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The study of cardiac regeneration can have many forms in which it is defined. It can not only be the ability to add new myocardium to dead or dying tissues, but also include the prevention of cardiac tissue degeneration, reversal of tissue remodeling, and the maintenance of systolic and diastolic function in the incidence of tissue damage, which can lead to subsequent heart failure progression. The use of stem cells for cardiac regeneration represents a growing field of new therapies for patients with end stage cardiac disease. Various studies have noted promising results in the recovery and reparation of these tissues. Cumulatively, their goals have become the identification of the most suitable cell type, as well as how to maximize functional efficiency and cost effectiveness for practical application. Many protocols simply do not ensure adequate cell engraftment, viability, and ultimately the return of normal tissue function. Investigators seek to determine how these processes can be enhanced or manipulated to promote cardiac regeneration in hopes of eventually making their clinical use a standard practice. / Physiology

Heart disease has been the leading cause of death in the United States for more than 90 years. The leading cause of death in individuals aged 65 and older has remained diseases of the heart from 1950 to the current time. According to the CDC, once diagnosed with heart disease, individuals have an approximately 50% chance of dying within 5 years, regardless of race. Mortality related to heart disease increased dramatically from the start of the 1900s to 1921, but subsequently experienced a steady decline from the mid-1960’s to 2000. However, when the decrease in heart disease is examined at the level of race it is clear that the decrease is not equally shared. While the leading cause of death among both Caucasian American men and women and African American men and women remains heart disease, the decrease in incidence of coronary heart disease among African American men was only half of the decrease in incidence among Caucasian American men. Genetic variants in BAG3 (Bcl-2 associated athanogene 3), a highly evolutionarily conserved gene that has recently emerged as a major dilated cardiomyopathy locus, are prevalent in isolated populations. This led us to hypothesize that variants in BAG3 might contribute to the increased prevalence of IDC in individuals of African ancestry. Expressed predominantly in the heart, the skeletal muscle and in many cancers, BAG3 has pleotropic effects in the heart. It inhibits apoptosis by binding to Bcl-2, facilitates protein quality control by binding to both large and small heat shock proteins, mediates adrenergic responsiveness by coupling the β-adrenergic receptor and the L-type Ca2+ channel, and maintains the integrity of the sarcomere by anchoring actin filaments to the Z disc. However, a paucity of subjects of African ancestry have been included in cohorts of probands with familial dilated cardiomyopathy whose exomes or genomes have been sequenced. Based on our previous observations and reports from other groups we postulated: 1) that mice with haplo-insufficiency of BAG3 will re-capitulate disease seen in humans and serve as a model for studying the pathogenesis of BAG3. 2) The prevalence or identification of specific BAG3 variants will differ by race and/or ethnicity. 3) SNVs of BAG3 may contribute to disease progression and thereby be pathogenic. Our study points out that we cannot understand population-based differences without enhancing the diversity of populations included in genomic studies. Similarly, in the era of big data, efforts must be undertaken to assess the genetic profile of both probands and their family members as without the ability to measure segregation, penetrance and plasticity we can only ascribe associations to functional genetic variants. / Biomedical Sciences

Heart failure (HF) affects many older Canadians with recurrent hospitalizations despite post-discharge strategies to prevent readmission. Self-care is key to the management of HF in the home setting and can potentially lead to better clinical outcomes. Proper HF self-care includes tasks such as daily weight and symptom monitoring, as well as adjusting diuretics based on weight. Patients find HF self-care challenging, with less than 50% of patients regularly weighing themselves. Mobile applications to support self-care have been shown to be effective, however, due to their lack of consideration for barriers such as literacy, numeracy and cognitive impairment within their design, these applications are not usable for many older patients. Previous work supports the use of a paper-based standardized diuretic decision support tool (SDDST) to promote self-care in older individuals with HF. The objective of this study was to use participant (HF patients, informal care-providers) input to convert the paper-based SDDST into a user-centered electronic mobile application. We recruited 12 patients (male and female, age > 60 years) with a confirmed diagnosis of HF, and 7 informal caregivers from the Heart Function Clinic at the Hamilton Health Sciences General site. HF patients were categorized into three groups, 1) adequate self-care patients (6), 2) inadequate self-care patients without a CP (2) or 3) inadequate self-care patients with a CP (4), based on their self-care abilities measured with the Self-Care Heart Failure Index (SCHFI) where a score of > 70 is considered self-care adequate. We conducted semi-structured interviews with HF patients and CPs using Persona-Scenarios. Interviews were analyzed using NVivo, version 10, for emerging themes regarding self-care. Following data analysis, we identified 6 major themes, 1) Usability of technology, 2) Communication, 3) Application customization, 4) Complexity of Self-Care, 5) Usefulness of HF Related Information and 6) Long-Term Use and Cost. Many of the challenges patients and CPs mentioned involved their unfamiliarity with technology. However, by addressing these themes, we were able to develop a series of requirements and modifications to improve the usability of our app design. / Thesis / Master of Science (MSc) / Heart failure (HF) is one of the leading causes of hospitalization and re-hospitalization in older adults. . If patients are able to take care of themselves (self-care) at home they will be less likely to be readmitted to the hospital. However, many patients find self-care difficult, so they do not manage their symptoms. To assist patients in understanding or following their treatment, various mobile health applications have been developed. Unfortunately, older patients do not commonly use these applications because of their complicated design. In this study, we interviewed patients and their informal caregivers to help design our HF self-care app. We gathered information on features they may perceive to be helpful. Our goal was to use their feedback to make the app simpler and more user-oriented, which will make self-care easier.

