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Aim: The aim of the study was to investigate the degree of adherence and non-adherence to treatment regimen in the population with heart failure, as well as to explore relationships to symptom burden and hospitalization-frequency. Introduction: Heart failure – a chronic disease with a somber prognosis and high mortality, incidence and prevalence increasing world-wide. Adherence to treatment regimen mitigates symptom flare-up, increases life quality and impedes hospitalizations. Non-adherence is a global problem, historically underestimated and difficult to measure. The level of non-adherence to medical treatment in the heart failure-population is about 50 %, degree of non-adherence from a wider perspective implicates a gap of knowledge. Methods: A cross-sectional survey-study was conducted via the electronic survey: ”Living with heart failure”. Selection was consecutive, based on patients visiting the Cardiac outpatient-clinic, in a Swedish University Hospital. Data was transferred to descriptive statistics using the statistical processing program SPSS. Results: 479 individuals participated, non-adherent were 73,6 % and adherent 26,4 %. There was a significant difference between symptom burden among the non-adherent and the adherent. A trend also appeared between low hospitalization-frequency, high degree of adherence and low symptom burden, an equivalent trend among the most frequently hospitalized which exhibited the lowest degree of adherence and the most severe symptom burden. Conclusion: The results pinpoint the need to further draw attention to non-adherence, repeatedly representing the majority of the population. With a patient-centered approach nurses/caregivers could have an empowering effect on the patient´s ability to health literacy and thus promote conditions for adherence.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23771号 / 医博第4817号 / 新制||医||1056(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 藤渕 航, 教授 阪上 優, 教授 小杉 眞司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23809号 / 医博第4855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 渡邊 直樹, 教授 浅野 雅秀, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p><strong>Background:</strong> Heart failure (HF) constitutes an important growing medical and economic problem with high prevalence and mortality. Prognosis assessment remains a challenge because of the dynamic nature of HF and the existence of some unexplained variation in outcomes. Our objective was to refine the process of prognostic assessment in current HF patients.</p> <p><strong>Methods:</strong> We conducted a systematic review to identify existing risk prediction models in ambulatory HF patients, a meta-analysis to identify mortality predictors in HF patients treated with an implantable cardioverter defibrillator (ICD), a retrospective cohort study to validate a new model, the HF Meta-Score, derived from the results of the meta-analysis and a cross-sectional and prospective cohort study to evaluate whether circulating progenitor cells (CPCs) are associated with functional capacity and mortality in ambulatory HF patients.</p> <p><strong>Results:</strong> We identified 20 risk prediction models in ambulatory HF patients; only five were externally validated showing limited discrimination and calibration. The two most validated models were derived from HF cohorts from the 1990s and reported limited performance in ICD patients. In a meta-analysis, we identified that age, baseline renal function, history of heart failure, chronic obstructive pulmonary disease, diabetes, peripheral vascular disease, left ventricular ejection fraction, NYHA class, atrial fibrillation, wide QRS and the occurrence of appropriate or inappropriate ICD shocks were independent mortality predictors. Some of these predictors were omitted in previously identified models. From the results of the meta-analysis, we developed the HF Meta-Score that showed better performance that an existing model. We observed that CPCs were independently associated with functional capacity and outcomes in ambulatory HF patients.</p> <p><strong>Conclusions:</strong> These results open many pathways to further refine the prognostic assessment in ambulatory HF patients. The HF Meta-Score is a promising score. The clinical utility of the HF Meta-Score and of the incorporation of new predictive factors, such as CPCs, needs to be tested.</p> / Doctor of Philosophy (PhD)

The high metabolic demand of the heart makes it essential that an efficient and tightly controlled system be in place to regulate energy production. Contractility is mediated by a variable flux in intracellular calcium (iCa2+), which is proposed to be integrated into mitochondria to regulate cardiac energetics. Moreover, mitochondrial Ca2+ (mCa2+)-overload is known to activate the mitochondrial permeability transition pore (MPTP) and induce cell death. However, the true function of cardiac mCa2+ in physiology remains unknown. Recent studies have reported that the Mcu gene encodes the channel-forming portion of the mitochondrial calcium uniporter (MCU) and is required for mCa2+ uptake (Baughman et al., 2011; De Stefani, Raffaello, Teardo, Szabo, & Rizzuto, 2011). To examine the role of mCa2+ in the heart, we generated a conditional, cardiac-specific knockout model and deleted Mcu in adult mice (Mcu-cKO). Loss of Mcu protected against myocardial ischemia-reperfusion (IR) (40 min occlusion of the left coronary artery (LCA) followed by 24h reperfusion) injury by preventing the activation of the MPTP. We observed a 45% reduction in infarct size per area-at-risk and a 65% reduction in cardiac troponin-I serum levels from 24h post-IR. In