation in TnI and MyBPC and measure the changes in the degree of phosphorylation in transverse-aortic constriction (TAC) mouse hearts, a model representing HFpEF, and sham (control) mouse hearts. The initial approach of the project was to develop a method for quantification of phosphopeptides using synthesized stable isotope labeled (SIL) peptides, both with and without phosphate modification. To accomplish this goal, a multiple reactions monitoring (MRM)-LC-MS method for the quantification of the synthesized SIL peptides was first developed. This method, using low picomole amounts, is applicable to researchers in the field using SIL peptides for quantification. However, when the SIL peptides were actually applied, we determined that there was a selective absorption of some phosphate peptides in the LC column, limiting the use of the SIL peptides for quantification. This result is also of general interest to others trying to identify phosphopeptides, not realizing that some peptides will go unmeasured. Thus, we returned to expanding an earlier method developed in our research group to quantify the degree of phosphorylation. Key to this work was the development of a quantification method directly from heart myofibrillar protein preparations without requiring isolation of individual proteins by gel electrophoresis. Using the LC-MS method developed, we quantified phosphorylation sites of TnI and MyBPC in the TAC and control mouse hearts. The phosphorylation measurements showed no significant difference in phosphorylation between the TAC and control mice, except for one site, S302 in MyBPC that had a 13% decrease in phosphorylation with TAC. We conclude that in our TAC model, PKA dysfunction may not play a role in the initial development of HFpEF.

The outpatient care of the heart failure (HF) patient is fragmented due to the lack of evidence-based practice guidelines use. The primary goal of this project was to improve the care of the HF patient in the outpatient arena through use of clinical pathways using the logic model as the project framework. The intervention was carried out over a 4-week period on a convenience, random sample of patients (n = 80) attending a cardiology practice. The patients were recruited from 2 physicians' patient populations and were selected based on an adult diagnosis of HF, reduced ejection fraction of <40% at some point in time, and the New York Heart Association (NYHA) functional class II-V. Comparisons were made in the documentation of care between patients on or off the pathway. The intervention included documentation of patient education, care follow-up, medications, NYHA functional class, and symptom exacerbation, documented in the electronic medical record. The quality of care data were evaluated based on 3 of the Joint Commission core measures for outpatient care of the HF patient. Additional data were collected regarding use of the clinical pathway based on provider and week of implementation. Data were analyzed via a Chi-square test of independence comparing pathway use by provider and use of pathway as study progressed. The comparative results show statistically significant differences in use of the pathway by provider and a statistically significant increase in use during the project . The quality of care results varied in statistical significance. The pathway utilization increased over time and provided a method for standardizing documentation of care for the HF patient in this outpatient clinic, a benefit for HF patients and providers in this cardiology practice and beyond.

Hospital readmissions related to chronic heart failure (CHF) are costly, widespread, and often avoidable. Patient education that includes diagnosis, causes, medications, diet, exercise, and exacerbation warning signs has been shown to reduce the number of CHF readmissions. The purpose of this study was to use risk stratification to identify CHF patients at high risk for 30-day readmission. Once a high-risk CHF patient was identified, nursing interventions would be triggered to reduce readmissions and close the gaps in the continuum of care following acute care admission. Transitions of care theory was used as the framework for this project. The methodology had a quality improvement focus. The patient population consisted of high-risk CHF patients (n = 25) with NYHA classification of II-IV using the risk identification tool. Patients were identified using the tool, were followed for 30 days, and received nursing interventions to reduce the possibility of readmission. Only one of the identified patients was readmitted within 30 days for a diagnosis unrelated to CHF, resulting in no readmissions within this sub group. This study suggests that risk stratification can identify and direct resources to CHF patients, decreasing their likelihood for readmission. Nurse leaders can use standardized tools such as the risk identification tool, thereby reducing readmissions along with associated costs for readmissions.

