The tumour suppressor p27kip1 (p27) is a potent inhibitor of cell growth and proliferation. We identified NF-κB activator, IKKα, as a novel interacting partner of p27 in a protein microarray screen. Both the IKKα and IKKβ components of the IKK complex were mapped to the C-terminal domain of p27. To investigate the physiological function of the p27-IKK interaction, we employed a well-established model of LPS-induced sepsis which is known to activate the IKK/NF-κB pathway. Lentivirally-mediated overexpression of p27 blocked LPS activation of NF-κB. Furthermore, in LPS-injected animals transduced with TAT-p27, a significant improvement in the left ventricular function of the heart was observed. TAT-p27 treatment was also shown to attenuate the endotoxin effect and significantly improve survival compared to both saline and TAT-LacZ controls. Our results indicate that p27 attenuates inflammation, possibly through inhibiting the IKK-dependent activation of NF-κB, thus supporting a novel link between both cell cycle regulation and inflammation.

Sodium restriction is the primary dietary therapy for individuals with heart failure (HF); however, there is little information available to support or refute the use of sodium restriction to manage HF. The overall goal of this work was to generate data related to dietary sodium in patients with chronic HF that would contribute to the development of evidence-based guidelines. The specific objectives were to investigate the optimal methods for measuring sodium intake in HF, to describe the habitual consumption of sodium and other nutrients in HF, and to evaluate the relationship between sodium intake and clinical outcomes in HF. We studied stable ambulatory HF patients who were optimally medicated and participating in multidisciplinary HF programs. We determined that: (1) a strong relationship exists between 24-hour urine collections and food records for sodium intake assessment in non-HF cardiac patients and HF patients not taking loop diuretics. However, the relationship between urinary sodium excretion and sodium intake in HF patients taking loop diuretics was disturbed, suggesting that food records may be a better method for estimating sodium intake in this group. (2) Mean sodium intake in HF and non-HF cardiac patients was similar, and approximately half of patients in each group had sodium intake levels that exceeded the Dietary Reference Intakes tolerable upper level of 2300 mg/d. We also found that both groups had inadequate intakes of several nutrients, including potassium, calcium, magnesium, folate, and vitamin D and E. (3) Finally, we showed that a high sodium diet (>2800 mg/day) in HF was associated with risk of acute decompensated HF, all-cause hospitalization, and all-cause mortality over a median 3 year follow-up period. This is the first published study that prospectively related sodium intake to clinical outcomes in HF. In summary, these data provide novel contributions related to the measurement of sodium intake that can be used in clinical or academic settings. We also describe inadequacies in intake of several vitamins and minerals, which could be addressed through dietary counselling. Finally, we importantly offer insight into a threshold of sodium intake (>2800 mg/day) that could contribute to adverse clinical outcomes in HF.

Bakgrund: Hjärtsvikt är en kronisk sjukdom som påverkar livet både för den drabbade och dess närstående. Prognosen är allvarlig och slutskedet kan liknas vid cancersjukdom. Allt fler vårdas i hemmet, vilket ställer krav på egenvård och närståendes delaktighet. Närstående är ofta inte förberedda för den nya ansvarsfyllda rollen som sjukdomen kan medföra. Syfte: Syftet var att beskriva närståendes upplevelser av att leva nära en person med hjärtsvikt. Metod: En allmän litteraturstudie genomfördes och baserades på tolv kvalitativa och tre kvantitativa vetenskapliga artiklar. Resultat: Det framkom fyra kategorier av upplevelser i resultatet; ovisshet, förändrade roller, social påverkan samt fysisk och psykisk påverkan, som var för sig och tillsammans kunde leda fram till att livet förändrades för närstående till personer med hjärtsvikt. Slutsats: Hjärtsvikt förändrar livet för närstående och innebär nya krav och anpassning i vardagen. Hälsan påverkas både fysisk och psykiskt. Risken att drabbas av egen ohälsa ökar. Konsekvenserna av att vara närstående är flera särskilt då närstående själva ofta är äldre och har egna hälsoproblem. För att kunna stödja närstående måste sjuksköterskan förstå deras upplevelser. Att synliggöra dem kan främja både den sjuke och dess närstående. / Background: Heart failure is a chronic disease and effects life both for the ill person and their family. The prognosis is serious and can be compared with cancer. More people receive care in their home which increases the demands in self-care and their families’ participation. With the disease come new responsibilities, which families aren’t always prepared for, including new roles. Aim: To describe experiences of living close to a person with heart failure. Method: A literature review was conducted which was based on twelve qualitative and three quantitative scientific articles. Results: Four main categories were identified: experience of uncertainty, changing roles, physical and psychological effects and social effects. Conclusion: Heart failure changes the lives of the families. It involves new demands and adjustment in every-day-life and affects both their physical and mental health. The risk of developing health problem increases. The consequences of living close to a person with heart failure are many, especially if they are older and have health problems of their own. Nurses need to be aware of families’ experiences to be able to support them. We believe that both the ill person and their family can benefit from nurses making their experiences visible.

