Cardiovascular Diseases Commons^™

The Impact Of Simulated Image Acquisition Time Reduction On Image Quality And Parameters Of Myocardial Perfusion Imaging Using A Dedicated Cardiac Camera, Alireza Khatami

Electronic Thesis and Dissertation Repository

Heart disease is the second leading cause of death in Canada, highlighting the crucial role of early diagnosis in disease management. Myocardial perfusion imaging (MPI), is widely employed for this purpose, involves injecting a radiopharmaceutical into the body, imaging its distribution with a gamma camera, and revealing cardiac blood flow patterns. A significant challenge in MPI is the lengthy 8 to 10 minutes required for stress and rest imaging, potentially causing patient discomfort and compromising image quality due to movement. In a clinical study with 26 patients, post-processed data manipulation simulated a reduction in MPI imaging time. The findings indicated …

Interaction Of Circularrna And Microrna-9-5p In The Mediation Of Cardiac Fibrosis In Diabetic Cardiomyopathy, Honglin Wang

Electronic Thesis and Dissertation Repository

Diabetic cardiomyopathy (DCM) is a chronic diabetic complication affecting the heart. It is a significant and independent contributor to heart failure and characterized by cardiac fibrosis and left ventricular hypertrophy. Endothelial cells are the first cells to be damaged by hyperglycemia, leading to epigenetic modifications and subsequent signaling and transcription derangements that lead to endothelial dysfunction and therefore cardiac fibrosis. The role of the two noncoding RNA microRNA-9-5p and circRNA_012164 are investigated using in vivo and in vitro models of hyperglycemia. CircRNA_012164 is upregulated in the hearts of diabetic mice and in cells exposed to high glucose. This results in …

Do Clinical Exercise Tests Permit Exercise Threshold Identification In Patients Referred To Cardiac Rehabilitation?, Randi R. Keltz

Electronic Thesis and Dissertation Repository

The purpose of this thesis was to quantify the proportion of patients whose clinical cardiopulmonary exercise test (CPET) permitted identification of estimated lactate threshold (θ_LT) and respiratory compensation point (RCP) and to characterize the variability at which these thresholds occur to evaluate the feasibility of “threshold-based” aerobic exercise prescription. We retrospectively analyzed CPET data of 1102 patients (65±12 yrs; 306 females) referred to cardiac rehabilitation. θ_LT and RCP were identified and reported as oxygen uptake (V̇O₂), heart rate (HR), %V̇O_2peak, and %HR_peak. Patients were grouped by threshold identification: group 0) neither …

Lipoprotein(A), Oxidized Phospholipids, And Vascular Smooth Muscle Cell Phenotype And Viability, Michael Dunphy

Electronic Thesis and Dissertation Repository

Genetic studies have shown elevated plasma lipoprotein(a) (Lp(a)) levels to be an independent and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease, however a definite mechanism for this pathogenicity has yet to be clearly identified. Oxidized phospholipids (oxPLs) have been implicated in facilitating atherogenic changes in the gene expression of vascular cells. As the primary carrier of oxPLs in the plasma, we hypothesize that Lp(a) contributes to vascular diseases by its enhanced ability to bind to and deliver oxPLs to tissue through a strong lysine binding site on its apolipoprotein(a) (apo(a)) component. Using a cultured primary …

Noninvasive Quantification Of Tissue Sodium Concentration In The Kidney Disease Spectrum Using 23na Magnetic Resonance Imaging, Fabio R. Salerno

Electronic Thesis and Dissertation Repository

Chronic kidney disease (CKD), especially when requiring kidney replacement therapy (hemodialysis (HD) and peritoneal dialysis (PD)), is associated with extracellular water expansion with increased total body sodium. Sodium can also be accumulated in tissues independently of extracellular water. Sodium-23 magnetic resonance imaging (²³Na MRI) can quantify the concentration of sodium nuclei in tissues. Applied to the human leg, quantification of tissue sodium concentrations mainly at the skin and muscle level is possible. We hypothesized that increased tissue sodium concentrations exert toxic effects in CKD and dialysis. We aimed to (1) compare tissue sodium concentrations in adults, children and …