Thesis (M.Sc. (Chemical Pathology) --University of Limpopo, 2013 / Cardiovascular diseases (CVDs) are among one of the well documented conditions and pose a significant health burden in the world as they areconsidered to be of adult onset. However, recent studies have shown that in developed countries CVD risk factors are becoming prevalent in young people which isof great concern. Therefore, the aim of this study was to determine if CVD risk factors are present in young subjects aged 15-20 years of age residing in a rural area of a developing country. Methods: Subjects aged between 15-20 years who participated in the “Gene - Environment interaction project” were included in this sub-study. Total cholesterol, triglycerides, HDL-cholesterol, LDLcholesterol, insulin, glucose, creatinine, Lp(a), apoB, apoA-1 and hs-CRPwere determined. Blood pressure, physical activity (number of steps/day), weight, height, waist circumference and hip circumference were obtained from the database. Subjects with CRP levels above 10mg/L and creatinine levels above 130 mmol/L were excluded. Results: The present study showed an overall high prevalence of some CVD risk factors. There was high prevalence of insulin resistance (23.0% in females and 34.7% in males), and high hs-CRP (18.4% in females, 12.9% in males). The prevalence of low HDL-C levels was high (55.2% in females and 16.8 % in males), however, the prevalence of abnormal levels of other lipids such as total cholesterol/HDL-cholesterol ratio was low in both males and females. The prevalence of an increased apoB/apoA ratio was significantly higher in females 26.4% compared to males 7.9%. The prevalence of overweight (12.6%) and obesity (9.2%) was higher in females than in males (overweight 1%, obesity 0 %). The prevalence of hypertension was comparable between the two genders (5.7% in females and 10.9 % in males). Conclusion: The results showed a relatively high prevalence of non-traditional risk factors for cardiovascular diseases in adolescents residing in a rural area, Limpopo Province, while the prevalence of traditional risk factors such as total cholesterol and triglycerides was low.

Background/Significance: Heart failure patients have high mortality, co-morbidity, hospitalization rates, costs and numerous recommendations to follow. Non-cardiac pain is common and an additional compounding problem as it decreases heart failure (HF) patients’ ability to follow recommendations, decreases quality of life and increases the likelihood of being hospitalized. When depression is combined with HF and pain, patients are even less able to follow recommendations, treatment plans, and self-care behaviors. Exercise is an important, low-cost intervention for pain that has considerably fewer adverse effects/interactions than pharmacologic therapies. Given the low rates of participation in exercise and the many barriers that discourage exercise participation, an essential first step is to establish current physical activity levels and how pain may further influence potential engagement in exercise programs. Objectives: To characterize and describe: the experience of pain, pain management, the self-reported physical activity level including relationships between pain intensity, pain interference, total activity time, sitting time, perceptions of exercise, and depression, in older depressed HF participants. Methods: This prospective cross-sectional study analyzed data from 62 participants with depression and Class II-IV HF. Data from the Brief Pain Inventory, Rand 36, International Physical Activity Questionnaire, Beck Depression Inventory II, and Exercise and Pain Management Questionnaire were used in the analysis. Results: The majority of depressed HF patients had moderate to severe pain intensity and interference and no differences were found in demographics between those who had pain and those who didn’t. Depression level did not have an additional impact on pain intensity or pain interference. Non-pharmacological treatments were severely underutilized. The majority of participants think exercise will be helpful to treat their pain. The most common barriers to exercise for depressed HF patients include: shortness of breath 72%, having no one to exercise with 59%, fatigue 56%, other health conditions 56%, and the weather is too hot or too cold 55%. Those who had higher pain intensity, pain interference, or depression scores were not more likely to say exercise would be unhelpful than those with lower scores. Lastly, the majority would like to be more physically active. Conclusion: The prevalence of pain reported by this sample, combined with the diverse pain locations, reliance on medications that are well-known for having untoward side-effects in this population, and generally poor treatment responses reported, make it clear that thorough pain assessment and additional pain treatment strategies are needed to decrease the impact of pain on this population. Findings suggest that depressed patients with HF believe exercise would be helpful to treat their pain and would also like to be more active. Decreasing sitting time and increasing light activity levels hold promise to improve pain and depression symptoms. Interventions to increase physical activity levels that are acceptable to depressed HF patients need to be identified and offered as treatment options, including referral to cardiac rehab as an important starting point for individualized support and education that may increase long-term adherence.