N/A / Thesis / Master of Science (MS)

Left ventricular diastole (filling) is a complex process with many features and coupled compensatory mechanisms which coordinate to maintain optimal filling and ejection of the left ventricle. Diastolic filling is controlled by the left ventricular recoil, relaxation, and compliance as well as atrial and ventricular pressures making left ventricular diastolic dysfunction very difficult to understand and diagnose. An improved understanding of these unique flows is important to both the fundamental mechanics of the cardiac diastolic filling as well as the development of novel and accurate diagnostic techniques. This work includes studies of in-vivo and in-vitro vortex rings. Vortex rings created in the left ventricle past the mitral valve during diastole are produced in a confined domain and are influenced by the left ventricular walls. Therefore, an in-vitro analysis of the formation and decay of vortex rings within confined cylindrical domains using particle image velocimetry was conducted. Varying mechanisms of vortex ring breakdown were observed over a wide range of Reynolds numbers, and an analytical model for vortex ring circulation decay of laminar vortex rings was developed. Also, in this work a novel method for analyzing color M-mode echocardiography data using a newly developed automated algorithm is introduced which examines the pressure gradients and velocities within the left ventricle. From this analysis, a new diagnostic filling parameter is introduced which displays a greater probability of detection of diastolic dysfunction over the conventionally used diagnostic parameter. / Ph. D.

Phospholamban (PLN) is an integral membrane protein that regulates the sarco(endo)plasmic Ca2+-ATPase (SERCA2a) within the cardiac sarcoplasmic reticulum (CSR). SERCA2a regulates intracellular Ca2+- handling and thus plays a critical role in initiating cardiac contraction and relaxation. It is believed that dysregulation of SERCA2a is a contributing factor in human heart failure patients. Even though there have been substantial advancements in understanding heart failure pharmacological therapies, patient prognosis remains poor. Nitroxyl (HNO), a new candidate heart failure drug therapy, has been shown to enhance overall cardiovascular function in both healthy and failing hearts, at least in part, by increasing Ca²⁺ re-uptake into the CSR. Previous research has shown that activation of SERCA2a by HNO is PLN-dependent; however, the mechanism of action of HNO remains unknown. We propose that HNO, a thiol oxidant, modifies one or more of the three PLN cysteine residues (C36, C41, C46) affecting the regulatory potency of PLN toward SERCA2a. To test this hypothesis, a series of PLN mutants were constructed containing single, double and triple cysteine substitutions. Using the baculovirus expression insect cell system, each PLN cysteine mutant was expressed alone and co-expressed with SERCA2a in insect cells and isolated in cellular endoplasmic reticulum (ER) microsomes. Samples were treated with Angeli's salt (an HNO donor) to determine the role of each PLN cysteine residue in the mechanism of SERCA2a activation by nitroxyl. Using a standard phosphate activity assay and SDS-PAGE/immunoblot techniques, we determined that the PLN cysteine residues at positions 41 and 46 are important in HNO activation of SERCA2a. Both SERCA2a + 41C PLN and SERCA2a + 46C PLN microsomal samples showed a ΔK0.5 of ~0.33 μM and evidence of reversible HNO induced disulfide bond formation. These studies provide important new insight into the mechanism of action of HNO on cardiac SR and thereby help evaluate the drug as a candidate therapy for congestive heart failure. / Ph. D.

