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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23795号 / 医博第4841号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 石見 拓, 教授 湊谷 謙司, 教授 山本 洋介 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Rationale: Pathological remodeling of the heart is a hallmark of chronic heart failure (HF) and these structural changes further perpetuate the disease. Cardiac fibroblasts are the critical cell type that is responsible for maintaining the structural integrity of the heart. Stress conditions, such as a myocardial infarction (MI), can activate quiescent fibroblasts into synthetic and contractile myofibroblasts. G protein-coupled receptor (GPCR) kinase (GRK) 5 is an important mediator of cardiovascular homeostasis through dampening of GPCR signaling, and is expressed in the heart and upregulated in human HF. Of note, GRK5 has been demonstrated to translocate to the nucleus in cardiomyocytes in a calcium- calmodulin (Ca2+-CAM)-dependent manner, promoting hypertrophic gene transcription through activation of NFAT. Interestingly, NFAT is also involved in fibroblast activation. GRK5 is highly expressed and active in cardiac fibroblasts (CFs), however its pathophysiological role in these crucial cardiac cells is unknown. Objective: The aim of this study is to elucidate the role of GRK5 in the activation of cardiac fibroblasts in vitro and cardiac fibrosis after injury in vivo. Methods and Results: We demonstrate using adult cardiac fibroblasts that genetic deletion of GRK5 inhibits Angiotensin II (AngII) mediated fibroblast activation. Fibroblast-specific deletion of GRK5 in mice decreased fibrosis and cardiac hypertrophy after chronic AngII infusion compared to non-transgenic littermate controls (NLCs). Fibroblast-specific deletion of GRK5 was also protective in mice after ischemic injury as they presented with preserved systolic function, decreased fibrosis, and decreased hypertrophy compared to NLCs. Mechanistically, we show that nuclear translocation of GRK5 is involved in fibroblast activation. Conclusions: We present novel data demonstrating that GRK5 is a regulator of fibroblast activation in vitro and cardiac fibrosis in vivo. This adds to previously published data which demonstrates the potential beneficial effects of GRK5 inhibition in the context of cardiac disease. / Biomedical Sciences

Recent work has found that a frequency domain and time domain analysis of the heart rate variability signals can provide significant insights into function of the heart in healthy subjects and in patients with heart disease. Patients with congestive heart failure are an important clinical health issue and it is hoped that this work will contribute towards gaining knowledge of this debilitating pathological condition. Our laboratory has recently acquired more than three thousand 24-hour ECG tapes recorded during called Study of Left Ventricular Dysfunction (SOLVD). The SOL VD trial was conducted between 1987-1990 to test the efficacy of a medication called, Enalapril, to treat patients with heart failure. There were an equal number of patients with (group A) and without overt heart failure (group B). The work reported in this thesis describes the development of a hardware and software framework used to analyze the ECG signals recorded on these tapes. Primary objective of this work was to develop and test a system which would assist in analyzing the above tapes so as to examine if there are differences between two groups using the HRV parameters from both frequency and time domain. The research was conducted in three steps: Hardware design, software and algorithm development and finally the validation phase of the design, to test the usefulness of the overall system. The tapes were replayed on a tape recorder and the ECG was digitized at a rate corresponding to 500 samples/second. Labview software was invoked for this task. Secondly a set of algorithms were developed to perform QRS-detection and QT-interval identification. The detection algorithms involved placing critical ECG fiducials onto the ECG waveform through the use of a trained model. The model construction used patient specific pre-annotated data coupled with statistical and genetic algorithm techniques. The beat-to-beat HRV signal was thus generated using the annotation data from the ECG. Frequency domain indices were obtained using power spectral computation algorithms while time domain statistical indices were computed using standard methods. QT-interval algorithms were tested using a set of manually and automatically tagged set of beats from a sample of subjects. For the third part of this research, i.e. validation phase, we set up a test pool of 200 tapes each from patients with overt heart failure and with no heart failure, recorded at the baseline before the subjects entered the study. This phase of the study was conducted with the help of a statistician in a blinded fashion. Our results suggest that there is significant difference between frequency domain and time domain parameters computed from the HRV signals recorded from subjects belonging to group A and group B. The group A patients had a lot of ectopic beats and were challenging to analyze. These results provide a confirmation of our analytical procedures using real clinical data. The QT-analysis of the ECG signals suggest that automatic analysis of this interval is feasible using algorithms developed in this study. / Thesis / Master of Applied Science (MASc)

