There are an estimated 5 million family caregivers supporting persons suffering from advanced heart failure (AHF) which constitutes the final stage of cardiovascular disease and is the primary cause of death for 1 in 8 Americans. AHF caregivers are instrumental in monitoring symptoms, promoting adherence, communicating with healthcare providers and making treatment choices for their care recipients (CRs) at the end of life. What little is known about the AHF caregiver experience comes from surveys, instruments and structured interviews and tends to exclude caregivers of CRs with advanced disease. The purpose of this interpretive phenomenology was to elicit the meaning of caring for a spouse with AHF and is the first of its kind in the US. Seven older spouses caring for persons with NYHA class III-IV HF recruited by the Advance Practice RN of a large regional hospital participated in 3 reflective interviews over the course of 2 months. Grounded in the Philosophy of Ethics by Paul Ricoeur and using a method based on his Theory of Interpretation, their reflections revealed the essence of the caregiver experience as "being fearfully vigilant, at the mercy of the disease while worrying about that which remains unspoken". Separate inquiries invited participants to explore the meaning of symptom interpretation which was likened to "a walk in the fog on the rocky shore by a treacherous river"; and communication which illuminated caregivers' ethical intention in caring for themselves and their loved ones. The fourth and final research question explored caregivers' meaning making in the experience, symptom interpretation and communication over time which uncovered several missed opportunities for advance care planning. Findings support and add to recent models in palliative care, shared care and advance care planning in AHF. This study gives healthcare providers insight into the challenges to respect, self esteem and autonomy encountered by aging couples in the context of AHF. Participants identified personal learning needs related to being a caregiver, symptom interpretation, and managing clinical and emotional manifestations of AHF. Naming specific barriers in communication with their CRs as well as with healthcare providers they called for relationship counseling for the CG-CR dyad, and to be respected as part of the team by healthcare providers. Participants gave moving examples of how current models of care failed to meet their needs, with urgent implications for coordinated care by an interdisciplinary team of healthcare providers. This study identified the need for more phenomenological inquiry to understand (1) implications of CR's cognitive fluctuations on decision making for preferences of care, (2) CRs' personality changes attributed to an awareness of death being near, (3) the need to retain a purpose in living both as individuals and as a couple, and (4) how CRs reconcile daily choices in illness management and adherence with preferences for care at the end of life.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第22835号 / 社医博第111号 / 新制||社医||11(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 佐藤 俊哉, 教授 川上 浩司, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

Antibodies to tropomyosin, cardiac troponin I, myosin, and the beta-adrenergic receptors have been implicated in myocarditis, dilated cardiomyopathy, and heart failure. However, in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), there are only a few studies on how autoantibodies play a role in autoimmune mediated heart disease, despite the prevalence of these conditions. Ro52 antibodies have been implicated in fetal heart block, but their role in adult myocarditis remains elusive. In this study, we look beyond Ro52 and characterized the relevant autoantibodies in adult patients with SLE and RA myocarditis. An optimized immunoprecipitation followed by liquid chromatography mass spectrometry methodology was performed to determine putative auto-antigens in the human heart. The quantity and specificity of auto-antibodies was correlated with clinical measures of myocardial cellular infiltration, as determined by fluorodeoxyglucose (FDG)-positron emission tomography (PET) in patients with SLE and RA. We created autoantibody profiles that are complimentary to SLE and RA patients' clinical profile. Autoantibodies that correlated with cellular infiltration included TPI1, TPM1, MYL2, XRCC6 and APOA4. We then explored methodologies for testing patient autoantibodies using engineered cardiac tissues derived from human induced pluripotent stem cells (iPSCs). These tissues are increasingly used for drug discovery, pharmacology and in models of development and disease. While there are numerous platforms with engineered cardiac tissues, they often require expensive and non-conventional equipment and utilize complex video processing algorithms. As a result, only specialized academic labs have been able to harness this technology. In addition, methodologies and tissue features have been challenging to reproduce between different groups and models. Here, we describe a facile technology (milliPillar) that covers the entire pipeline required for studies of engineered cardiac tissues: (i) platform fabrication, (ii) cardiac tissue generation, (iii) electrical stimulation, (iv) automated real-time data acquisition, and (v) advanced video analyses. We validate these methodologies and demonstrate the versatility of the platform by showcasing the fabrication of tissues in different hydrogel materials and by using cardiomyocytes derived from different iPSC lines in combination with different types of stromal cells. We also validate the long-term culture (100 days) of tissues within the platform and provide protocols for automated analysis of force generation and calcium flux using both brightfield and fluorescent imaging. Lastly, we demonstrate the compatibility of the milliPillar platform with electromechanical stimulation to enhance cardiac tissue function. milliPillar tissues were cultured in the presence of patient autoantibodies to recapitulate the phenotype of myocardial disease, and the calcium transients and force generation were measured. Our results indicated that milliPillar tissues exhibited a decrease in force generation after 6 days in culture with SLE autoantibodies. Separately, our results indicated a prolonged calcium transient after 7 days in culture with SLE and RA autoantibodies. Changes to the downstroke of the calcium transient correlated most with patients’ autoantibody profiles and cellular infiltration. We confirmed autoantibody binding to live tissues/cells in 25% of the patients with SLE and myocarditis. Finally, we used changes in cardiac tissue function in the presence of autoantibodies to classify patients with SLE myocarditis with an accuracy of 87.5%.

