Background: Heart failure (HF) is a complex, costly and debilitating chronic health condition. Symptom recognition and self-care are crucial components of heart failure management; however, many HF patients struggle to perform these behaviors and skills at a proficient level. A transitional care program in the Southwest provides services to heart failure patients. A primary program aim is to help facilitate enhanced symptom recognition and self-care among heart failure patients. This project focuses on the assessment of the impact of such a transitional care program on HF patients' ability to perform symptom recognition and self-care. Methods: Demographic questionnaires were distributed to collect socioeconomic data and clinical characteristics of participants. A pre and post SCHFI survey was completed by participants, and analysis of data performed using a paired t-test. Results: The 15 participants were primarily Hispanic, elderly, and male. The majority of participants reported an annual income less than $10,000, lived in close proximity to the transitional care clinic, reported living with family and/or friends, and had at least one additional comorbidity. There was improvement in self-care maintenance scores following the initial transitional care encounter; however, participants did not achieve self-care adequacy in this domain. Participants also did not achieve self-care adequacy in self-management. Self-confidence scores improved to reach adequacy following the initial transitional care encounter; however, results were not statistically significant. Conclusion: With the complexities of HF self-management, it is not alarming that these patients have continued to struggle with symptom recognition and self-care. Recommendations are made for future research and interventions.

Class of 2006 Abstract / Objectives: To evaluate the group clinic patients’ visit satisfaction and self-efficacy assessments at baseline and six months after the implementation of the heart failure group clinic. Additional outcomes of interest included health service utilization and medication management. Methods: This study utilized a pre-experimental design to compare patients’ clinic visit satisfaction and self-efficacy assessments at baseline and six months. Demographic variables, diagnoses, vitals, health service utilization and medication management data were obtained retrospectively from the computerized patient record system (CPRS). Results: Eleven patients met the inclusion criteria, agreed to participate and completed the informed consent. Mean age was 64.1 years (± 11.28); 100% were male; 45.5% were white, not of Hispanic origin. Health service utilization could not be compared using the planned analysis because of the limited data available for this outcome. Medication management trends included titrating angiotensin-converting enzyme inhibitors (n=1), titrating beta-blockers (n=6), and converting from non-preferred HF medications to ACC/AHA guideline recommended agents (n=3). The mean self-efficacy score increased at follow-up when compared to baseline data (7.4 ± 1.7 versus 6.4 ± 2.7, respectively) with no statistical significance shown between the two groups (p=0.12). Additionally, the mean patient satisfaction score increased at follow-up when compared to the baseline scores (74.5 ± 12.3 versus 71.0 ± 15.1 respectively); however, data analysis revealed no statistical significance (p=0.50). Conclusions: Our study demonstrated trends suggesting improved patient satisfaction and improved self-efficacy with a group clinic model in veteran patients with heart failure. Group clinic settings have the potential to optimize HF medication management in the setting of enormous demand for VA healthcare services and limited financial resources.

