Publications by authors named "Mansoor Husain"

112 Publications

Dapagliflozin effects on lung fluid volumes in patients with heart failure and reduced ejection fraction: results from the DEFINE-HF Trial.

Diabetes Obes Metab 2021 Feb 19. Epub 2021 Feb 19.

Saint Luke's Mid America Heart Institute, Kansas City, Missouri.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have been shown to reduce the risk of CV death or worsening heart failure, improve symptom burden, physical function and quality of life in patients with heart failure and reduced ejection fraction. The mechanisms of HF benefits of SGLT-2is, however, remains unclear. In this substudy of the DEFINE-HF trial, patients randomized to dapagliflozin or placebo had lung fluid volumes measured by remote dieletric sensing at baseline and after twelve weeks of therapy. A significantly greater proportion of dapagliflozin-treated patients (as compared with placebo) experienced improvement in lung fluid volumes and fewer dapagliflozin-treated patients had no change or deterioration in lung fluid volumes after 12 weeks of treatment. To our knowledge, this is the first study to suggest a direct effect of dapagliflozin (or any SGLT2i) on more effective "decongestion", contributing in a meaningful way to the ongoing debate regarding the mechanisms of SGLT2i HF benefits. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/dom.14352DOI Listing
February 2021

Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide.

Diabetes Obes Metab 2021 Feb 19. Epub 2021 Feb 19.

University of North Carolina School of Medicine, Chapel Hill, NC, USA.

In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes (T2D) in both the 'established CV disease' (CVD) and 'CV risk factor' subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD than REWIND. This post hoc analysis assessed the effect of semaglutide on major adverse cardiovascular events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% versus 83.8%, respectively). After re-categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR], 95% confidence interval [CI]: 0.74 [0.59, 0.92]) and non-significantly lower in the CV risk factor subgroup (HR, 95% CI: 0.84 [0.55, 1.28]) (P-interaction=0.60). These results suggest that the CV effects of semaglutide may extend to patients with T2D across the CV risk continuum. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/dom.14360DOI Listing
February 2021

Découverte fortuite d’un cas de COVID-19 par TEP-TDM.

CMAJ 2020 11;192(45):E1425-E1426

Hôpital SickKids (Amin); Hôpital général de North York (Grinblat); Centre MyHealth (Grinblat); Réseau universitaire de santé (Husain), Toronto, Ont.

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http://dx.doi.org/10.1503/cmaj.200831-fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669302PMC
November 2020

Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials.

Cardiovasc Diabetol 2020 09 30;19(1):156. Epub 2020 Sep 30.

University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: Semaglutide is a glucagon-like peptide-1 (GLP-1) analog treatment for type 2 diabetes (T2D) available in subcutaneous (s.c.) and oral formulations. Two cardiovascular (CV) outcomes trials showed that in subjects with T2D at high risk of CV events there were fewer major adverse CV events (MACE; defined as CV death, non-fatal stroke, non-fatal myocardial infarction) with semaglutide than with placebo (hazard ratio [95% CI]: 0.74 [0.58;0.95] for once-weekly s.c. semaglutide and 0.79 [0.57;1.11] for once-daily oral semaglutide). However, there is little evidence for an effect of semaglutide on MACE in subjects not at high risk of CV events. This post hoc analysis examined CV effects of semaglutide in subjects across a continuum of baseline CV risk.

Methods: Data from the s.c. (SUSTAIN) and oral (PIONEER) semaglutide phase 3a clinical trial programs were combined according to randomized treatment (semaglutide or comparators) and analyzed to assess time to first MACE and its individual components. A CV risk model was developed with independent data from the LEADER trial (liraglutide vs placebo), considering baseline variables common to all datasets. Semaglutide data were analyzed to assess effects of treatment as a function of CV risk predicted using the CV risk prediction model.

Results: The CV risk prediction model performed satisfactorily when applied to the semaglutide data set (area under the curve: 0.77). There was a reduced relative and absolute risk of MACE for semaglutide vs comparators across the entire continuum of CV risk. While the relative risk reduction tended to be largest with low CV risk score, the largest absolute risk reduction was for intermediate to high CV risk score. Similar results were seen for relative risk reduction of the individual MACE components and also when only placebo comparator data were included.