Exploration Of The Pathophysiological Mechanisms Underlying Hemodialysis Associated Cardiac Ischemic Injury, Lisa Yun Jeong Hur

Electronic Thesis and Dissertation Repository

Hemodialysis (HD) provides life-saving treatment in individuals with kidney failure. However, HD is associated with poor quality of life and extremely high mortality rates mainly caused by cardiovascular disease due to heart failure and sudden cardiac death. Standard pharmacological treatment developed within the non-kidney disease community are largely ineffective in HD patients because of the difference in pathophysiology of cardiovascular mortality. HD treatment causes hypotension and recurrent ischemic injury to multiple vascular beds including the heart, leading to heart failure. These injuries can be abrogated by improving the patient’s tolerability of the treatment. To apply interventions that may improve hemodynamic …

Technical Adaptations For Cardiac Sodium Mri, Taylor L. Marcus

Electronic Thesis and Dissertation Repository

Cardiac sodium (Na⁺) MRI has the potential to unveil relationships between chronic kidney disease (CKD) and cardiovascular disease (CVD). Unfortunately, this modality requires many technical adaptations before it’s possible to extract and compare image data between individuals. This study investigated whether cardiac electrocardiogram (ECG) gating could improve image quality, and whether a uniform phantom could increase signal uniformity if a surface coil is used to acquire the image. Healthy participants were imaged with a custom-built surface coil and 3.0-T MR system. Cardiac gated images presented with a decreased signal-to-noise ratio (SNR), but intensity correction significantly increased image signal …

Feasibility And Clinical Value Of 3-Dimensional Myocardial Deformation Analysis By Computed Tomography In Transcatheter Aortic Valve Replacement Patients, Mohamad Rabbani

Electronic Thesis and Dissertation Repository

Purpose: Multi-phase computed tomography angiography (CTA) for the pre-procedural planning of TAVR presents a unique opportunity to assess 3D myocardial biomechanics. This study aimed to assess the feasibility and predictive utility of 3D myocardial deformation analysis (3D-MDA) based principal strain to predict heart failure or death following TAVR using pre-procedural, multi-phase computed tomography angiography (CTA) datasets.

Methods: Two hundred and five patients undergoing pre-TAVR multi-phase gated CTA followed by successful TAVR were retrospectively identified. Whole heart 3D mesh chamber models were generated followed by 3D-MDA of the left ventricle (LV) to determine global LV minimum principal strain (minPS) for endocardial, …

Mechanisms Underlying Enhanced Bone Marrow Adipogenesis In Diabetes, Jina J.Y. Kum

Electronic Thesis and Dissertation Repository

Morbidity and mortality associated with diabetes are due to secondary vascular complications that include both micro- and macro-vascular organ dysfunctions. Our recent studies show that vascular dysfunction and inadequate vessel repair in diabetes may potentially be due to impaired vasculogenesis (de novo vessel formation). Specifically, we have shown that diabetes enhances adipogenesis in the bone marrow and reduces the number of marrow-resident vascular regenerative stem cells. In this study, I have determined the mechanisms of deleterious bone marrow adipogenesis, which may alter the cellular composition of the marrow and lead to the depletion of vascular regenerative stem cells.

My …

Endothelial Cell-Specific Loss Of Breast Cancer Susceptibility Gene 2 Exacerbates Atherosclerosis, David C.R. Michels

Electronic Thesis and Dissertation Repository

Despite mounting concern over the increased risk of cardiovascular disease in breast cancer patients, studies evaluating the common genetic/molecular link between these diseases are limited. Mutations in the breast cancer susceptibility genes (BRCA1&2) predispose carriers to breast and ovarian cancers due to compromised DNA damage repair capacity leading to DNA damage accumulation; in cancer cells, and in other cell-types including endothelial cells, causing atherosclerotic hallmarks of endothelial dysfunction/apoptosis. We present a new understanding of BRCA2’s protective functionality in the setting of atherosclerosis. Studies have thus far demonstrated that while loss of endothelial BRCA2 in mice does not affect a molecular …

Effects Of Ergothioneine On Endothelial Cell And Macrophage Characteristics, And Markers Of Atherosclerosis Risk Under High Lipid Conditions, Daniel Lam-Sidun