Heart failure (HP) is a common, disabling and deadly condition that causes high rates of morbidity and mortality worldwide. It is widely recognised that the failing heart is energy-starved, and that restoring energy homeostasis is a promising approach towards improving cardiac output. This thesis aims to address the role of energetics in the failing heart, by focussing on modulation of the creatine transporter (CrT). Creatine (Cr), together with the phosphocreatine shuttle, plays a vital role in maintaining energy supplies via ATP in times of high energy demand. Key to the regulation of intracellular [Cr] is the CrT, a Na+ and Cl - dependent membrane transporter. Previous CrT genetic mouse models include a knockout model, found to still express cardiac CrT, and a cardiac-specific CrT overexpressing (OE) model with large variations in myocardial [Cr] between animals and Cr levels high enough to cause spontaneous hypertrophy. To overcome the shortfalls of this CrT-OE model, a novel in vivo model of temporal inducible expression of CrT is described, using a cardiac-specific tetracycline inducible (Tet-On) system . ..,. .A' Ten transgenic lines (RCT) were created with a construct containing . zhe CrT-HA (CrT cDNA with an haemagglutinin epitope tag), following successful doxycyline-inducibility in vitro. Eight lines showed germline transmission, with LV CrT OE achieved in an individual mouse that displayed double LV [Cr] compared to WT. Issues with the inducer line (rtTA) were ruled out by its use in the creation of a luciferase overexpressing mouse line; all mice tested demonstrated LV luciferase expression in response to doxycycline feeding. The failure to overexpress CrT could be attributed to position or copy number dependent suppression, or to position effect variegation in the case of the single OE mouse obtained. Subsequent work focus sed on regulatory pathways in vitro in a cell line of mouse fibroblasts stably overexpressing CrT·HA. Post-translational modifications (PTMs) had been previously suggested to regulate CrT activity. Two N-linked glycosylation sites exist, in addition to the putative phosphorylation sites. Inhibition of glycosylation by tunicamycin led to decreased CrT activity, reflected by decreased Cr uptake capacity. Strategies to confirm the presence of phosphorylation were employed, including isolation of CrT -HA by immunoprecipitation and subsequent LC-MS / MS analysis to identify PTMs. Although the presence of CrT was confirmed in 5 different sized species- one previously unreported- inadequate sequence coverage prevented identification of any PTM sites. Tyrosine phosphorylation was not detected using a phosphospecific antibody on immunopurified CrT -HA. Candidate signalling pathways in vitro were then investigated to elucidate CrT regulation, namely the IGF-IR signalling pathway. This study included a cardiomyocyte-like mouse cell line (HL-l) in addition to 3T3-CrT -HA. Exposure of cells to extracellular insulin, growth hormone and IGF-1 led to increased Cr uptake of 125% - 300% of normal. Pharmacological inhibition of the downstream kinases PKA and PKC reduced the effect of insulin and GH, while PMA, sapintoxin (STX) and Go 6976 induced CrT activity. The mammalian target of rapamycin (mTOR) is also a candidate regulator of CrT, as incubation with rapamycin decreased Cr uptake in 3T3-CrT -HA. Finally, a targeted approach on transcription factors in the 5'UTR region of mouse CrT identified HEYl as a highly conserved site. In siRNA experiments, HEYl was found to exert a mild effect on CrT activity, suggesting that regulation at the transcriptional level merits further investigation. Together, this work has provided novel insights into the modulation of CrT in vitro, identifying molecular and pharmacological targets in a known therapeutic signalling pathway. Further work could potentially develop these findings by identifying candidate compounds that would increase CrT activity, potentially in a tissue-specific manner. 3

Master of Science / Department of Kinesiology / Timothy I. Musch / Impaired vasomotor control in chronic heart failure (CHF) limits the delivery of O[subscript]2 to skeletal muscle during exercise. Previous results demonstrate significant increases in skeletal muscle blood flow (BF) during exercise with omega-3 polyunsaturated fatty acid (PUFA) supplementation via fish oil (FO) versus safflower oil (SO) in healthy rats (Stebbins CL et al., Int J Sport Nutr Exerc Metab 20:475-86, 2010). Whether PUFA supplementation with FO will improve vasomotor control in CHF and skeletal muscle BF during exercise remains to be determined. This investigation tested the hypothesis that PUFA supplementation with FO would augment the skeletal muscle BF response to exercise in rats with CHF when compared to SO. CHF was induced in male Sprague-Dawley rats by myocardial infarction produced via left coronary artery ligation. Rats were then randomized to dietary FO (20% docosahexaenoic acid and 30% eicosapentaenoic acid, n = 8) or SO (5% safflower, n = 6) supplementation for 6 weeks. Rats remained on their respective diets until final experiments were conducted. Following acute instrumentation and recovery (> 1 hour), mean arterial pressure (MAP), skeletal muscle BF to the total hindlimb and individual muscles (via radiolabeled microspheres), and blood lactate concentration were determined during rest, submaximal treadmill exercise and exercise+LNAME (20 m · min[superscript]-[superscript]1, 5% incline). Left ventricular end-diastolic pressure (LVEDP) measured in the SO and FO groups during instrumentation were similar and demonstrated moderate CHF (LVEDP; SO: 14 ± 2; FO: 11 ± 1 mmHg, P>0.05). During submaximal exercise, MAP (SO: 128 ± 3; FO: 132 ± 3 mmHg) and blood lactate (SO: 3.8 ± 0.4; FO: 4.6 ± 0.5 mmol · l[superscript]-[superscript]1) were similar (P>0.05) between groups. Exercising hindlimb skeletal muscle BF was higher in SO compared to FO (SO: 120 ± 11; FO: 93 ± 4 ml · min[superscript]-[superscript]1 · 100 g[superscript]-[superscript]1). Specifically, 17 of 28 individual hindlimb muscle BF’s were higher (P<0.05) in SO. These data suggest that PUFA supplementation with FO in rats with moderate CHF decreases the skeletal muscle BF response to submaximal whole body exercise.