Conclusion: Semaglutide reduced the risk of MACE vs comparators across the continuum of baseline CV risk in a broad T2D population. Trial registrations ClinicalTrials.gov identifiers: NCT02054897, NCT01930188, NCT01885208, NCT02128932, NCT02305381, NCT01720446, NCT02207374, NCT02254291, NCT02906930, NCT02863328, NCT02607865, NCT02863419, NCT02827708, NCT02692716, NCT02849080, NCT03021187, NCT03018028, NCT03015220.
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http://dx.doi.org/10.1186/s12933-020-01106-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526237PMC
September 2020

Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial.

Clin Trials 2020 10 20;17(5):491-500. Epub 2020 Aug 20.

Max Rady Faculty of Health Sciences, Max Rady College of Medicine, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.

Background: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care.

Methods: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death.

Conclusion: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.
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http://dx.doi.org/10.1177/1740774520943846DOI Listing
October 2020

Incidental COVID-19 on PET/CT imaging.

CMAJ 2020 06 22;192(23):E631. Epub 2020 May 22.

SickKids Hospital (Amin); North York General Hospital (Grinblat); MyHealth Centre (Grinblat); University Health Network (Husain), Toronto, Ont.

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http://dx.doi.org/10.1503/cmaj.200831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867216PMC
June 2020

Functional culture and in vitro genetic and small-molecule manipulation of adult mouse cardiomyocytes.

Commun Biol 2020 May 11;3(1):229. Epub 2020 May 11.

Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada.

Primary adult cardiomyocyte (aCM) represent the mature form of myocytes found in the adult heart. However, culture of aCMs in particular is challenged by poor survival and loss of phenotype, rendering extended in vitro experiments unfeasible. Here, we establish murine aCM culture methods that enhance survival and maintain sarcomeric structure and Ca cycling to enable physiologically relevant contractile force measurements. We also demonstrate genetic and small-molecule manipulations that probe mechanisms underlying myocyte functional performance. Together, these refinements to aCM culture present a toolbox with which to advance our understanding of myocardial physiology.
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http://dx.doi.org/10.1038/s42003-020-0946-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214405PMC
May 2020

Effects of Liraglutide on Cardiovascular Outcomes in Patients With Diabetes With or Without Heart Failure.

J Am Coll Cardiol 2020 03;75(10):1128-1141

University of North Carolina School of Medicine, Chapel Hill, North Carolina.

Background: More data regarding effects of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes (T2D) and heart failure (HF) are required.

Objectives: The purpose of this study was to investigate the effects of liraglutide on cardiovascular events and mortality in LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) participants, by HF history.

Methods: In the multinational, double-blind, randomized LEADER trial, 9,340 patients with T2D and high cardiovascular risk were assigned 1:1 to liraglutide (1.8 mg daily or maximum tolerated dose up to 1.8 mg daily) or placebo plus standard care, and followed for 3.5 to 5 years. New York Heart Association (NYHA) functional class IV HF was an exclusion criterion. The primary composite major adverse cardiovascular events outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Post hoc Cox regression analyses of outcomes by baseline HF history were conducted.

Results: At baseline, 18% of patients had a history of NYHA functional class I to III HF (liraglutide: n = 835 of 4,668; placebo: n = 832 of 4,672). Effects of liraglutide versus placebo on major adverse cardiovascular events were consistent in patients with (hazard ratio [HR]: 0.81 [95% confidence interval (CI): 0.65 to 1.02]) and without (HR: 0.88 [95% CI: 0.78 to 1.00]) a history of HF (p interaction = 0.53). In both subgroups, fewer deaths were observed with liraglutide (HR: 0.89 [95% CI: 0.70 to 1.14] with HF; HR: 0.83 [95% CI: 0.70 to 0.97] without HF; p interaction = 0.63) versus placebo. No increased risk of HF hospitalization was observed with liraglutide, regardless of HF history (HR: 0.98 [95% CI: 0.75 to 1.28] with HF; HR: 0.78 [95% CI: 0.61 to 1.00] without HF; p interaction = 0.22). Effects of liraglutide on the composite of HF hospitalization or cardiovascular death were consistent in patients with (HR: 0.92 [95% CI: 0.74 to 1.15]) and without (HR: 0.77 [95% CI: 0.65 to 0.91]) a history of HF (p interaction = 0.19).