Heart failure is a chronic condition that increases the risk for death and disability. Beta blockers and ACE inhibitors have become standard treatments in heart failure because clinical trials have demonstrated their beneficial effect on mortality and morbidity in these patients. As not much is known about adherence to these medications, the main objectives of this project were to determine long term adherence to ACE inhibitors and beta blockers and determine how various degrees of adherence to a beta blocker can affect major health outcomes in patients with heart failure.<p> Data was obtained from Saskatchewan health from January 1, 1994 to December 31, 2003 for all heart failure patients from their first hospitalization for heart failure. Adherence was calculated using the fill frequency measure of adherence, and all survival analyses were completed using the Cox proportional hazards model.<p>Although 14, 000 patients were admitted to hospital for a first admission for heart failure, only 1143 subjects started a beta blocker and 5084 subjects started an ACE inhibitor within 3 months of the index hospitalization. Within the first year, adherence was excellent for both beta blockers (80.8 percent) and ACE inhibitors (82.5 percent). The proportion of patients remaining adherent slowly decreased to reach approximately 60 percent, for both medication classes, after 4 years. There was no significant difference in all-cause mortality between patients with high adherence and low adherence, but there appeared to be a trend towards decreased survival time in those remaining adherent throughout the study period [HR = 1.18 (95% CI: 0.98 to 1.43; p=0.07)].<p>Since the overall rate of adherence to beta blockers was excellent in most patients during the first year, it is possible that non-adherence is not responsible for a significant burden of mortality in Saskatchewan heart failure patients, and perhaps and the focus of quality improvement should be optimal prescribing of evidence-based therapies, and continued adherence over time.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 122-130). Available also in a digital version from Dissertation Abstracts.

Chronic heart failure is one of the commonest fatal diseases in the world. Much work has been done to reveal its complicated pathogenesis and develop effective therapy. Xinmailong (XML), a compound extracted from Periplaneta americana, has been launched on the market in Mainland China as a proprietary medication for treating patients with chronic heart failure. Although it is highly effective, its mechanism of action is still not completely understood. In this study, the results of calcium (〖Ca〗^(2+)) imaging demonstrated that XML increased electrical impulse-induced intracellular calcium ([〖Ca〗^(2+)]i), in H9c2 cells, an rat embryonic cardiomyocytes cell line. This effect was dependent on extracellular 〖Ca〗^(2+) but not the 〖Ca〗^(2+) store from sarcoplasmic reticulum because XML had no effect on thapsigargin -induced 〖Ca〗^(2+) release. The effect of XML was inhibited by ML218-HCl but not nimodipine, indicating that XML interacted with T-type 〖Ca〗^(2+) channels but not L-type 〖Ca〗^(2+) channels. Unlike KB-R7943, which is a sodium calcium exchanger inhibitor, XML did not affect [〖Ca〗^(2+)]i in the absence of electric stimulation, implying that XML did not work on sodium calcium exchanger. Ouabain, a sodium-potassium ATPase inhibitor, increased the electrical impulse-induced [〖Ca〗^(2+)]i and the effect of ouabain and XML were not additive, suggesting that the site of action of ouabain and XML was overlapped. Biochemical assay on phosphate concentration showed that XML was able to inhibit the activity of sodium-potassium ATPase. Our study also demonstrated that XML reduced the production of reactive oxygen species in H9c2 cells. Western blotting showed that such antioxidant properties mechanism might involve the increased expressions of antioxidant enzymes including superoxide dismutase 1, superoxide dismutase 2 and heme oxygenase 1. In conclusion, our study has provided evidence that XML increases [〖Ca〗^(2+)]i level by activating T-type 〖Ca〗^(2+) channels and inhibiting sodium-potassium ATPase. The antioxidant effect of XML may also contribute to the cardioprotective effect of XML but further investigation is required. / published_or_final_version / Pharmacology and Pharmacy / Master / Master of Philosophy