Changes in myocardial energetics have been implicated in the pathophysiology of heart failure (HF). However, the precise contribution of creatine (Cr) / phosphocreatine (PCr) / creatine kinase (CK) energy buffer and transfer remains unclear. The aim of this thesis was to study the effects on murine cardiac function of both impairment and enhancement of creatine metabolism. In order to longitudinally follow the cause and effect relationship of myocardial creatine concentration, a non-invasive method of quantification was required. Cardiac Cr levels measured in vivo by 1H-MRS were therefore compared with gold-standard invasive HPLC and found to correlate over a wide-range (r2=0.91). 1H-MRS was reproducible for measuring Cr levels in the heart, brain, and skeletal muscle. The cardiac phenotype of a novel model of creatine depletion, the AGAT-/- mouse, was characterized using in vivo MRI, 1H-MRS and LV catheterisation, under conditions of gradually reducing Cr concentrations; zero Cr; and attempted phenotype rescue with dietary Cr. For the first time in the heart, the rate of Cr turnover was quantified (~3 % per day) and demonstrated that cardiac function was preserved even when creatine levels reduced by ~70-90%. Total absence of myocardial Cr induced impairment of inotropic and lusitropic cardiac function and reduced inotropic reserve. Cardiac dysfunction was only partially rescued by replenishment of the Cr pool, suggesting this to be a consequence of long-term adaptations to chronic low Cr. Finally, we tested the hypothesis that combined elevation of myocardial creatine and ribose would be beneficial in a mouse model of chronic HF by increasing cardiac energy availability. Despite an increase in myocardial ribose concentration, this did not prevent loss of total adenine nucleotides (TAN), and there was no improvement in post-infarct LV remodeling or function. Future studies are needed to explore alternative approaches for maintaining TAN in combination with total creatine.

