1,721,216 research outputs found
The Role of Endothelial-specific Autophagy-related Protein 7 in Doxorubicin-induced Cardiotoxicity
Full text linkDoxorubicin (DOX) is an effective, broad-spectrum antineoplastic agent with serious cardiotoxic side effects. Recent evidence has linked the dysregulation and destruction of the endothelium in the development of DOX-induced heart disease. Autophagy is an important pro-survival mechanism to recycle and remove damaged cellular constituents. Autophagy-related protein 7 (ATG7) catalyzes autophagosome formation, a critical step in autophagy. In this study, we used endothelial cell-specific Atg7 knockout (EC-Atg7-/-) mice to characterize the role of endothelial cell-specific autophagy in DOX-induced cardiotoxicity. DOX-treated EC-Atg7-/- mice showed reduced survival and a greater decline in cardiac function compared to wild-type controls. Histological assessments revealed increased cardiac fibrosis in DOX-treated EC-Atg7-/- mice. DOX-treated EC-Atg7-/- mice had elevated serum levels of creatine kinase-myocardial band, a biomarker for cardiac damage. Thus, endothelial cell-specific autophagy represented a protective pathway against DOX-induced cardiotoxicity.M.Sc.2021-06-22 00:00:0
The Effect of Empagliflozin on Kidney Injury Markers in Subjects with Type 2 Diabetes and Cardiovascular Disease: A Sub-analysis of the EMPA-HEART CardioLink-6 Trial
No full textSodium-glucose cotransporter 2 (SGLT2) inhibitors confer profound cardiorenal protection in type 2 diabetes (T2D). To better define potential mechanisms that underlie the renal benefits of SGLT2 inhibition, we assessed changes in various urinary biomarkers, sodium and glucose excretion, in a prespecified sub-analysis of the EMPA-HEART CardioLink-6 trial. In a cohort of patients with T2D at relatively low risk for diabetic kidney disease progression, empagliflozin treatment for six months reduced urinary kidney injury molecule-1 (KIM-1) excretion by 34% (p=0.03). No significant differences were observed with the other renal biomarkers. The reduction in KIM-1, in the absence of changes in albuminuria, raises the possibility that SGLT2 inhibitors act primarily to protect the proximal tubule, thus delaying the progression of diabetic kidney disease. Importantly, empagliflozin treatment did not significantly increase sodium excretion, suggesting that SGLT2 inhibitor-induced plasma volume reduction is a consequence of osmotic (glucose) diuresis rather than natriuresis.M.Sc
Long Non-coding RNA Fingerprint Regulated by Cyclic Mechanical Stress in Vascular Smooth Muscle Cells: Implications for Hypertension and Aortic Aneurysms
Full text linkLong noncoding RNAs (lncRNAs) are a new class of noncoding RNA and emerging evidence suggests that they represent a cellular hub for coordination of various cellular processes involved in health and disease. We hypothesized that lncRNAs may be involved in mechanical stretch-induced alterations in human aortic smooth muscle cells (HASMCs), which play a critical role in the pathophysiology of aneurysms and hypertension. Transcriptome analysis was performed on HASMCs that had been subjected to mechanical stretch. Human long intergenic non-coding RNA-p21 (hLincRNA-p21) was found to be significantly up-regulated in stretched HASMCs as well as in aneurysmal samples from patients undergoing aortic valve replacement (both PM.Sc
Long Non-coding RNA Fingerprint Regulated by Cyclic Mechanical Stress in Vascular Smooth Muscle Cells: Implications for Hypertension and Aortic Aneurysms
No full textLong noncoding RNAs (lncRNAs) are a new class of noncoding RNA and emerging evidence suggests that they represent a cellular hub for coordination of various cellular processes involved in health and disease. We hypothesized that lncRNAs may be involved in mechanical stretch-induced alterations in human aortic smooth muscle cells (HASMCs), which play a critical role in the pathophysiology of aneurysms and hypertension. Transcriptome analysis was performed on HASMCs that had been subjected to mechanical stretch. Human long intergenic non-coding RNA-p21 (hLincRNA-p21) was found to be significantly up-regulated in stretched HASMCs as well as in aneurysmal samples from patients undergoing aortic valve replacement (both PM.Sc
A Randomized Investigation of Icosapent Ethyl in Outpatients with COVID-19: Results from the VASCEPA-COVID-19 CardioLink-9 Trial
Full text linkCoronavirus disease 2019 (COVID-19) has had immense global implications on morbidity and mortality. At present, the development of therapeutic agents to combat COVID-19-related insults are considerably restrained. Safe and effective treatment options are urgently needed to reduce disease proliferation, inflammation and symptomatology. In response, the open-label VASCEPA-COVID-19 trial randomized 100 symptomatic COVID-19-positive outpatients in Toronto, Canada, to icosapent ethyl or usual care. Over a 14+3-day follow-up period, treatment with icosapent ethyl (4 g twice per day for 3 days, followed by 2 g twice per day for 11 days) was shown to significantly reduce high-sensitivity C-reactive protein, as well as, improve symptomatology. This study provides novel evidence of icosapent ethyl to have an early anti-inflammatory impact in a modest sample size of COVID-19 ambulatory patients, including the first demonstration of a well-tolerated icosapent ethyl loading dose. ClinicalTrials.gov Identifier: NCT04412018.M.Sc.2023-06-29 00:00:0
