Thesis (Ph. D.)--University of Chicago, Dept. of Pathology, June 1999. / Includes bibliographical references. Also available on the Internet.

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Heart failure (HF) is one of the commonest complications of Diabetes Mellitus (DM) with the prevalence of DM reported at around 30% in many pivotal heart failure studies. However the pathophysiological mechanisms that contribute to HF development in diabetes are poorly understood. To investigate this we used a novel human relevant mouse model of DM (GENA348) in which there is a point mutation in the glucokinase (Gck) gene, the glucose sensor which regulates insulin secretion. A mutation in the same gene is known to underlie Maturity Onset Diabetes of the Young Type 2 (MODY 2) in humans. The mutant mice developed significant hyperglycaemia with normal insulin levels due to the altered glucose sensing. We examined the molecular mechanisms that contribute to the HF phenotype in DM. Mean random blood glucose was found to be increased in the GENA348 mutant(HO) mice compared to wild type (WT) litter mates (WT 6.9±0.3mmol/L vs HO20.6±0.8mmol/L, P<0.001). Serial echocardiography was performed, at 3, 6 and 12 months. No significant changes in echocardiographic parameters were observed at 3 months, although by 6 months development of significant cardiachypertrophy in HO mice was observed characterised by a 20% increase in the diastolic posterior wall thickness (dPW). At 12 months of age left ventricular dilatation was also evident. Systolic function was preserved although significant diastolic dysfunction was evident at 6 and 12 months. Histological staining illustrated significant cellular hypertrophy with real time PCR data demonstrating a relative 150% increase in the hypertrophic marker BNP. Hypertrophic pathways were examined through western blot analysis revealing an age dependent increase in Akt phosphorylation (6 months-140%, 12 months-460%). Serum levels of advanced glycation end products (AGEs) and expression of their receptors RAGE were also elevated. In vitro cellular experiments also revealed AGEs directly activate Akt through phosphorylation and increase levels of the receptor RAGE. AGE induced phosphorylation of Akt is inhibited in the presence of wortmannin, suggesting a PI3K dependent signalling mechanism. Wortmannin blocked the development of cardiac hypertrophy in the diabetic mice. In conclusion we demonstrate that the human relevant GENA348 mouse model of diabetes develops a progressive cardiac phenotype including cardiachypertrophy, LV dilatation and diastolic dysfunction similar to the clinical manifestations of diabetic cardiomyopathy. We propose a novel RAGE/PI3K/Akt pathway that for the first time provides insight into the molecular mechanisms that underlie the development of HF. Moreover, we show raised glucose alone is able to cause cardiotoxicity independently of insulin.

Information was collected in an eight and a half month prospective study about 358 recent cardiac disease-related cardiac arrest cases which were attended by personnel from the Provincial Ambulance Service in the Lower Mainland of British Columbia. When possible, advanced life support personnel (EMA Ills), regular ambulance attendants (EMA Ms) and Fire Department staff are dispatched to cardiac arrest calls. At the time of this study some areas in the region did not have advanced life support coverage, and some cardiac arrest calls occurred while the EMA Ills were already engaged with another case. Such calls, attended by EMA lis, but not by EMA Ills, served as the comparison group for paramedic performance in this study. Patient outcomes were compared at admission to hospital and at discharge from hospital for the group of patients treated by EMA Ms and the group of patients treated by EMA Ills, or by a combination of EMA Ills and EMA Ms. Strongly significant differences in initial outcome (hospital admission) were found between the two patient groups, with EMA IM patients faring better (p.=0.002). Marginally significant differences in final outcome (discharge alive) between the two patient groups were found, with the EMA III group again doing better (p.=0.10). Whether or not the receiving hospital had a coronary care unit was not associated with a difference in initial (p.=0.45) or final outcome (p.=1.0) for the entire group of patients in the study. Short time in arrest without CPR was associated with better initial outcome (p.=0.00), and with better final outcome (p.=0.01) for all patients. in the study, as was short time to definitive care (initial outcome p.=0.001; final outcome p.=0.03). EMA II patients had a better chance of survival when they arrested during attendance by EMA lis than they did when they were found in arrest. This study suggests that significantly more cardiac arrest victims reach hospital alive, and more survive to be discharged alive from hospital, when their prehospital treatment is provided by advanced life support personnel than when it is provided by regular ambulance personnel. / Medicine, Faculty of / Population and Public Health (SPPH), School of / Graduate