addition, while we found no baseline phenotype or change in baseline mCa2+ content, Mcu-cKO mice lacked contractile responsiveness to β-adrenergic receptor stimulation (isoproterenol infusion) as assessed by invasive hemodynamics, and, in parallel, were unable to activate mitochondrial dehydrogenases, thereby decreasing tricarboxylic acid (TCA) cycle flux and cardiac NADH. We found that Mcu-cKO mice had a 3-fold increase in pyruvate dehydrogenase (PDH) phosphorylation and a 50% decrease in PDH activity post-isoproterenol infusion. Further experimental analyses in isolated adult cardiomyocytes confirmed a lack of energetic responsiveness to acute sympathetic stress (isoproterenol failure to mediate an increase in oxidative phosphorylation capacity) supporting the hypothesis that the physiological function of the MCU in the heart is to modulate Ca2+-dependent metabolism during the ‘fight or flight’ response. However, questions still remain on how basal mCa2+ levels are regulated and if it contributes to cardiac disease. The mitochondrial sodium/calcium exchanger (mNCX) is hypothesized as the primary mechanism of mCa2+ efflux, but to date no study has confirmed its identity or function in an in vivo system (Palty et al., 2010). To investigate the role of mNCX in the heart, we generated mutant mice with loxP sites flanking exons 5-7 of the candidate gene, Slc8b1, and crossed them with a tamoxifen-inducible, cardiomyocyte-specific, αMHC-Cre mouse to delete mNCX in the adult heart (mNCX-cKO). Biophysical study of cardiomyocytes isolated from mNCX-cKO mice revealed a significant reduction in mCa2+ efflux rate. Tamoxifen-induced deletion of Slc8b1 in adult hearts caused sudden death with less than 15% of mice surviving after 10 days. Echocardiographic evaluation of mNCX-cKO hearts 3d post-tamoxifen revealed significant left ventricular (LV) remodeling, characterized by significant dilation and a substantial decrease in function. In addition, mNCX-cKO hearts exhibited increased reactive oxygen species generation when assessed by DHE imaging of live myocardial tissue and mitoSOX Red imaging in isolated adult cardiomyocytes. Using an Evan’s blue dye exclusion technique, we found that mNCX-cKO hearts displayed significant sarcolemmal rupture (~8% of all myocytes at a single time point 3d post-tamoxifen), indicative of cellular necrosis. To rescue the sudden death phenotype and acute loss of cells, we crossed our mNCX-cKO mice with the cyclophilin d (a mediator of MPTP-opening) knockout mice. mNCX-cKO x CypD-KO mice had a significant improvement in survival and LV-function. In addition, loss of MPTP activation also rescued mitochondrial pathology on the subcellular level. Since deletion of mNCX was detrimental on cardiac function, we thought that increasing mNCX could protect cardiomyocytes by reducing mCa2+-overload during cardiac disease. To test this, we generated a conditional, cardiac-specific mNCX overexpression mouse model (mNCX-Tg) to assess if increasing mCa2+ efflux would prevent cardiac injury in multiple pathological surgical models. mNCX-Tg and controls were subjected to in vivo IR injury followed by 24h reperfusion and myocardial infarction (MI) (permanent LCA ligation). mNCX-Tg mice displayed reduced cell death (a 43% reduction in infarct size 24h post-IR and a 33% reduction in scar size 4w post-MI), preserved LV function, a reduction in ROS generation, and a decrease in numerous HF indices. For the first time, we showed that mNCX is essential for maintenance of the mCa2+ microdomain in cardiomyocytes and that mNCX represents a novel therapeutic target in HF. / Biomedical Sciences

Pathological hypertrophy leads to cardiac dysfunction and heart failure. It is not clearly defined how this process occurs in the cardiomyocyte, or how the pathology can be effectively treated. There are numerous processes that lead to pathological hypertrophy. We developed two models to study pathological hypertrophy and the role that Ca2+ plays. In one model, we administered clinical doses of the leukemia therapeutic drug imatinib to neonatal ventricular cardiomyocytes. This drug has recently been found to be cardiotoxic, and we set out to understand if Ca2+ is involved. In the second model, we developed mice with overexpression of the Ca2+ entrance channel, the L-type calcium channel (LTCC), which leads to pathological hypertrophy over time. We instituted a chronic exercise regimen on these mice to learn if physiological hypertrophy can ameliorate detrimental aspects of pathological hypertrophy. After cardiomyocytes were treated with imatinib, they expressed enhanced Ca2+ activity. Levels of atrial natriuretic peptide (ANP) were up, signifying pathological hypertrophy. We determined that Ca2+ was activating Calcineurin, leading to translocation of nuclear factor of activated T-cells (NFAT) into the nucleus, resulting in hypertrophy. This activity was blocked by Ca2+ and Calcineurin inhibitors. We concluded that imatinib causes Ca2+ induced pathological hypertrophy. When mice with LTCC overexpression were exercised, they exhibited enhanced cardiac function. They also had thicker septal walls and increased chamber diameter, hallmarks of physiological hypertrophy. Heart weight to body weight ratio was significantly higher after exercise. When isolated hearts were administered ischemia/reperfusion injury, the exercised hearts showed a significant improvement in recovery compared to sedentary LTCC overexpressed hearts. Calcium activity was enhanced at the cardiomyocyte level in both mouse lines of exercised mice. In conclusion, hearts with a pathological hypertrophic phenotype can enhance function and achieve cardioprotection through chronic exercise. / Physiology