Impact of Bariatric Surgery on Circulating Inflammatory and Pro-vascular Progenitor Cell Populations
Full text linkObesity is a growing healthcare concern with more than 2 billion adults worldwide affected by unhealthy weight gain. Since bariatric surgery can induce significant cardiometabolic improvements and reduce adverse cardiovascular events, we hypothesized that these benefits may occur through decreased circulating inflammatory cell burden and increased pro-vascular progenitor cell content. High aldehyde dehydrogenase- (ALDH) activity and cell surface markers were assessed by flow cytometry for circulating progenitor cell content, M1/M2 macrophage balance, and pro-inflammatory cell burden between normal weight controls and individuals before and after bariatric surgery. At 3 months, ALDHhiSSChi granulocytes were reduced 2-fold and ALDHhiSSCmid monocyte/macrophage precursors were increased 2-fold, to frequencies equivalent to normal weight controls. Pro-angiogenic ALDHhiSSClow cells with primitive CD34+/CD133+ co-expression were enriched following surgery. Collectively, these data suggest that bariatric surgery induced beneficial changes in circulating progenitor cell content, consistent with improved vascular regenerative capacity and lower cardiovascular risk.M.Sc
Circulating Pro-vascular Progenitor Cell Content in Type 2 Diabetes
No full textThe chronic inflammation and oxidative stress associated with established type 2 diabetes (T2D) remains a major proponent of ischemic cardiovascular complications. Importantly, the bone marrow (BM) microenvironment plagued by hyperglycemia and oxidative stress hinders pro-vascular progenitor cells from self-renewing and undergoing pro-vascular cell differentiation through a process called “regenerative cell exhaustion”. This phenotype ultimately reduces progenitor cells’ ability to migrate to areas of ischemia and aid in the process of revascularization. Using multi-parametric flow cytometry, we hypothesized that this cellular phenotype, characterized by reduced migration and pro-angiogenic progenitor cell content, could be detected within the peripheral blood of individuals with established T2D. Patients with T2D displayed increased pro-inflammatory granulocyte precursors and reduced circulating progenitor cells with a pro-angiogenic phenotype. This translational work may create the foundation for diagnostic tests that monitor the capacity for revascularization and the efficacy of cellular therapies through a minimally invasive procedure.Ph.D
Cardiac Reverse Remodeling as a Mechanism for the Cardioprotective Benefits Offered by Sodium-Glucose Cotransporter 2 Inhibitors
Full text linkSodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated a marked ability to reduce the occurrence of adverse cardiovascular and heart failure events across a wide variety of patient populations. These benefits have been reported in patients with pre-existing heart failure, as well as in patients without prior documented heart failure who have risk factors. The profound clinical benefits associated with SGLT2i have sparked significant interest in elucidating the underlying mechanism(s) responsible for how SGLT2i delay the development and progression of heart failure. One postulated mechanism with merit involves the SGLT2i-mediated reversal of adverse cardiac remodeling. Within the current thesis, we aimed to investigate the mechanism responsible for the cardiac benefits associated with SGLT2i, to understand whether 6-month treatment with empagliflozin promoted cardiac reverse remodeling in patients without prevalent heart failure but who had risk factors. We also aimed to assess underlying factors that could influence the degree of benefit derived from SGLT2i treatment in relation to cardiac reverse remodeling. All assessments of cardiac structure and function in our studies were performed using gold-standard cardiac magnetic resonance imaging. We reported that (1) in patients with diabetes and coronary artery disease, those with an increased left ventricular mass indexed to body surface area (LVMi) at baseline experienced greater LVMi regression with empagliflozin over 6 months compared to patients with lower baseline LVMi. (2) Among individuals without diabetes or significant HF but with risk factors for adverse cardiac remodeling, as represented by an increased baseline LVM, SGLT2 inhibition with empagliflozin did not result in a significant reduction in LVMi after 6 months. This thesis presents novel insights suggesting that the cardiac reverse remodeling benefits derived from SGLT2i treatment may vary depending on the baseline demographics of the patient population, including the baseline severity of cardiac remodeling, baseline cardiovascular risk, and other currently unknown factors that may influence reverse remodeling. Overall, cardiac reverse remodeling may not be the only mechanism, but rather one of several mechanisms working simultaneously to improve outcomes in individuals treated with SGLT2i.Ph.D