Conclusions: Based on these findings, liraglutide should be considered suitable for patients with T2D with or without a history of NYHA functional class I to III HF. (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER]; NCT01179048).
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http://dx.doi.org/10.1016/j.jacc.2019.12.063DOI Listing
March 2020

Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α.

J Clin Invest 2020 03;130(3):1392-1404

Ted Rogers Centre for Heart Research, University of Toronto, Toronto, Ontario, Canada.

Mechanisms mediating the cardioprotective actions of glucagon-like peptide 1 (GLP-1) were unknown. Here, we show in both ex vivo and in vivo models of ischemic injury that treatment with GLP-1(28-36), a neutral endopeptidase-generated (NEP-generated) metabolite of GLP-1, was as cardioprotective as GLP-1 and was abolished by scrambling its amino acid sequence. GLP-1(28-36) enters human coronary artery endothelial cells (caECs) through macropinocytosis and acts directly on mouse and human coronary artery smooth muscle cells (caSMCs) and caECs, resulting in soluble adenylyl cyclase Adcy10-dependent (sAC-dependent) increases in cAMP, activation of protein kinase A, and cytoprotection from oxidative injury. GLP-1(28-36) modulates sAC by increasing intracellular ATP levels, with accompanying cAMP accumulation lost in sAC-/- cells. We identify mitochondrial trifunctional protein-α (MTPα) as a binding partner of GLP-1(28-36) and demonstrate that the ability of GLP-1(28-36) to shift substrate utilization from oxygen-consuming fatty acid metabolism toward oxygen-sparing glycolysis and glucose oxidation and to increase cAMP levels is dependent on MTPα. NEP inhibition with sacubitril blunted the ability of GLP-1 to increase cAMP levels in coronary vascular cells in vitro. GLP-1(28-36) is a small peptide that targets novel molecular (MTPα and sAC) and cellular (caSMC and caEC) mechanisms in myocardial ischemic injury.
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http://dx.doi.org/10.1172/JCI99934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269572PMC
March 2020

CFTR Therapeutics Normalize Cerebral Perfusion Deficits in Mouse Models of Heart Failure and Subarachnoid Hemorrhage.

JACC Basic Transl Sci 2019 Dec 27;4(8):940-958. Epub 2019 Nov 27.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

Heart failure (HF) and subarachnoid hemorrhage (SAH) chronically reduce cerebral perfusion, which negatively affects clinical outcome. This work demonstrates a strong relationship between cerebral artery cystic fibrosis transmembrane conductance regulator (CFTR) expression and altered cerebrovascular reactivity in HF and SAH. In HF and SAH, CFTR corrector compounds (C18 or lumacaftor) normalize pathological alterations in cerebral artery CFTR expression, vascular reactivity, and cerebral perfusion, without affecting systemic hemodynamic parameters. This normalization correlates with reduced neuronal injury. Therefore, CFTR therapeutics have emerged as valuable clinical tools to manage cerebrovascular dysfunction, impaired cerebral perfusion, and neuronal injury.
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http://dx.doi.org/10.1016/j.jacbts.2019.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939007PMC
December 2019

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk.

Diabetes Obes Metab 2020 03 5;22(3):442-451. Epub 2020 Feb 5.

Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Aim: To investigate the effects of semaglutide versus comparators on major adverse cardiovascular events (MACE: cardiovascular [CV] death, nonfatal myocardial infarction [MI] and nonfatal stroke) and hospitalization for heart failure (HF) in the SUSTAIN (subcutaneous semaglutide) and PIONEER (oral semaglutide) trials across subgroups of varying CV risk.