Electronic Thesis and Dissertation Repository

Ergothioneine (EGT) is an antioxidant and potential anti-inflammatory molecule that may have protective effects against the lipid-induced oxidative stress and inflammation that occurs in the vasculature of individuals with obesity and metabolic syndrome. This thesis addresses the hypothesis that EGT supplementation decreases endothelial cell dysfunction and macrophage inflammatory characteristics under high lipid conditions, and markers of atherosclerotic risk in diet-induced obese mice. Results showed that EGT did not influence endothelial tube formation or stability but reduced nitric oxide production in endothelial cells. Moreover, EGT decreased the production of reactive oxygen species, and potentially nitric oxide, by macrophages. In diet-induced obese …

Genetic Approaches For The Study Of Complex Human Diseases, Julieta Lazarte

Electronic Thesis and Dissertation Repository

The field of human genetics has evolved from its initial narrow focus on single-gene Mendelian disorders, which largely affect children, to our current understanding that for most diseases there is continuum of rare to common variants which can exert a range of phenotypic effects. Despite advances in sequencing capabilities and our overall understanding of diseases, there remains a large proportion of heritability unexplained. Through the use of next-generation sequencing technologies and DNA microarray, I have explored a spectrum of genetic variations from rare, single and structural variants to common variants in individuals with i) “lone” atrial fibrillation; ii) familial hypercholesterolemia; …

Measuring The Impact Of Atrial Fibrillation On Patients, Justine Chang

Electronic Thesis and Dissertation Repository

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Patients experience the effects of AF from early symptom onset to treatment and beyond. A previous qualitative study found AF to substantially affect patients’ emotional wellbeing, social relationships, employment, and finances. Existing quality of life questionnaires do not adequately assess the AF impact. In this thesis, a new patient-reported questionnaire was developed to measure the impact of AF as experienced by patients. An exploratory factor analysis was conducted on the new questionnaire, revealing five domains: “Affect”, “Social Support”, “Major Life Events”, “Financial Impact”, and “Diagnostic Experience”. Age, marital status, educational …

Novel Imaging Tools Reveal The Dynamics Of The Myocardial Growth Hormone Secretagogue Receptor In Heart Disease And Heart Failure, Rebecca Sullivan

Electronic Thesis and Dissertation Repository

Heart disease (HD) is the leading cause of mortality worldwide. Currently, diagnosis is based on clinical features, imaging, and circulating cardiac biomarkers. Cardiac imaging technologies, such as echocardiography and cardiac magnetic resonance imaging (cMRI), enable the non-invasive detection of changes in heart function. Although these modalities can detect changes in structure and anatomy, it is usually at later stages, where prevention may not be possible. In conjunction with imaging, circulating biomarkers of heart failure (HF), notably B-type natriuretic peptide (BNP) and cardiac troponin I and T, can be detected with increased levels in the blood. These biomarkers are associated with …

The Effects Of Maternal Delta-9-Tetrahydrocannabinol And Cannabidiol Exposure On Fetal Heart Development In Mice, Gregory Robinson

Electronic Thesis and Dissertation Repository

Up to 22.6% of pregnant women consume cannabis during pregnancy despite the uncertainty of teratogenicity of the main ingredients in cannabis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). This study tested the hypothesis that gestational THC and CBD exposure leads to heart abnormalities. Daily, oral THC exposure induced heart abnormalities in 68% of offspring with three main phenotypes including thickened semilunar valves, ventricular myocardial hypertrophy and hypoplastic coronary arteries in fetuses, and postnatal cardiac dysfunction. Altered gene expression of key cardiogenic regulators, increased proliferation, and reduced epicardial epithelial-to-mesenchymal-transition were demonstrated implicating potential mechanisms responsible for these abnormalities. Also, maternal CBD exposure resulted …

Ultrasound-Guided Resuscitation In Open Aortic Surgery - The Aortus Trial, John H. Landau

Electronic Thesis and Dissertation Repository

Introduction: Major abdominal aortic surgery requires significant fluid resuscitation in the post-operative phase. Patients are at significant risk of perioperative morbidity and mortality which can be affected by the approach to post-operative fluid resuscitation. Point of care ultrasonography (POCUS) has evolved as a tool to perform whole-body assessments at the bedside to augment the physical exam and guide the resuscitation of the critically ill. This study will aim to explore the value of rigorous goal-directed resuscitation in aortic surgery using point of care ultrasonography (POCUS).