The Role of Autophagy in the Pathogenesis and Clinical Course of Abdominal Aortic Aneurysms
No full textAbdominal aortic aneurysm (AAA) is a permanent progressive focal dilation of the aorta that is â Ľ 50% of the normal aortic diameter, due to loss of wall structural integrity. A fatal outcome of the progressive dilation due to the compromised aortic wall integrity is rupture. Mortality associated with rupture is ~88%. While the histopathological characteristics of AAA are well documented, cellular and molecular mechanisms involved in AAA pathogenesis are not entirely understood. Autophagy is a conserved housekeeping basal cellular process for the turnover of organelles and proteins that occur in all eukaryotic cells. It can also be activated as an adaptive response to stressful and pathological conditions to promote cell survival. However, contrary to the classical autophagy pro-survival role, in some circumstances, autophagy can lead to cellular demise. Increasing evidence suggests that autophagy perturbation is associated with the development of multiple age-related and chronic disorders. Also, preclinical studies have identified autophagy as a process that is activated in cardiovascular diseases such as atherosclerosis, which share several pathological features to AAA. Importantly, emerging evidence suggest that vascular cell autophagy is a reparative and protective process in atherosclerosis pathogenesis. While several autophagy-related genes were found to be upregulated in human aneurysmal tissue, the role of autophagy in AAA pathogenesis remains undefined. My research aim was to evaluate the potential role of autophagy in the development, progression and rupture of AAA. To achieve this, we initially sought to define autophagy gene expression in an experimental mouse model of AAA. Then to elucidate the functional role of autophagy in AAA evolution, we utilized both global and cell-specific loss of functional approaches. Our study demonstrated that autophagy was activated in the Ang II-infused ApoE-/- AAA mouse model. Global loss of functional approach via systemic administration of the autophagy inhibitor chloroquine (CQ) did not alter the development, progression or rupture of AAA in mice. However, smooth muscle specific (SMC) ATG7 deficiency enhanced the susceptibility to AAA formation evident by the formation of pre-aneurysmal changes, emphasizing the significance of intact SMC autophagy in impeding the development of pre- aneurysmal changes that otherwise may lead to AAA development.Ph.D.2018-12-19 00:00:0
The Effect of Empagliflozin on Left Ventricular Mass and Myocardial Extracellular Volume in Patients with Type 2 Diabetes and Cardiovascular Disease
Full text linkBackground: The sodium glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular (CV) outcomes in patients with type 2 diabetes (T2DM) and established CV disease (CVD) but the mechanism driving their cardio-benefit remains poorly understood. Specifically, whether SGLT2 inhibitors have direct cardiac effects remains unknown.
Objective: To evaluate the effects of the SGLT2 inhibitor empagliflozin on left ventricular (LV) mass index (LVMi) and myocardial extracellular volume (ECV) in individuals with T2DM and CVD.
Method: We randomized 97 participants with T2DM and CVD to receive empagliflozin 10 mg daily or placebo for 6 months in addition to standard of care therapy. The primary outcome was change in LVMi from baseline to 6 months determined by cardiac magnetic resonance. Other outcomes included change in indexed LV end diastolic volume (LVEDVi), end systolic volume (LVESVi) or ejection fraction (LVEF) and in circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponin I. For our sub-study with 74 participants we assessed ECV, indexed intracellular and extracellular compartment volume (iICV, iECV), the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase-2 (MMP-2).
Results: In the primary study, change in LVMi from baseline to 6-months was -2·6 (7·8) g/m2 for the empagliflozin group and -0·01 (5·7) g/m2 for placebo (adjusted difference between groups -3·4 g/m2; 95% Confidence Interval (CI), -5·9 to -0·8; P=0·01). There were no significant differences between groups for LVEDVi, LVESVi, LVEF nor in NT-proBNP and troponin I. In our sub-study, empagliflozin reduced ECV compared to placebo (adjusted difference: -1.4%; 95% CI, -2.6 to -0.14; P=0.03). This reduction in ECV in the empagliflozin group was observed after 6 months, alongside the reduction in LVMi. Empagliflozin therapy compared with placebo, also reduced iECV (adjusted difference: -1.5 mL/m2; 95% CI, -2.6 to -0.5; P=0.006) with a trend towards reduction in iICV (adjusted difference: -1.7 mL/m2; 95% CI, -3.8 to 0.3; P=0.09). Empagliflozin had no difference in impact upon circulating levels of MMP-2 or sST2 when compared to placebo.
Conclusions: In patients with T2DM and CVD, empagliflozin therapy was associated with a reduction in ECV in parallel to a reduction in LVMi which may contribute to its CV benefits.Ph.D
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