Background-Heart failure (HF) is the leading cause for hospital readmission. Hospice care may help palliate HF symptoms but its association with 30-day all-cause readmission remains unknown. Methods and Results-Of the 8032 Medicare beneficiaries hospitalized for HF in 106 Alabama hospitals (1998-2001), 182 (2%) received discharge hospice referrals. Of the 7850 patients not receiving hospice referrals, 1608 (20%) died within 6 months post discharge (the hospice-eligible group). Propensity scores for hospice referral were estimated for each of the 1790 (182+1608) patients and were used to match 179 hospice-referral patients with 179 hospice-eligible patients who were balanced on 28 baseline characteristics (mean age, 79 years; 58% women; 18% non-white). Overall, 22% (1742/8032) died in 6 months, of whom 8% (134/1742) received hospice referrals. Among the 358 matched patients, 30-day all-cause readmission occurred in 5% and 41% of hospice-referral and hospice-eligible patients, respectively (hazard ratio associated with hospice referral, 0.12; 95% confidence interval, 0.06-0.24). Hazard ratios (95% confidence intervals) for 30-day all-cause readmission associated with hospice referral among the 126 patients who died and 232 patients who survived 30-day post discharge were 0.03 (0.04-0.21) and 0.17 (0.08-0.36), respectively. Although 30-day mortality was higher in the hospice referral group (43% versus 27%), it was similar at 90 days (64% versus 67% among hospice-eligible patients). Conclusions-A discharge hospice referral was associated with lower 30-day all-cause readmission among hospitalized patients with HF. However, most patients with HF who died within 6 months of hospital discharge did not receive a discharge hospice referral.

Heart failure (HF) hospital readmission reductions are linked to nursing interventions that include scheduling a hospital follow-up appointment with the patient's health care provider within a week of discharge. Yet, patients often leave the hospital without an appointment scheduled. The focus of this integrative literature review was on analyzing data that associated follow-up within 7 days with reduced 30-day readmissions. A search of articles using CINAHL, MEDLINE, Cochrane Database of Systematic Reviews, and ProQuest databases resulted in 4,813 articles retrieved using the following search terms: heart failure, readmissions, follow-up appointments, and heart failure guidelines. Scholarly articles selected for inclusion were published between January 1, 2007, and June 30, 2017, in the English language, regarding studies completed in the United States, available online in full text, and specific to patients with HF. The Melnyk Critical Appraisal Guide was used for the appraisal, evaluation, and synthesis of the evidence. The transitional care model served as the theoretical framework for the project. A key finding of the review was that follow-up appointment scheduling within 7 days was associated with a modest reduction in readmissions; more research is needed to produce additional evidence on this topic. Project dissemination may result in positive social change by raising awareness of health disparities and empowering patients and staff to work collaboratively. Through improved communication and follow-up between patients and the interdisciplinary team, patients with HF may be able to experience improved disease management and a reduced number of hospitalizations.