Methods: In an open-label, randomized, feasibility trial we enrolled 17 patients to receive resuscitation guided …

An Approach For The In-Vivo Characterization Of Brain And Heart Inflammation In Duchenne Muscular Dystrophy, Joanne Tang

Electronic Thesis and Dissertation Repository

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin loss—notably within muscles and CNS neurons. DMD presents as cognitive weakness, progressive skeletal and cardiac muscle degeneration until pre-mature death from cardiac or respiratory failure. Innovative therapies improved life expectancy, but this is accompanied by increased late-onset heart failure and emergent cognitive degeneration. Thus, there is an increasing need to both better understand and track disease pathophysiology in the dystrophic heart and brain prior to onset of severe degenerative symptoms. Chronic inflammation is strongly associated with skeletal and cardiac muscle degeneration, however chronic neuroinflammation’s role is largely unknown in …

The Role Of Regulator Of G Protein Signaling 2 In Inflammatory Cytokine Release In Endotoxemia In Mice, Xin Tong Ma

Electronic Thesis and Dissertation Repository

In sepsis, lipopolysaccharide (LPS) activates toll-like receptor 4 to stimulate the release of inflammatory cytokines (e.g. tumor necrosis factor-alpha, TNF-α), leading to cardiac dysfunction. Regulator of G protein signaling 2 (RGS2) limits G protein-coupled receptor signaling by increasing the rate of G protein deactivation or inhibiting G protein-effector interactions. We hypothesized that RGS2 deficiency would enhance proinflammatory responses in endotoxemia. Adult wild-type and RGS2^-/- C57BL/6 mice and neonatal cardiomyocytes were treated with LPS and assessed for inflammatory responses and cardiac function. Myocardial TNF-α expression was higher in RGS2^-/- mice during endotoxemia. Additionally, cardiac function was impaired in …

Boosting Cellular Nad+ Concentration With Nicotinamide Mononucleotide Prevents Doxorubicin-Induced Cardiotoxicity, Rebecca Dang

Electronic Thesis and Dissertation Repository

Doxorubicin (DOX) is a powerful chemotherapy that functions by interfering with cancer cells’ growth. However, the use of DOX is limited due to its detrimental side effects that can lead to serious cardiovascular complications. Our goal is to determine if nicotinamide mononucleotide (NMN) and histone acetyltransferase (HAT) inhibitors can protect against DOX-induced cardiotoxicity. Our findings revealed that DOX reduced NAD⁺ concentration and induced damage to H9c2 cells as evidenced by higher caspase-3 activity and lactate dehydrogenase release. Pre-incubation with NMN increased NAD⁺ concentration and attenuated DOX-induced damage. There was higher cell viability in the NMN pre-incubated group compared …

In-Hospital Outcomes Following Left Atrial Appendage Closure, Shubrandu S. Sanjoy

Electronic Thesis and Dissertation Repository

Left atrial appendage closure (LAAC) is a non-pharmacologic approach for stroke prevention in patients with atrial fibrillation. The impact of comorbidity burden on adverse outcomes following LAAC is very important for clinical decision making. Cohort-based observational study was conducted to evaluate the association of comorbidity burden with in-hospital complications. Of 3294 participants (mean age was 75.7±8.2 years), 60% were male and 86% whites. The majority of participants undergoing LAAC presented with a significant number of comorbid conditions. The occurrence of in-hospital major adverse events (MAE) was 4.6%. Women and patients exhibiting higher Charlson Comorbidity Index (adjusted odds ratio [aOR]: 1.14, …

Junctophilin-2 Protects Cardiomyocytes Against Palmitate-Induced Injury, Xiaoyun Ji