Methods: Post hoc analyses of individual patient-level data combined from SUSTAIN 6 and PIONEER 6 were performed to assess MACE and HF. MACE were analysed in subjects with and without: established CV disease and/or chronic kidney disease; prior MI or stroke; and prior HF. MACE in the SUSTAIN and PIONEER glycaemic efficacy trials were also assessed.

Results: In SUSTAIN 6 and PIONEER 6 combined, the hazard ratio (HR) for effect of semaglutide versus placebo on overall MACE was 0.76 (95% CI 0.62, 0.92), which was mainly driven by the effect on nonfatal stroke (HR 0.65 [95% CI 0.43, 0.97]). The HR for hospitalization for HF was 1.03 (95% CI 0.75, 1.40). The HRs for MACE were <1.0 in all subgroups, except for those with prior HF (HR 1.06 [95% CI 0.72, 1.57]); P-values for interaction of subgroup on treatment effect were >0.05, except for HF (0.046). In the combined glycaemic efficacy trials, the HR for effect of semaglutide versus comparators on MACE was 0.85 (95% CI 0.55, 1.33).

Conclusions: In SUSTAIN and PIONEER combined, glucagon-like peptide-1 analogue semaglutide showed consistent effects on MACE versus comparators across varying CV risk. No effect of semaglutide on MACE was observed in subjects with prior HF.
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http://dx.doi.org/10.1111/dom.13955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064975PMC
March 2020

Oral Semaglutide and Cardiovascular Outcomes in Type 2 Diabetes. Reply.

N Engl J Med 2019 11;381(21):2076-2077

Swansea University Medical School, Swansea, United Kingdom.

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http://dx.doi.org/10.1056/NEJMc1913157DOI Listing
November 2019

Heart failure with insulin degludec versus glargine U100 in patients with type 2 diabetes at high risk of cardiovascular disease: DEVOTE 14.

Cardiovasc Diabetol 2019 11 15;18(1):156. Epub 2019 Nov 15.

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Background: Heart failure (HF) is a common cardiovascular complication of type 2 diabetes (T2D). This secondary analysis investigated baseline factors and treatment differences associated with risk of hospitalization for HF (hHF), and the possible association between severe hypoglycemia and hHF.

Methods: DEVOTE was a treat-to-target, double-blind cardiovascular outcomes trial in patients (n = 7637) with T2D and high cardiovascular risk randomized to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). The main endpoint of this secondary analysis was time to first hHF (standardized MedDRA Query definition). Severe hypoglycemia was adjudicated (American Diabetes Association definition). The main endpoint and the temporal association between severe hypoglycemia and hHF were analyzed with a Cox proportional hazards regression model. Predictors of time to first hHF were identified using baseline variables.

Results: Overall, 372 (4.9%) patients experienced hHF (550 events). There was no significant difference in the risk of hHF between treatments (hazard ratio [HR] 0.88 [0.72;1.08], p = 0.227). Prior HF (HR 4.89 [3.90;6.14], p ≤ 0.0001) was the strongest predictor of future hHF events. The risk of hHF significantly increased after (HR 2.2), and within a week after (HR 11.1), experiencing a severe hypoglycemic episode compared with before an episode.

Conclusions: In patients with T2D and high cardiovascular risk there were no treatment differences in terms of hHF. Prior HF was the strongest predictor of future hHF events, and there was an association between severe hypoglycemia and subsequent hHF. Further research should evaluate whether the risk of hHF can be modified by treatments aimed at reducing hypoglycemia. Trial Registration NCT01959529.
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http://dx.doi.org/10.1186/s12933-019-0960-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858747PMC
November 2019

Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial.

Circulation 2019 10 16;140(18):1463-1476. Epub 2019 Sep 16.

Saint Luke's Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.).

Background: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown.

Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP.

Results: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), =0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal =0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all values for interaction=NS).

Conclusions: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042929DOI Listing
October 2019

Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

N Engl J Med 2019 08 11;381(9):841-851. Epub 2019 Jun 11.

From the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).

Background: Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide.

Methods: We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome).

Results: A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide.

Conclusions: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.).
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http://dx.doi.org/10.1056/NEJMoa1901118DOI Listing
August 2019

c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells.