Women are thought to be under-represented as clinical trial participants and as clinical trialists in heart failure. We reviewed randomized controlled trials of heart failure published in high impact medical journals and examined the representation of women as both participants and authors. Furthermore, we explored clinical trial characteristics independently associated with women as clinical trial participants and as lead authors. Our analysis demonstrated that women are under-represented as both clinical trial participants and leaders, with no change in temporal trends over time. Addressing clinical trial characteristics associated with under-representation and developing strategies to overcome barriers may be a strategic way to improve the representation of women in heart failure research. / Thesis / Master of Science (MSc)

Background: Heart Failure (HF) is a frequent cause of mortality and recurrent hospitalization. Although HF databases are assembled based on left ventricular (LV) ejection fraction, patients without LV ejection fraction determination are not further analyzed. Objective: The purpose of this study is to characterize patient attributes and outcomes in this group-HF with unknown Ejection Fraction (HFunEF). Methods: We queried the electronic medical record from a community-based university practice for patients with a HF diagnosis. We included patients with >60 days follow-up and had interpretable Doppler-echocardiograms. We recorded demographic, Doppler-echocardiographic, and outcome variables (up to 2083 days). Results: There were 820 patients: 269 with HF with preserved Ejection Fraction (HFpEF), 364 with HF with reduced Ejection Fraction (HFrEF), of which 231 had a LV ejection fraction=40-49% and 133 had a LV ejection fraction<40%, and 187 with HFunEF. As compared to patients with HFunEF, HFpEF patients were younger, had a higher coronary disease and hyperlipidemia prevalence. Patients with HFrEF had more prevalent coronary disease, myocardial infarction, and hyperlipidemia. Patients with HFunEF were more likely to be seen by non-cardiology providers. All-cause mortality (ACM) was greater in HFunEF patients than patients with HFpEF (Hazard Ratio (HR)=1.60 (1.16-2.29), p=0.004). Furthermore, HF readmission rates were lower in HFunEF as compared to HFpEF (HR=0.33 (0.27-0.54), p<0.0001) and HFrEF (HR=0.30 (0.028-0.50), p<0.0001). Conclusion: Patients with HFunEF have greater ACM and lower HF re-admission than other HF phenotypes. Adherence to core measures, including LV ejection fraction assessment, may improve outcomes in this cohort of patients.

Approximately half a million people in Canada suffer from heart failure (HF), a leading cause of hospital admission. HF outcomes can be improved by self-care behaviors, to which patients often show low adherence. This study focuses on the co-design of an online self-care application and community intervention, called HFApp, which patients with HF and their informal caregivers could use to potentially improve HF outcomes. The intended users for HFApp are older adults with HF and their informal caregivers. The primary objective of this study is to identify themes for the development of HFApp. The secondary objective is to apply these findings to identify user needs and preferences for HFApp. Persona-scenario discussion sessions were conducted with 4 older patients with HF (≥ 60 years) and 4 informal caregivers from the Hamilton Health Sciences Heart Function Clinic. One persona-scenario discussion session was held for each participant type (i.e. patients with HF or informal caregivers). Participants were divided into pairs and participant pairs created personas and scenarios together. Scenarios included: (1) how they learn about HFApp, (2) how they might access HFApp, (3) where they are when they use HFApp, (4) who might help them with HFApp, and (5) how often they use HFApp. All discussions were audio recorded. Data analysis, using NVivo 10 , provided six categories of design themes which were used to develop a list of user requirements for HFApp. Some of these requirements help users perceive HFApp to be more useful and give a sense of self-care confidence. However, some requirements may be excluded due to low feasibility. It is recommended that a larger persona-scenario group session be conducted in the future to support the requirements gathered in this study as well as identify any new requirements. / Thesis / Master of Science (MSc) / Approximately half a million Canadians suffer from heart failure (HF), a leading cause of hospitalization. This study focuses on the involvement of potential users in the design of HFApp, an online HF self-care application (“app”). These users include older patients with HF and their family and close friends. One of HFApp’s objectives is to potentially decrease hospital visits for older patients with HF. A design based on patient preferences called persona-scenarios was used to conduct this study. Participants were asked to create pretend individuals that were similar to themselves and describe scenarios in which these individuals would interact with HFApp. These could include: (1) how they learn about HFApp, (2) how they might access HFApp, (3) where they are when using HFApp, (4) who might help them with HFApp, and (5) how often they use HFApp. These interactions will be used to identify user requirements and preferences for HFApp’s design.