Electronic Thesis and Dissertation Repository

Cardiac lipotoxicity may induce cardiomyocyte apoptosis, eventually leading to myocardial dysfunction and heart failure. This study investigated whether and how junctophilin-2 (JPH2) plays a role in palmitate-induced apoptosis in cardiomyocytes. Here, we found palmitate incubation reduced JPH2 protein levels, increased cytosolic Ca²⁺ and induced apoptosis in cardiomyocytes. JPH2 over-expression prevented the increased cytosolic Ca²⁺ and apoptosis in palmitate-stimulated cardiomyocytes. JPH2 over-expression also attenuated palmitate-induced CCAAT-enhancer-binding protein homologous protein (CHOP) expression and CHOP deletion alleviated palmitate-induced apoptosis. Furthermore, blocking Ca²⁺ release from ryanodine receptor-2 (RyR2) prevented palmitate-stimulated CHOP induction and apoptosis. Additionally, JPH2 silencing elevated cytosolic Ca^{2+ …}

Assessing The Structure-Function Relationships Of The Apolipoprotein(A) Kringle Iv Sub-Type 10 Domain, Matthew J. Borrelli

Electronic Thesis and Dissertation Repository

Elevated plasma lipoprotein(a) (Lp(a)) is the most prevalent heritable risk factor in the development of cardiovascular disease. The apolipoprotein(a) (apo(a)) component of Lp(a) is strongly implicated in the pathogenicity of Lp(a). It is hypothesized that the inflammatory potential of Lp(a)/apo(a) is mediated by the lysine binding ability of the apo(a) kringle IV10 (KIV10) domain, along with its covalently bound oxidized phospholipid (oxPL). Using targeted mutagenesis, two novel null alleles for the LPA gene that generate non-secretable apo(a) species have been identified, resulting from amino acid substitutions in the KIV10 domain. A potential mechanism by which KIV10 oxPL modification is enriched …

Pregestational Diabetes Induced Congenital Heart Defects And Coronary Artery Malformations; Mechanisms And Preventative Therapies, Anish Engineer

Electronic Thesis and Dissertation Repository

Congenital heart defects (CHDs) arise from perturbations in complex molecular and cellular processes underlying normal embryonic heart development. CHDs are the most common congenital malformation, occurring in 1 to 5% of live births, and are the leading cause of pediatric mortality. Adverse genetic and environmental factors can impede normal cardiogenesis and increase the likelihood of CHDs. Pregestational maternal diabetes increases the risk of CHDs in children by more than four-fold. As the prevalence of diabetes rapidly rises among women of childbearing age, there is a need to investigate the mechanisms and potential preventative strategies for these defects. The aim of …

Microvascular Stenosis In Critical Limb Ischemia: Role Of Partial Endothelial To Mesenchymal Transition, Jacqueline M. Chevalier

Electronic Thesis and Dissertation Repository

Critical limb ischemia (CLI) is a widespread and debilitating manifestation of atherosclerosis. Unfortunately, revascularization strategies are often precluded or unsuccessful, resulting in amputation. A major reason for treatment failure is likely co-existing abnormalities in ­­the microvasculature. However, the specific microvascular defects present in end-stage PAD in humans remain unknown.

The purpose of this study was to delineate abnormalities in the microvascular wall in the critically ischemic skeletal muscle of patients with CLI.

To elucidate the microvascular landscape in CLI, we studied human tibialis anterior and gastrocnemius muscles harvested from below-knee amputations of 10 individuals with CLI. Control muscles are from …

Maternal Nicotine Exposure Induces Congenital Heart Defects In The Offspring Of Mice, Elizabeth Greco

Electronic Thesis and Dissertation Repository

Congenital heart defects are the most prevalent birth defect, and maternal cigarette smoking is a known risk factor. Nicotine replacement therapies are recommended to pregnant women who smoke to aid in smoking cessation, as this alternative is thought to be much safer compared to cigarette smoking. However, these products contain nicotine, and the safety of nicotine on the developing heart is not well known. In this thesis, a mouse model was used to test the hypothesis that maternal nicotine exposure (MNE) during pregnancy leads to congenital heart defects and coronary artery defects in the offspring of mice. MNE resulted in …