Wnt/β-catenin signaling is activated in the heart after myocardial infarction (MI). This study aims to investigate if β-catenin deletion affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific β-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at 8 weeks after MI, associated with reduced scar size and attenuated chamber dilation. qPCR analyses of both myocardial tissues and purified cardiomyocytes demonstrated upregulation of Wnt pathway genes in border and infarct regions after MI, including Wnt ligands (such as Wnt4) and receptors (such as Fzd1 and Fzd2). At 1 week after MI, cardiac sodium channel gene (Scn5a) transcript was reduced in WT but not in KO hearts, consistent with previous studies showing Scn5a inhibition by Wnt/β-catenin signaling. At 8 weeks after MI when Wnt genes have declined, Scn5a returned to near sham levels and K⁺ channel gene downregulations were not different between WT and KO mice. This study demonstrated that VT susceptibility in the chronic phase after MI is reduced in mice with cardiomyocyte-specific β-catenin deletion primarily through attenuated structural remodeling, but not ion channel gene alterations.

Purpose: Adaptive servoventilation (ASV) has been reported to show improvement in patients with sleep-disordered breathing (SDB) and heart failure (HF); however, its role as a second-line or adjunctive treatment is not clear. We conducted a systematic review and meta-analysis of new existing data including cardiac mechanistic factor, geometry, and cardiac biomarkers. Methods: We systematically searched for randomized controlled trials (RCTs) and cohort studies that assessed the efficacy or effectiveness of ASV compared to conventional treatments for SDB and HF in five research databases from their inception to November 2018. Random-effects meta-analyses using the inverse variance method and stratified by study design were performed. Results: We included 15 RCTs (n = 859) and 5 cohorts (n = 162) that met our inclusion criteria. ASV significantly improved left ventricular ejection fraction (LVEF) in cohorts (MD 6.96%, 95% CI 2.58, 11.34, p = 0.002), but not in RCTs. Also, the ASV group had significantly lower apnea-hypopnea index (AHI) in both cohorts (MD − 26.02, 95% CI − 36.94, − 15.10, p < 0.00001) and RCTs (MD − 21.83, 95% CI − 28.17, − 15.49, p < 0.00001). ASV did not significantly decrease the E/e′ ratio in RCTs or in cohorts. Finally, ASV significantly decreased brain natriuretic peptide (BNP) in the cohorts (SMD − 121.99, CI 95% − 186.47, − 57.51, p = 0.0002) but not in RCTs. ASV did not have a significant effect on systolic blood pressure, diastolic blood pressure, and cardiac diameters. Conclusions: ASV therapy is associated with improvements of AHI in comparison to alternative treatments in patients with SDB and HF. ASV did not improve LVEF or E/e′ ratios in randomized trials; other intermediate outcomes did not improve significantly. / Revisión por pares

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The advantages of upgrade to cardiac resynchronisation therapy (CRT) have not been explored as carefully as the outcomes of de novo CRT implantations. Furthermore selection criteria for patients with the potential to benefit the most from this therapy are unknown. Therefore, we analyzed the long term outcome and its predictors in a real-world cohort receiving a CRT upgrade from previous pacemaker (PM) and defibrillator devices (ICD). We analyzed 86 patients (mean age 68 ± 9 years; 89% male) undergoing CRT upgrade procedures. Response to CRT as well as long term patient outcome was analyzed. NYHA class improved in majority of the patients during short term period (61%), and this trend remained constant during long term follow-up (54%). The observed all-cause mortality was 54% with mean survival of 49 ± 4 months. 11 patients underwent left ventricular assist device implantation or heart transplantation. In the multivariate analysis, only kidney function assessed by GFR (HR 0.97; 95% CI 0.95-0.99; p = 0.009) and LVEF (HR 0.92; 95% CI 0.87-0.97; p = 0.002) remain predictors for mortality. Patients who undergo an upgrade procedure to CRT demonstrate a significant response rate assessed by improvement in NYHA class, with initial baseline parameters such as LVEF and kidney function remaining significant predictors for mortality.