The purpose of this investigation was to examine the potential differences in autonomic nervous system adaptations, as assessed by heart rate variability techniques, between a group of stabilized CHF patients randomized to either a training group (aerobic+resistance) or a control group (usual care). In a single-blind, randomized controlled trial of 3-months of supervised exercise training and a further 3-months of home-based exercise, 28 stabilized CHF patients (NYHA 1-111) were randomized to either a training (AERWT) (n=16;11M,5F; age, 64.9±2.3; LVEF, 29.4±1.7%) or usual care (UC) (n=12; 10M,2F; age, 58.0±2.8; LVEF, 24.4±2.0%) group. Upon completion of the supervised exercise program, the AERWT group increased peak oxygen uptake (V02) (13.2±0.5 to 15.5±0.84 ml/kg/min, p<0.05), and single-arm curl scores (16.2±2.8 to 19.2±3.3 kg, p<0.05) significantly compared to the UC group, without any deleterious effect upon clinical status or left-ventricular function (LVEF: 31.3±1.7 to 33.2±1.9%, p=0.99). Physical training reduced expired ventilation and carbon dioxide based on successive workloads during symptom-limited incremental cycle ergometry in the AERWT group; however, this was found to be non-significant, in addition to changes in resting heart rate, anaerobic threshold, maximal exercise duration, maximal power output, and double product following training. Supine, resting power spectral indices remained unchanged from baseline to 6-months in both groups, as did the recovery of power spectral indices during supine rest following a symptom-limited incremental cycle ergometry test. A qualitative comparison of the power spectral changes from supine to standing revealed no significant differences between groups with respect to improvements in the baroreceptor response to orthostatic stress. Time domain parameters, derived from 24-hour ambulatory bolter monitoring, were also obtained at baseline, 3-months, and 6-months. The indices believed to be largely representative of vagal modulation, SDNN-Index, r-MSSD, and pNN50, tended to increase in the AERWT group with increased participation in the training program; however, the results did not obtain statistical significance (p=0.07). In addition, there were no significant changes in mean 24-hour heart rate or NN-interval, SDNN, or SDANN in the AERWT group (p=0.21). The present investigation revealed some evidence to suggest that exercise training in selected populations of CHF patients results in favourable changes in vagal modulation and baroreceptor sensitivity; however, unlike Coats et al. (1992), the present investigation failed to note any significant alterations in HRV frequency domain indices as a result of exercise training despite identical improvements in peak V02. The lack of significant findings in both the frequency and time domain HRV data could indicate that the autonomic dysfunction is so widespread and rampant in CHF that we cannot induce alterations through training as would be demonstrated in normal, healthy controls. In effect, these findings reinforce the hypothesis that in CHF the heart is the 'slave' of the periphery, and that due to the progressive lack of neural control of both the heart and circulation, in addition to an impairment in pump function, that the only effective means of improving physiological variables is through changes at the peripheral level. / Thesis / Master of Science (MS)

Bakgrund: Hjärtsvikt är en sjukdom som påverkar cirka 64 miljoner människor i världen. Hjärtsvikt kan visa sig med eller utan symtom och är en stor anledning till inläggning på sjukhus. För att personer ska kunna leva med sin hjärtsvikt används både medicinsk och icke-medicinsk behandling, det vill säga egenvårdsåtgärder för symtomlindring. Syfte: att beskriva personers erfarenheter av egenvård vid hjärtsvikt. Metod: litteraturöversikt med kvalitativ metod med en induktiv ansats genomfördes baserad på tolv vetenskapliga artiklar tagna från CINAHL och Medline. Artiklarna analyserades med hjälp av Fribergs (2022) innehållsanalys. Resultat: Det framkom tre huvudteman med subteman. Behov av socialt stöd (stöd från vårdpersonal och stöd från relationer), fysiska svårigheter (att hantera det dagliga livet och den fysiska påverkan) och psykiska svårigheter (att vara självständighet och att lära känna sin sjukdom). Slutsats: Personernas erfarenheter skiljer sig gentemot varandra. Den gemensamma nämnaren är den sociala interaktionen, hur stödet av omgivningen påverkar personens motivation. Det är viktigt med den personcentrerade vården för att hjälpa personerna med hjärtsvikt med deras besvär och utmaningar i vardagen gällande egenvårdsåtgärder. / Background: Heart failure is a disease that affects approximately 64 million people worldwide. Heart failure can manifest with or without symptoms and is a major cause of hospital admissions. Both medical and non-medical treatments, such as self-care measures for symptom relief, are used to help individuals live with their heart failure. Purpose: To describe individuals' experiences of self-care in heart failure. Method: A literature review using a qualitative method with an inductive approach was conducted, based on twelve scholarly articles retrieved from CINAHL and Medline. The articles were analyzed using Friberg's (2022) content analysis. Results: Three main categories with subcategories emerged. These were the need for social support (support from healthcare professionals and support from relationships), physical difficulties (managing daily life and physical impact), and psychological difficulties (maintaining independence and understanding one's illness). Conclusion: Individuals' experiences vary, but a common theme is the importance of social interaction and how support from their environment influences their motivation. Person-centered care is crucial in assisting individuals with heart failure in managing their symptoms and daily challenges related to self-care measures.

Yes / Technology has the potential to provide support for self-management to people with congestive heart failure (CHF). This paper describes the results of a realist evaluation of the SMART Personalised Self-Management System (PSMS) for CHF. Methods The PSMS was used, at home, by seven people with CHF. Data describing system usage and usability as well as questionnaire and interview data were evaluated in terms of the context, mechanism and outcome hypotheses (CMOs) integral to realist evaluation. Results The CHF PSMS improved heart failure related knowledge in those with low levels of knowledge at baseline, through providing information and quizzes. Furthermore, participants perceived the self-regulatory aspects of the CHF PSMS as being useful in encouraging daily walking. The CMOs were revised to describe the context of use, and how this influences both the mechanisms and the outcomes. Conclusions Participants with CHF engaged with the PSMS despite some technological problems. Some positive effects on knowledge were observed as well as the potential to assist with changing physical activity behaviour. Knowledge of CHF and physical activity behaviour change are important self-management targets for CHF, and this study provides evidence to direct the further development of a technology to support these targets.