Apolipoprotein(A) Secretion Is Modulated By Sortilin, Proprotein Convertase Subtilisin/Kexin Type 9, And Microsomal Triglyceride Transfer Protein, Justin Clark

Electronic Thesis and Dissertation Repository

Elevated plasma lipoprotein(a) (Lp(a)) levels are a causal risk factor for cardiovascular disease (CVD), but development of specific Lp(a) lowering therapeutics has been hindered by insufficient understanding of Lp(a) biology. For example, the location of the noncovalent interaction that precedes the extracellular disulfide linkage between apolipoprotein(a) (apo(a)) and apolipoprotein B-100 (apoB-100) in Lp(a) biosynthesis is unclear. In this study we modulated known intracellular regulators of apoB-100 production and then assessed apo(a) secretion from human HepG2 cells expressing 17-kringle (17K) apo(a) isoform variants using pulse-chase analysis. Treating 17K-expressing HepG2 cells withproprotein convertase subtilisin-kexin type 9(PCSK9) significantly increased apo(a) secretion. Treating the …

Effects Of Niacin And Vitamin D On Endothelial Cell Angiogenic Function And Vascular Regeneration During Lipotoxicity, Kia Mae Peters

Electronic Thesis and Dissertation Repository

Observational studies have suggested an association between low levels of niacin and vitamin D and increased cardiovascular disease risk. Both vitamins have been shown to improve endothelial functions and vascular regeneration following vascular injury, however, it appears vitamin D may promote or inhibit neovascularization in a context-dependent manner. We hypothesized that supplementation of vitamin D alone and in combination with niacin, would improve endothelial cell function under lipotoxic conditions and promote revascularization and functional recovery in obese mice with ischemic injury. Matrigel assays, mRNA microarray analyses and growth rate assays were used to investigate angiogenic function of endothelial cells exposed …

The Purification Of Human Adult Progenitor Cell Types To Promote Angiogenesis, Stephen E. Sherman

Electronic Thesis and Dissertation Repository

Cellular transplantation strategies have aimed to combat critical limb ischemia (CLI) by inducing endogenous blood vessel regeneration. Transplantation of mesenchymal stromal cells (MSC) for CLI has proven safe and well-tolerated but demonstrated only modestly improved clinical outcomes explained in part by a lack of MSC survival and/or potency in ischemic tissues. This thesis focuses on the development of improved transplantation strategies for patients with CLI utilizing purified pro-angiogenic subsets of MSC and endothelial colony forming cells (ECFC) seeded within decellularized adipose tissue (DAT) bioscaffolds. First, I investigated whether purification of bone marrow-derived MSC based on a conserved stem cell function, …

Improving The Genetic Diagnosis Of Familial Hypercholesterolemia, Michael Iacocca

Electronic Thesis and Dissertation Repository

Familial hypercholesterolemia (FH) is a genetic disorder of severely elevated low-density lipoprotein (LDL) cholesterol that is widely underdiagnosed and undertreated. To improve the identification of FH and initiate timely and appropriate treatment strategies, genetic testing is becoming increasingly offered worldwide as a central part of diagnosis. I describe three main ways providing a genetic diagnosis in FH can be improved. First, next-generation sequencing (NGS)-based approaches can be used to reliably identify large-scale variant types known as copy number variations (CNVs) in the LDL receptor gene (LDLR); second, NGS methodology can be further applied to extend CNV screening to …

Analyzing Myocardial R2* Mapping Pre- And Post-Myocardial Infarction In A Canine Model, Khalid Abdalla

Electronic Thesis and Dissertation Repository

Myocardial hemorrhage (MH) may occur following myocardial infarction (MI). Myocardial hemorrhage can be assessed by image-based measurements of R2* (1/T2*) which are sensitive to iron-based byproducts of hemorrhage. However, automated detection of MH throughout the entire left ventricle (LV) is challenging due to R2* contributions from magnetic field distortions (susceptibility artifact). To provide insight for improved MH detection, we analyzed canine cardiac magnetic resonance images that had previously been acquired at baseline and several time points (3 to 41 days) following experimentally induced MI. The images were processed to generate R2* maps and cardiac polar plots. A baseline composite polar …