SAMMANFATTNING  Introduktion: Att leva med hjärtsvikt är vårdkrävande och det ses en ökning av antal drabbade och många av dessa omhändertas i öppenvården.   Syfte: Att undersöka personers upplevelser av att leva med hjärtsvikt och vara beroende av vård.  Metod: En litteratursammanställning av artiklar som har använt kvalitativ metod. De som valdes kvalitetsgranskades och resultatet analyserades enligt en metasyntes som för samman forskningsresultat som finns presenterat från olika kvalitativa studier för att visa på en fördjupning av ämnet. Examensarbetet beskriver valda delar av Roys teori. Inklusionskriterier var vuxna med hjärtsvikt och erfarenhet av dess vård, artiklar på engelska som var publicerade mellan åren 2016 - 2021.   Resultat: Resultatet bygger på sjutton artiklar. Vid bearbetningen av metasyntesen bildades kategorier och vissa subkategorier. Kategorierna som framkom ur resultatet var besvärande symtom vid hjärtsvikt, skillnader i vård och socialt nätverk påverkade. Subkategorierna var fysiska symtom, psykiska symtom och existentiella funderingar, specialiserad palliativ vård, primärvård och sjukhusvård, övrig vård inklusive egenvård, anhöriga och närstående, social isolering och ekonomisk påverkan.   Slutsats: Att få hjärtsvikt innebär en enorm påfrestning både fysiskt, psykiskt, socialt och ekonomiskt. Att inte få behov tillgodosedda i vården ökar symtombördan ytterligare. Därav finns behovet att öka förståelsen kring upplevelser av hjärtsvikt och dess vård. Egenvård är en stor del av vården vid hjärtsvikt och där har distriktssköterskor en möjlighet att bidraga till egenvården genom att använda sig av Roys teori.  Nyckelord: Hjärtsvikt, Vård, Upplevelser / ABSTRACT  Introduction: Heart failure leads to different sorts of symptoms that gradually gets worse. That means a lot of suffering for those persons and their relatives'. People with heart failure often seeks care and most of them are treated in the primary care.   Aim: To investigate people's experiences of living with heart failure and being dependent of care.   Method: A literature review of articles that have used a qualitative method. The inclusion criteria's were adults with heart failure and experience of their care, articles in English published between the years 2016 - 2021. The selected articles were quality reviewed and the results were analyzed according to a meta-synthesis. That method brings together research results that are presented from various qualitative studies to show a deeper understanding of the subject. The thesis describes selected parts of Roy's theory.   Result: Seventeen articles were included in this study. The meta-synthesis generated in three, main categories and six subcategories. The categories that emerged from the results were troublesome symptoms of heart failure, differences in care and social network. The subcategories were physical symptoms, mental symptoms and existential considerations, specialized palliative care, primary care and hospital care, other care including self-care, relatives and close relatives, social isolation and financial impact.   Conclusion: To live with heart failure means a huge strain both physically, mentally, socially and financially. Not having their needs met in care further increases the burden of symptoms. Therefore there is a need to understand about experiences of heart failure and its care. Self-care is a large part of the care for heart failure and district nurses have an opportunity to contribute to self-care by using Roy's theory.  Keywords: Heart Failure, Care, Experiences

Background: A 73-year-old man with a history of myocardial infarction and hypertension for 5 years suffered heart failure (NYHA III-IV). Methods: 2D echo indicated hypokinesia at septal, left ventricular anterior wall and apical regions. Coronary angiograms demonstrated 60% stenosis in distal left main and 99% stenosis in proximal and distal left anterior descending coronary arteries (LAD). Both proximal artery and middle left circumflex coronary artery (LC) had 90% stenosis, and diffuse stenosis of right coronary artery (RC) was found. Myocardial perfusion imaging using 99mTc-MIBI indicated defective perfusion of left ventricular apex, anterior wall and septal region and severe reduced perfusion of posterior inferior wall. Myocardial metabolic activities (18F-deoxyglucose) also showed comparable reductions. After exposing the heart, LAD, LC, and RC were all completely occluded and bypass procedure could not be completed. Autologous satellite cells were implanted without any complication and the patient had an uneventful recovery. Results: During the first 2 months, he remained in heart failure, and by the third month, he gradually improved and reached NYHA II. At fifth month after the procedure, significant increased ejection fraction (37.1-48.6%) and wall movement with modest reduction of left ventricular systolic diameter (48-45 mm) were observed. Imaging with 18F-deoxyglucose showed dramatic improvement in myocardial metabolic activity with similar improvement in myocardial perfusion (99mTc-MIBI). Conclusion: This is the first successful case of cellular cardiomyoplasty without any conjunctional procedure for patient with severe coronary heart disease and heart failure.