Yes / Abstract: Background: Medicines are often suboptimally managed for heart failure patients across the transition from hospital to home, potentially leading to poor patient outcomes. The Improving the Safety and Continuity Of Medicines management at Transitions of care programme included: understanding the problems faced by patients and healthcare professionals; developing and co-designing the Medicines at Transitions of care Intervention (MaTI); a cluster randomized controlled trial testing the effectiveness of a complex behavioural MaTI aimed at improving medicines management at the interface between hospitals discharge and community care for patients with heart failure; and a process evaluation. The MaTI included a patient-held My Medicines Toolkit; enhanced communication between the hospital and the patient's community pharmacist and increased engagement of the community pharmacist postdischarge. This paper reports on the patients' experiences of the MaTI and its implementation from the process evaluation. Design: Twenty one-to-one semi-structured patient interviews from six intervention sites were conducted between November 2018 and January 2020. Data were analysed using the Framework method, involving patients as co-analysts. Interview data were triangulated with routine trial data, the Consolidated Framework for Implementation Research and a logic model. Results: Within the hospital setting patients engaged with the toolkit according to whether staff raised awareness of the My Medicines Toolkit's importance and the time and place of its introduction. Patients' engagement with community pharmacy depended on their awareness of the community pharmacist's role, support sources and perceptions of involvement in medicines management. The toolkit's impact on patients' medicines management at home included reassurance during gaps in care, increased knowledge of medicines, enhanced ability to monitor health and seek support and supporting sharing medicines management between formal and informal care networks. Conclusion: Many patients perceived that the MaTI offered them support in their medicines management when transitioning from hospital into the community. Importantly, it can be incorporated into and built upon patients' lived experiences of heart failure. Key to its successful implementation is the quality of engagement of healthcare professionals in introducing the intervention. Patient or Public Contribution: Patients were involved in the study design, as qualitative data co-analysts and as co-authors. / Programme Grants for Applied Research. Grant Number: RP-PG-0514-20009

Few drugs are available to treat congestive heart failure and other cardiac diseases in horses. Pimobendan is an inodilator drug approved as Vetmedin® for treatment of canine cardiac disease. Previous research shows that pimobendan increases heart rate and contractility following intravenous administration in horses. The pharmacokinetics of oral pimobendan have not been investigated in horses. The hypothesis of this study was that pimobendan would be absorbed following oral administration to healthy adult horses and reach concentrations known to be therapeutic in other species. Additional objectives were to compare the absorption of compounded pimobendan capsules (C) and suspension (S) to Vetmedin® (V) and determine the effects of sample site on plasma drug concentrations in a pilot study using two horses. These two horses received C, S, or V (0.5 mg/kg via oral syringe, once) following a minimum 10 hour fast, using a crossover design with a minimum 1-week washout period. Samples were collected simultaneously from lateral thoracic and jugular catheters before and after drug administration at predetermined time points. Differences between formulation and sample site were analyzed by one-way ANOVA. After evaluation of the data from the initial 2 horses, an additional 4 horses received pimobendan, in the form of Vetmedin tablets® (V), in a similar manner. Only jugular samples were collected at the same predetermined time points. Plasma concentrations were determined by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and pharmacokinetic parameters determined by noncompartmental analysis. No significant differences were noted between formulations or sample site (P < 0.05). Concentrations in compounded formulations were 88%(S) and 90%(C) of label. For V, mean (±SD) maximum plasma concentration (Cmax) was 4.96 ± 2.13 ng/mL at 2.17 ± 0.98 hours, and area under the curve (AUC0-∞) was 22.1 ± 8.8*ng/mL. Concentration of the active metabolite of pimobendan, o-desmethyl-pimobendan, was below the limit of detection (0.07ng/mL) for all samples. At 0.5mg/kg orally, pimobendan plasma concentrations were considerably lower than reported in dogs and other species. There was no evidence of oral transmucosal absorption. Pimobendan was poorly absorbed in horses, regardless of formulation, and appears unlikely to have clinical effects. / Master of Science / The objective of this study was to determine the pharmacokinetics (i.e. evaluation of the drug concentration in the bloodstream over time by means of mathematical modeling) of pimobendan in healthy horses. Pimobendan is a drug used to treat two types of heart disease, myxomatous mitral value disease and dilated cardiomyopathy, in dogs. These diseases often lead to a syndrome, congestive heart failure (CHF), that has high mortality. CHF in horses also has high mortality, and treatments for horses in CHF are based on information from other species. In this study, the FDA approved formulation of pimobendan, Vetmedin®, was administered to six healthy mature horses at a dose of 0.5 mg/kg, which is twice the amount typically administered to dogs in a single dose. Additionally, we gave two of the horses compounded (uniquely formulated) pimobendan capsules and suspension to evaluate their equivalence to Vetmedin® tablets. We serially collected blood samples to measure plasma concentrations of pimobendan after administration of each drug. Our results showed that all three formulations of pimobendan lead to similar blood concentrations in each of the two horses individually. No formulation of pimobendan resulted in plasma levels of pimobendan known to be effective in other species. Overall, the average plasma concentrations of pimobendan in these horses was very low, it was approximately 1/10th the amount reported in canine pharmacokinetic studies of pimobendan. In conclusion, we determined that at a 0.5 mg/kg dose orally, pimobendan is poorly absorbed in horses and seems unlikely to have medical effects.