M.Sc. (Med.)--Faculty of Health Sciences, University of the Witwatersrand, 2011 / In-part through a decrease in cardiac cavity dimensions (reverse remodelling), β-adrenergic receptor blockers have been demonstrated to produce marked benefits to morbidity and mortality in patients with chronic heart failure. However, maximum doses of these agents are often difficult to achieve in patients with chronic heart failure because of the negative inotropic, hypotensive and other side effects. Whether blockade of the excessive adrenergic effects achieves complete reverse remodelling in progressive heart failure is nevertheless uncertain. To test this hypothesis I simulated the adverse effects of chronic adrenergic stimulation on the heart by administering daily doses of the β-adrenergic receptor agonist, isoproterenol (ISO) (2.42 X 10-8 mmol.kg-1) to rats for 6 months and compared left ventricular (LV) dimensions and systolic function to Saline-vehicle treated rats. To imitate the effects of complete adrenergic receptor blockade following the development of adrenergic-induced adverse cardiac changes, I similarly administered ISO for 6 months and then subsequently withdrew the daily ISO administration for a further 4 months (ISO+Recovery) before comparing left ventricular dimensions and function to Saline+Recovery treated rats. In comparison to a Saline vehicle-treated group, after 6 months of ISO administration, LV end diastolic and systolic diameters, and the volume intercept of the left ventricular diastolic pressure-volume relationship (LV V0), were markedly increased and LV endocardial fractional shortening (FSend), LV end systolic chamber (slope of the systolic pressure-volume relationship-Ees) and myocardial (slope of the systolic stress-strain relationship-En) contractility were substantially decreased. The extent of the adverse remodelling produced by chronic ISO administration was exemplified by the 2.5 times increase in LV V0 (ISO=0.40±0.04 vs Saline=0.16±0.01, p<0.001), a change proportionate to that noted in humans with chronic heart failure. iii The proportion of ISO-treated rats with LV chamber diameters, and LV V0 values above the 95% confidence interval for Saline-treated rats was markedly greater than the proportion of Saline-treated rats above their own 95% confidence intervals. Moreover, the proportion of ISO-treated rats with FSend, LV Ees and LV En values below the 95% confidence interval for Saline-treated rats was markedly greater than the proportion of Saline-treated rats below their own 95% confidence intervals. Following a 6 month period of ISO administration and a subsequent period of withdrawal of ISO administration for a further 4 months, LV chamber diameters, LV V0, FSend, LV Ees and LV En were all noted to be similar to age-matched Saline+Recovery control rats. Indeed, the increases in LV V0 observed after 6 months of ISO administration were completely reversed (ISO+Recovery=0.21±0.02 vs Saline=0.23±0.02, p<0.001). The proportion of ISO+Recovery rats with LV chamber diameters, and LV V0 values above the 95% confidence interval for the Saline+Recovery rats was similar to the proportion of Saline+Recovery rats above their own 95% confidence intervals. Moreover, the proportion of ISO+Recovery rats with FSend, LV Ees and LV En values below the 95% confidence interval for Saline+Recovery rats was similar to the proportion of Saline+Recovery rats below their own 95% confidence intervals. Chronic ISO administration and the withdrawal of ISO administration was not associated with changes in myocardial necrosis (pathological score and myocardial collagen concentrations). In conclusion, marked cardiac dilatation and pump dysfunction produced by chronic β-adrenergic receptor activation can be completely reversed by withdrawal of the excessive adrenergic stimulus. These data highlight the importance in chronic heart failure of achieving complete blockade of the pathways activated by excessive β-adrenergic receptor stimulation even in individuals with advanced cardiac dilatation.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy. Johannesburg, South Africa 2017. / Almost half of all cases of heart failure have a preserved ejection fraction. However, therapy targeting the mechanisms of this disorder has not improved outcomes. Left ventricular (LV) diastolic dysfunction is a characteristic feature of heart failure with a preserved ejection fraction. A more sound understanding of the mechanisms responsible for LV diastolic dysfunction produced by risk factors may lead to better approaches to preventing this syndrome. Although obesity is thought to be a major risk factor for LV diastolic dysfunction, this does not occur in all obese individuals. In the present thesis I have demonstrated in 737 randomly recruited participants from a community sample of African