Η γκρελίνη είναι ένα ακυλιωμένο πεπτίδιο που κατά κύριο λόγο παράγεται από το στόμαχο και αποτελεί το φυσικό μόριο-αγωνιστή του μέχρι πρόσφατα ορφανού υποδοχέα GHSR-1a (growth hormone secretagogue receptor type 1a).Η γκρελίνη διαθέτει ισχυρή ικανότητα απελευθέρωσης της αυξητικής ορμόνης καθώς επίσης ασκεί πολλαπλές δράσεις στο ΚΝΣ και σε άλλους ιστούς και όργανα που προκαλούν διέγερση της όρεξης, ρύθμιση του ενεργειακού ισοζυγίου, επίδραση στο γαστρεντερικό σύστημα και στην παγκρεατική λειτουργία.Επιπρόσ- θετα διαμεσολαβεί καρδιαγγειακές δράσεις όπως μείωση των περιφερικών αντιστάσεων, αύξηση της καρδιακής παροχής σε υγιή άτομα και σε ασθενείς με καρδιακή ανεπάρκεια,εξα- σθένηση της καρδιακής καχεξίας, αντιαποπτωτική δράση στην καρδιακή ανεπάρκεια και αντιφλεγμονώδη δράση στο σχηματισμό της αθηρωματικής πλάκας. Η παρούσα εργασία,προσδιορίζοντας τα επίπεδα της γκρελίνης σε ασθενείς με οξεία πρωτοεμφανιζόμενη ή απορρύθμιση χρόνιας συστολικής καρδιακής ανεπάρκειας και μετά την συσχέτισή τους με διάφορες κλινικές,αιμοδυναμικές και υπερηχογραφικές παραμέτρους σε μια περίοδο παρακολούθησης 6 μηνών-1 έτους και την εφαρμογή βέλτιστης εξατομικευμένης φαρμακευτικής αγωγής ,κατέληξε στο συμπέρασμα ότι η παρατηρούμενη διαχρονική αύξηση των επιπέδων της γκρελίνης σε συνδυασμό με την βελτίωση των ανωτέρω παραμέτρων προτείνει στην γκρελίνη ρόλο αιτίου ή αποτελέσματος στην πορεία βελτίωσης της καρδιακής ανεπάρκειας. / Ghrelin is an acylated peptide that mainly is produced from the stomach and constitutes the natural molecule-ligand of until recently orphan receptor GHSR-1a(growth hormone secretagogue receptor type 1a).Ghrelin allocates powerful ability of release of the growth hormone and also practices multiple actions in the CNS and in other tissues and organs that cause excitation of apetite, regulation of energy balance, effect in the gastrointestinal system and in function of pancreas.In addition, ghrelin mediates cardiovascular actions as reductions of systemic resistances, increase of cardiac output in healthy individuals and in patients with heart failure, attenuation of cardiac cachexia, inhibition of the apoptosis of myocardial cells in the heart failure and anti-inflammatory action in the progression of atherosclerosis. The present work, determining the levels of ghrelin in patients with acute de novo or decompensation of chronis systolic heart failure and afterwards their cross-correlation with various clinics, haemodynamic, and other parameters of the cardiac ultrasound in a period of follow-up of 6 months-1 year and the application of most optimal individualized pharmaceutical treatment, led to conclusion that the observed diachronic increase of levels of ghrelin in combination with the improvement of above parameters proposes in ghrelin role of reason or result in the course of improvement of heart failure.

This study had two purposes: 1) to compare the difference between home health care only and home health care plus telemonitoring on heart failure patients' symptom burden, self-care of heart failure and re-hospitalization; and 2) to explore which patient characteristics might moderate telemonitoring's impact.Heart failure has emerged as a major public health burden. Like other chronic conditions, heart failure patients have an important role to play in the day-to-day management of their condition. One of the principal reasons for introducing telemonitoring in home health care was to increase heart failure patients' capacity to self-manage their conditions at home.This study used a prospective, non-experimental, comparative, descriptive design. A total of 68 participants were recruited with 34 in each group. Symptom burden and self-care of heart failure were measured on enrollment and 40 days later. Hospitalization was measured as an event that either occurred or did not occur.Although no between-group differences in symptom burden were found, both groups showed significant decreased symptom burden over the 40-day period. Of the three self-care measures, only self-care maintenance differed significantly between the two groups at the 40-day follow-up (p<.05). Only the participant's functional status had significant moderator effect on the relation between type of service received and self-care maintenance (p<.05).The addition of telemonitoring produced similar outcomes to regular home health care, except for self-care maintenance. Like most prior study, this study focused on evaluating the overall relationship between telemonitoring and outcomes without concern for the transformation process. Although these evaluation were able to provide an overall assessment of whether or not the telemonitoring program worked, they cannnot identify the underlying mechanisms that generate the effects. Without knowing what make the program work or not work, it is difficult to pinpoint what needs to be done for future improvement. A theory-oriented evaluation will be needed in future research. Theory-oriented evaluation not only allow reseachers to clarify the connection between a program's operation and its effect, but also to specify intermediate effects of a program that might become evident and measurable.