Acute decompensation of chronic heart failure is common and results in many patients being re-hospitalized every year (Jancin 2008). One of four voluntary core measures deployed by the Joint Commission for evaluation of quality of heart failure care in hospitals is heart failure discharge instructions, also called core measure HF1. Although the core measure is a widely disseminated standardized measure related to discharge education, there is little evidence about its impact on patient or readmission outcomes. The purpose of this study was to determine the relationship between the completion of heart failure discharge instructions as defined by the Joint Commission core measure HF1 in a single site, 500 bed tertiary hospital population in the Upper Midwest and the primary endpoint of subsequent readmission to the hospital 30, 90, 180 and 365 days following an index discharge for primary diagnosis of heart failure. Secondary endpoints included hospital readmission charges and total hospital readmission days per year. Patient characteristics, clinical characteristics, unit factors and index visit utilization variables were controlled. This study also described the relationship between nursing unit factors and completion of HF1. A retrospective, descriptive design, and analyses using primarily generalized linear models, were used to study the relationship of HF1 to utilization outcomes (readmission, hospital days and cost) and unit context (discharge unit and number of inter-unit transfers). Individual level retrospective demographic, clinical, administrative and performance improvement data were used (n = 1034). Results suggested a weak and non-significant association of completion of the core measure HF1 bundle and readmission within 30 days for all cause readmissions (p = .22; OR 1.32), and no association with HF to HF readmissions at 30 days. There was an inverse association 2 after 6 months for all cause readmission, and after 90 days for HF to HF readmission. There was a non-significant trend toward a relationship to total hospital days, but no relationship of HF1 to total annual charges. The study did find a significant relationship between type of discharge nursing unit and HF1 completion, and type of discharge unit and readmission. The discharge nursing unit was quite consistently and strongly related to all cause readmissions in binary (p = .029: OR 1.58) and counts analyses (p = .001; OR 1.52), but was not related to the subset of HF to HF readmissions. The study concludes that there is limited relationship between HF1 and 30 day all cause hospital readmission and total readmission days, but a stronger relationship between HF1 and discharge from a cardiology specialty unit. There was also a relationship between cardiology discharge unit and reduction in all cause readmissions.

Clinical and preclinical studies revealed that heart failure induces depression. Injury of myocardial tissue initiates an inflammation cascade that extends to the CNS and might contribute to depression following myocardial infarction (MI). Sex differences were noticed in the progression of heart failure and depression in clinical studies. We hypothesized that depression-like behavior induced by HF post-MI is influenced by sex through modulation of inflammation pathway. First, we evaluated sex differences in depression-like behavior in male and female rats at 8-10 weeks post-MI, as well as circulating cytokines, the extent of inflammation in the PFC, PVN, and amygdala, and mBDNF levels in the PFC and amygdala that are affected by neuroinflammation. Then we evaluated the effect of ovariectomy (OVX) and whether estrogen replacement with 17β-estradiol (E2) prevents post-MI induced depression-like behavior through inhibiting neuroinflammation. Thirdly we evaluated the role of inflammation for cardiac dysfunction and development of depression-like behavior in OVX female rats post-MI by oral treatment with pentoxifylline (PTX). Male rats developed depression-like behavior by ten weeks post-MI but not females as assessed by sucrose preference test (SPT) and forced swim test (FST). Both developed similar cardiac dysfunction and a comparable increase in plasma and PVN cytokine levels, but cytokine levels increased and mBDNF levels decreased only in the PFC of male rats post-MI. OVX per se decreased sucrose consumption and induced passive behavior assessed by SPT and FST, respectively.The combination of MI and OVX aggravated depression-like behvaiour. E2 treatment prevented the development of mild depression-like behavior in OVX and severe symptoms in OVX female rats post-MI. E2 had no effect on cardiac dysfunction in OVX female rats at 10 weeks post-MI. Despite the similar increase in circulating cytokines in OVX ± E2 at 10 weeks post-MI, E2 decreased the proinflammatory cytokines and increased IL-10 (anti-inflammatory cytokine) in the PFC. Finally, we evaluated the role of neuroinflammation in depression-like behavior in OVX female rats post-MI through inhibiting cytokine production by administering oral PTX. PTX prevented depression-like behavior in OVX female rats post-MI and reduced cytokines levels in plasma, PVN and PFC. However, PTX did not affect the progression of cardiac dysfunction at 10 weeks post-MI. Sex determines the development of depression-like behavior in HF post-MI and neuroinflammation appears to play a critical pathway that is affected by sex and can be inhibited by hormonal replacement or anti-inflammatory agents.