Publications by authors named "Paymon M Azizi"

5 Publications

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The cost-effectiveness of transcatheter aortic valve replacement in low surgical risk patients with severe aortic stenosis.

Eur Heart J Qual Care Clin Outcomes 2020 Jul 9. Epub 2020 Jul 9.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.

Aims: The economic value of transcatheter aortic valve replacement (TAVR) in low surgical risk patients with severe, symptomatic aortic stenosis is not known. Our objective was to determine the cost-effectiveness of balloon-expandable TAVR and self-expandable TAVR relative to surgical aortic valve replacement (SAVR) in low risk patients.

Methods/results: A fully probabilistic Markov cohort model was constructed to estimate differences in costs and effectiveness (quality-adjusted life years [QALYs]) over the patient's life-time time from the third party payer's perspective. Clinical outcomes modeled were: alive/well (no complications), permanent stroke, ≥moderate paravalvular leak, new pacemaker, rehospitalization, and death. A network meta-analysis of the PARTNER 3 and Evolut Low Risk trial was performed to compare balloon-expandable TAVR, self-expandable TAVR, and SAVR for the efficacy inputs. Incremental-cost effectiveness ratios (ICER) were calculated.The total lifetime costs in the balloon-expandable TAVR, self-expandable-TAVR, and SAVR arms were $37,330±4,724, $39,660±4,862, and $34,583±6,731 respectively and total lifetime QALYs gained were 9.15±3.23, 9.13±3.23, and 9.05±3.20 respectively. The ICERs for balloon-expandable TAVR and self-expandable TAVR against SAVR were $27,196/QALY and $59,641/QALY respectively. Balloon-expandable TAVR was less costly and more effective than self-expandable TAVR. There was substantial uncertainty, with 53% and 58% of model iterations showing balloon-expandable TAVR to be the preferred option at willingness-to-pay thresholds of $50,000/QALY and $100,000/QALY respectively.

Conclusions: Compared to SAVR, TAVR, particularly with balloon-expandable prostheses may be a cost-effective option for patients with severe aortic stenosis at low surgical risk.
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http://dx.doi.org/10.1093/ehjqcco/qcaa058DOI Listing
July 2020

Left ventricular strain analysis using cardiac magnetic resonance imaging in patients undergoing in-centre nocturnal haemodialysis.

Nephrology (Carlton) 2019 May;24(5):557-563

Division of Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada.

Aim: Intensified haemodialysis is associated with regression of left ventricular (LV) mass. Compared to LV ejection fraction, LV strain allows more direct assessment of LV function. We sought to assess the impact of in-centre nocturnal haemodialysis (INHD) on global LV strain (radial, circumferential, and longitudinal) and torsion by cardiac MRI (CMR).

Methods: In this prospective, two-centre cohort study, 37 participants on conventional haemodialysis (CHD, 3-4 h/session for three sessions/week) converted to INHD (7-8 h/session for three sessions/week) and 30 participants continued CHD. Participants underwent CMR using a standardized protocol and had biomarker measurements at baseline and 52 weeks.

Results: Among the 55 participants (mean age 55; 40% women) with complete CMR data, those who converted to INHD had a significant improvement in their global circumferential strain (GCS, P = 0.025), while those continuing CHD did not have any significant changes in LV strain. When the two groups were compared, there was significant improvement in torsion. LV strains were significantly correlated with each other, but not with troponin I, C-reactive protein, or brain natriuretic protein (NT-proBNP), except for global longitudinal strain (GLS) with troponin I (P = 0.001) and NT-proBNP (P = 0.038).

Conclusion: Conversion to INHD was associated with significant improvement in GCS over one year of study, although comparisons with the CHD group were not significant. There was also a significant decrease in torsion in the INHD group compared with CHD. Improvement in LV regional function would support the notion that INHD has favourable effects on both LV structure and function.
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http://dx.doi.org/10.1111/nep.13404DOI Listing
May 2019

Prostaglandin I2 Receptor Agonism Preserves β-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms.

Diabetes 2016 05 11;65(5):1398-409. Epub 2016 Feb 11.

Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada

Discovery of common pathways that mediate both pancreatic β-cell function and end-organ function offers the opportunity to develop therapies that modulate glucose homeostasis and separately slow the development of diabetes complications. Here, we investigated the in vitro and in vivo effects of pharmacological agonism of the prostaglandin I2 (IP) receptor in pancreatic β-cells and in glomerular podocytes. The IP receptor agonist MRE-269 increased intracellular 3',5'-cyclic adenosine monophosphate (cAMP), augmented glucose-stimulated insulin secretion (GSIS), and increased viability in MIN6 β-cells. Its prodrug form, selexipag, augmented GSIS and preserved islet β-cell mass in diabetic mice. Determining that this preservation of β-cell function is mediated through cAMP/protein kinase A (PKA)/nephrin-dependent pathways, we found that PKA inhibition, nephrin knockdown, or targeted mutation of phosphorylated nephrin tyrosine residues 1176 and 1193 abrogated the actions of MRE-269 in MIN6 cells. Because nephrin is important to glomerular permselectivity, we next set out to determine whether IP receptor agonism similarly affects nephrin phosphorylation in podocytes. Expression of the IP receptor in podocytes was confirmed in cultured cells by immunoblotting and quantitative real-time PCR and in mouse kidneys by immunogold electron microscopy, and its agonism 1) increased cAMP, 2) activated PKA, 3) phosphorylated nephrin, and 4) attenuated albumin transcytosis. Finally, treatment of diabetic endothelial nitric oxide synthase knockout mice with selexipag augmented renal nephrin phosphorylation and attenuated albuminuria development independently of glucose change. Collectively, these observations describe a pharmacological strategy that posttranslationally modifies nephrin and the effects of this strategy in the pancreas and in the kidney.
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http://dx.doi.org/10.2337/db15-0783DOI Listing
May 2016

Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promote monocyte adhesion and impair insulin transcytosis.

Am J Physiol Endocrinol Metab 2015 Jul 5;309(1):E35-44. Epub 2015 May 5.

Cell Biology Program, the Hospital for Sick Children, Toronto, Ontario, Canada;

Obesity is associated with inflammation and immune cell recruitment to adipose tissue, muscle and intima of atherosclerotic blood vessels. Obesity and hyperlipidemia are also associated with tissue insulin resistance and can compromise insulin delivery to muscle. The muscle/fat microvascular endothelium mediates insulin delivery and facilitates monocyte transmigration, yet its contribution to the consequences of hyperlipidemia is poorly understood. Using primary endothelial cells from human adipose tissue microvasculature (HAMEC), we investigated the effects of physiological levels of fatty acids on endothelial inflammation and function. Expression of cytokines and adhesion molecules was measured by RT-qPCR. Signaling pathways were evaluated by pharmacological manipulation and immunoblotting. Surface expression of adhesion molecules was determined by immunohistochemistry. THP1 monocyte interaction with HAMEC was measured by cell adhesion and migration across transwells. Insulin transcytosis was measured by total internal reflection fluorescence microscopy. Palmitate, but not palmitoleate, elevated the expression of IL-6, IL-8, TLR2 (Toll-like receptor 2), and intercellular adhesion molecule 1 (ICAM-1). HAMEC had markedly low fatty acid uptake and oxidation, and CD36 inhibition did not reverse the palmitate-induced expression of adhesion molecules, suggesting that inflammation did not arise from palmitate uptake/metabolism. Instead, inhibition of TLR4 to NF-κB signaling blunted palmitate-induced ICAM-1 expression. Importantly, palmitate-induced surface expression of ICAM-1 promoted monocyte binding and transmigration. Conversely, palmitate reduced insulin transcytosis, an effect reversed by TLR4 inhibition. In summary, palmitate activates inflammatory pathways in primary microvascular endothelial cells, impairing insulin transport and increasing monocyte transmigration. This behavior may contribute in vivo to reduced tissue insulin action and enhanced tissue infiltration by immune cells.
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http://dx.doi.org/10.1152/ajpendo.00611.2014DOI Listing
July 2015

Clathrin-dependent entry and vesicle-mediated exocytosis define insulin transcytosis across microvascular endothelial cells.

Mol Biol Cell 2015 Feb 24;26(4):740-50. Epub 2014 Dec 24.

Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada Keenan Research Centre, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada Department of Microbiology and Immunology, University of Western Ontario, London, ON N6A 5C1, Canada Interdepartmental Division of Critical Care, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada

Transport of insulin across the microvasculature is necessary to reach its target organs (e.g., adipose and muscle tissues) and is rate limiting in insulin action. Morphological evidence suggests that insulin enters endothelial cells of the microvasculature, and studies with large vessel-derived endothelial cells show insulin uptake; however, little is known about the actual transcytosis of insulin and how this occurs in the relevant microvascular endothelial cells. We report an approach to study insulin transcytosis across individual, primary human adipose microvascular endothelial cells (HAMECs), involving insulin uptake followed by vesicle-mediated exocytosis visualized by total internal reflection fluorescence microscopy. In this setting, fluorophore-conjugated insulin exocytosis depended on its initial binding and uptake, which was saturable and much greater than in muscle cells. Unlike its degradation within muscle cells, insulin was stable within HAMECs and escaped lysosomal colocalization. Insulin transcytosis required dynamin but was unaffected by caveolin-1 knockdown or cholesterol depletion. Instead, insulin transcytosis was significantly inhibited by the clathrin-mediated endocytosis inhibitor Pitstop 2 or siRNA-mediated clathrin depletion. Accordingly, insulin internalized for 1 min in HAMECs colocalized with clathrin far more than with caveolin-1. This study constitutes the first evidence of vesicle-mediated insulin transcytosis and highlights that its initial uptake is clathrin dependent and caveolae independent.
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http://dx.doi.org/10.1091/mbc.E14-08-1307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325843PMC
February 2015
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