In previous studies on heartbeat series, it has been proposed that the healthy heartbeat pattern represents complex nonlinear dynamics, and such cardiac nonlinearity may be used as a clinical indicator for the diagnosis of certain types of heart disease. However, it is still not quite clear whether there is any difference among the heartbeat series of patients with congestive heart failure (CHF), or whether cardiac nonlinearity represents a severe heart disease situation. In the present study, parallel cascade identification (PCI), which frequently requires only short stretches of data to obtain highly promising results, is used to distinguish severe congestive heart failure, a clinical situation associated with a high-risk of sudden death, from low-risk CHF. Parallel cascade identification is an accurate and robust method for identifying dynamic nonlinear systems. The PCI algorithm combined with a specified statistical test may be used as a severe congestive heart failure marker by comparing a nonlinear model with a “linear” model (more precisely, a first-order Volterra series). In this thesis, PCI is applied to distinguish R-R wave intervals of CHF patients who died from those of patients who survived in a 5-year study. The detection accuracy of the PCI detector is evaluated over a first set of 49 patients, and then over a larger set of a further 352 patients, and consistent results are obtained between the two sets. Over the larger set, Matthews' correlation coefficient of nonlinearity with unfavorable outcome (death) is , sensitivity for predicting unfavorable outcome is , while the specificity is . The R-R wave interval exhibits nonlinearity in patients who died during the 5-year study. However, typically nonlinearity cannot be detected in patients who survived during the study. These findings show that for patients with congestive heart failure, nonlinearity is associated with unfavorable outcome (death), while patients for whom nonlinearity cannot be detected overwhelmingly have good outcomes. This is significant for clinical diagnosis and prognosis of severe congestive heart failure. / Thesis (Master, Electrical & Computer Engineering) -- Queen's University, 2007-09-28 11:54:57.695

Heart failure (HF) is a prevalent disease in society which is associated with decreased cardiac output. This thesis describes the proteomic analysis of cardiac tissue obtained from HF patients and a transgenic animal model of HF. Initial experiments optimized one proteomic technology, 2-dimensional gel electrophoresis (2-DE), to maximize the number of proteins which could be observed / resolved from human cardiac tissue. Protein abundance changes in cardiac tissue between normal patients and those with a diagnosis of ischemic cardiomyopathy were determined by performing 2-DE and identifying proteins by mass spectrometry. HF patients had a reduced abundance of proteins involved in energy production and the sarcomere. Sarcomeres contain the myofilament subproteome consisting of thick and thin filaments with the thick filaments primarily myosin. Thick and thin filament undergo Ca2+ induced ATP hydrolysis to form crossbridge cycles, resulting in muscle contraction. An assembly chaperone for myosin, UNC-45B, was found to be increased in HF patients. Western blot analysis confirmed that the abundance of UNC-45B was increased in different etiologies of heart failure. Follow up physiological measurements demonstrated that UNC-45B is most likely a protein necessary for transcriptional control of the α-isoform of myosin heavy chain. In a second proteomics study, abundance changes occurring in a pacing induced model of HF in wild-type (WT) and transgenic (TG) rabbits with increased expression of the α-isoform of myosin heavy chain were examined. WT and TG rabbits had a different response in their myofilament and intermediate filament abundance changes following induction of HF. TG rabbits had a decreased abundance of heat shock proteins and non-sarcomeric associated desmin. As well, TG rabbits had an increased ratio of actin:myosin heavy chain and UNC-45B suggesting an altered ratio of thick to thin filaments. In conclusion, an altered abundance of contractile proteins, regulated in part by UNC-45B, may be one cause of the contractile dysfunction which occurs in HF. / Thesis (Ph.D, Physiology) -- Queen's University, 2007-12-21 09:19:45.172