ancestry, that the relationship between insulin resistance (homeostasis model) and LV diastolic function, as assessed from trans-mitral velocity (E/A) and tissue Doppler imaging of the lateral and septal walls of the LV (e’ and E/e’), is markedly altered by the presence of a more concentrically remodelled LV (as indexed by LV relative wall thickness [RWT]). Importantly, insulin resistance was only associated with LV diastolic function or dysfunction in those with an RWT above a threshold value. In contrast no interactive effects on LV diastolic function between either blood pressure or age and RWT were noted. These data therefore suggest that obesity will only translate into LV diastolic dysfunction if it is associated with insulin resistance and a concentrically remodeled LV. Although hypertension is thought to play an important role in contributing to LV diastolic dysfunction, the pulsatile hemodynamic change primarily responsible for this effect is uncertain. In 524 randomly selected individuals from a community sample I have demonstrated that independent of confounders including left ventricular mass and RWT, aortic backward wave pressure effects (as determined using wave separation analysis), antedate the impact of aortic stiffness (indexed by aortic pulse wave velocity) or the factors determined by aortic stiffness (the time of backward wave return or forward wave pressures) on LV filling pressures (E/e’). These data therefore suggest that to adequately prevent LV diastolic dysfunction, targeting aortic backward wave pressures may be required. As conventional risk factors account for only a portion of the inter-individual variations in LV diastolic function, it is thought that the genetic factors may play a iv significant role. In 694 randomly recruited participants of African ancestry belonging to nuclear families, I demonstrated that independent of conventional risk factors, heritability accounts for approximately 50% of the variation in LV RWT, an important LV structural determinant of LV diastolic function. Moreover, in 442 randomly recruited individuals of African ancestry belonging to nuclear families, I also demonstrated that heritability accounts for approximately 50% of the variation in the index of LV filling pressures, E/e’, independent of LV mass or RWT remodeling and aortic function. These data provide strong evidence that genetic factors responsible for LV diastolic dysfunction and the structural determinants thereof should be sought. In conclusion, the results provided in the present thesis have advanced our knowledge of possible pathophysiological mechanisms that play a role in the development of LV diastolic dysfunction and hence possibly heart failure with a preserved ejection fraction. / MT2017

Heart failure is a devastating disease which despite significant advances in therapy over the past two decades still results in a poor prognosis. Metabolic dysregulation is associated with heart failure; however, it remains unclear whether isoproterenol exerts deleterious effects through altered metabolic regulation. Whether metformin, a metabolic modulator, prevents isoproterenol-induced heart failure is unknown. The aim of this study was to determine whether metformin prevents functional and metabolic changes seen in the isoproterenol model of heart failure. Male Sprague-Dawley rats were administered isoproterenol and metformin for seven months. Thereafter, cardiac dimensions, metabolic gene expression and myocardial structural changes were assessed. Chronic administration of isoproterenol induced left ventricular dilatation and pump dysfunction and mitochondrial structural derangement. No changes were seen in metabolic gene expression. However, co-administration of metformin prevented isoproterenol-induced heart failure and retained mitochondrial structural arrangement. Therefore, cardiac dilatation and pump dysfunction induced by chronic administration of isoproterenol can be prevented by co-administering metformin.

MSc (Med), University of the Witwatersrand, Faculty of Health Sciences, School of Physiology / The role of metabolic remodelling in heart failure is not fully understood, significant evidence has accumulated to suggest that it may be central to the development of left ventricular (LV) remodelling and LV dysfunction. Heart failure is also characterized by sustained neurohumoral activation. We have previously demonstrated that chronic low dose administration of isoproterenol contributes to cardiac structural and functional changes, however, little is known about metabolic and mitochondrial changes that may accompany the development of isoproterenol-mediated heart failure. In the current study, we hypothesised that metabolic dysregulation and loss of mitochondrial integrity mediates left ventricular hypertrophy (LVH) and left ventricular (LV) systolic dysfunction in the isoproterenol model of heart failure. Furthermore, modulation of expression of key metabolic genes and mitochondrial transcription factors by fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, will preserve left ventricular function. To achieve this, male Sprague-Dawley rats weighing between 250-300g were injected with low dose isoproterenol (0.04 mg.kg-1.day-1) and/or administered with fenofibrate (100 mg.kg-1.day-1) for five weeks. Thereafter, metabolic substrates such as glucose, FFAs and TG concentrations were obtained. Left ventricular hypertrophy (LVH) and cardiac function were assessed using echocardiography. Expressions of metabolic and mitochondrial genes such as PPARα, AMP-activated protein kinase alpha 2 (AMPKα2), PPARγ coactivator-1 (PGC-1α), mitochondrial transcription factor (TFAM) and nuclear respiratory factor-1 (NRF-1) were determined using real-time polymerase chain reaction. Mitochondrial integrity was assessed using transmission electron microscopy. Administration of isoproterenol significantly increased left ventricular mass (LVM) and decreased endocardial fractional shortening (FSend); isoproterenol also induced myofibrillar iv derangement, mitochondrial derangement and cristae disruption. Fenofibrate prevented isoproterenol-induced increase in LVM and improved FSend. Fenofibrate co-administration prevented loss of mitochondrial integrity possibly via TFAM. Furthermore, fenofibrate may have induced metabolic remodelling via upregulation of AMPKα2 and downregulation of cardiac PPARα and PGC-1α. Therefore our data suggests that fenofibrate-mediated cardioprotection against isoproterenol-induced LVH and LV systolic dysfunction was accompanied by metabolic switching and preservation of mitochondrial integrity. While isoproterenol did not induce any changes in metabolic genes, fenofibrate-mediated cardioprotection could have been through changes in metabolic genes.

O objetivo deste trabalho foi avaliar o status de ferro (Fe) em pacientes hospitalizados por insuficiência cardíaca avançada. Participaram do estudo 50 pacientes, sendo que 24 foram diagnosticados com anemia e desses 8 apresentam anemia por deficiência de ferro. Foram incluídos no estudo indivíduos do sexo masculino, com idade entre 30 e 60 anos e fração de ejeção do ventrículo esquerdo (FEVE) <0,45. Para análise dos níveis séricos de hepcidina, interleucina 6 (IL-6), fator de necrose tumoral-alfa (TNF-&#945;) e eritropoietina os pacientes foram submetidos a coleta de sangue após jejum de 8 horas. Os parâmetros hematológicos e bioquímicos foram avaliados por meio dos resultados de exames laboratoriais rotineiramente realizados e foram verificados em prontuário médico. O consumo alimentar foi avaliado pelo método direto de pesagem dos alimentos. Os resultados entre os grupos foram comparados pelo teste de Mann Whitney e foram feitas correlações de acordo com o teste de Spearman e teste de Pearson. Não foram encontradas diferenças nos níveis séricos de hepcidina entre os anêmicos com e sem deficiência de ferro. Houve correlação negativa entre a concentração de hepcidina e a de ferritina entre os anêmicos com deficiência de ferro e não foi observada correlações da hepcidina com os outros parâmetros inflamatórios. A desnutrição e a baixa ingestão calórica foram frequentes e não foi verificada baixa ingestão alimentar de ferro. Não foi caracterizada anemia de doença crônica com base na concentração sérica de hepcidina. / The aim of this study was to evaluate the iron status in hospitalized with advanced heart failure. 50 patients participated of this study, 24 of them have been diagnosed with anemia and among these 8 were identified with iron deficiency anemia. Males, aged between 30 and 60 years old, with left ventricular ejection fraction (LVEF) <0,45 were include in the study. For analysis of serum levels of hepcidin, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-&#945;) and erythropoietin patients underwent blood collection after 8 hours fasting. Haematological and biochemical parameters were obtained laboratory tests routinely performed and were checked in medical records. Food consumption was evaluated by direct weighing method. The results the groups anemic and nonanemic with or without iron deficiency groups were compared by Mann Whitney test and correlations was made according to the Spearman`s and Pearson`s tests. No differences were found in serum hepcidin levels between anemic patients with or without Fe deficiency. There was a negative correlation between hepcidin and ferritin iron-deficiency patients, and correlations of hepcidin with other inflammatory factors were not significant. Malnutrition and low caloric intake were frequent and dietary intake of iron intake was adequate. Chronic disease anemia was not characterized based on serum hepcidin.