Cell Rep 2019 05;27(8):2304-2312.e6

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada; Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada. Electronic address:

Mechanisms that govern transcriptional regulation of inflammation in atherosclerosis remain largely unknown. Here, we identify the nuclear transcription factor c-Myb as an important mediator of atherosclerotic disease in mice. Atherosclerosis-prone animals fed a diet high in cholesterol exhibit increased levels of c-Myb in the bone marrow. Use of mice that either harbor a c-Myb hypomorphic allele or where c-Myb has been preferentially deleted in B cell lineages revealed that c-Myb potentiates atherosclerosis directly through its effects on B lymphocytes. Reduced c-Myb activity prevents the expansion of atherogenic B2 cells yet associates with increased numbers of IgM-producing antibody-secreting cells (IgM-ASCs) and elevated levels of atheroprotective oxidized low-density lipoprotein (OxLDL)-specific IgM antibodies. Transcriptional profiling revealed that c-Myb has a limited effect on B cell function but is integral in maintaining B cell progenitor populations in the bone marrow. Thus, targeted disruption of c-Myb beneficially modulates the complex biology of B cells in cardiovascular disease.
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http://dx.doi.org/10.1016/j.celrep.2019.04.090DOI Listing
May 2019

Publisher Correction: Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction.

Nat Immunol 2019 May;20(5):664

Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, Canada.

In the version of this article initially published, the equal contribution of the third author was omitted. The footnote links for that author should be "Sara Nejat" and the correct statement is as follows: "These authors contributed equally: Sarah A. Dick, Jillian A. Macklin, Sara Nejat." The error has been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41590-019-0363-8DOI Listing
May 2019

B-Cell Deficiency Lowers Blood Pressure in Mice.

Hypertension 2019 03;73(3):561-570

From the Toronto General Hospital Research Institute, University Health Network, Canada (L.S.D., E.A.S., A.M., T.A., F.B., M.H.).

The proto-oncogene c-myb (and corresponding nuclear transcription factor, c-Myb) regulates the proliferation and differentiation of hematologic and vascular smooth muscle cells; however, the role of c-Myb in blood pressure regulation is unknown. Here, we show that mice homozygous for a hypomorphic c-myb allele ( c-myb ) conferring reduced c-Myb activity manifest reduced peripheral blood and kidney B220 B-cells and have decreased systolic (104±2 versus 120±1 mm Hg; P<0.0001) and diastolic blood pressure (71±2 versus 83±1 mm Hg; P<0.0001) compared with WT (wild type) mice. Additionally, c-myb mice had lower susceptibility to deoxycorticosterone acetate-salt experimental hypertension. Although cardiac (echocardiography) and resistance artery (perfusion myography) functions were normal, metabolic cage studies revealed that c-myb mice had increased 24-hour urine output and sodium excretion versus WT. Reconstitution of WT mice with c-myb bone marrow transplant and chimeric bone marrow transplant using mice lacking B-cells ( J T; h/h>WT and h/h:J T>WT, respectively) decreased blood pressure and increased 24-hour urine output compared with controls ( WT>WT; WT:J T>WT). J T mice also had decreased systolic (103±2 versus 115±1 mm Hg; P<0.0001) and diastolic blood pressure (71±2 versus 79±1; P<0.01) and increased 24-hour urine output versus WT. Real-time quantitative reverse transcription polymerase chain reaction of kidney medulla revealed reduced VR (vasopressin receptor 2) expression in c-myb and J T mice. These data implicate B-cells in the regulation of VR and its associated effects on salt and water handling and blood pressure homeostasis.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11828DOI Listing
March 2019

Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction.

Nat Immunol 2019 01 11;20(1):29-39. Epub 2018 Dec 11.

Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, Canada.

Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4LYVE1MHC-IICCR2 resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4LYVE1MHC-IICCR2 macrophages and fully replaced TIMD4LYVE1MHC-IICCR2 macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4 and TIMD4 resident macrophage abundance, whereas CCR2 monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages.
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http://dx.doi.org/10.1038/s41590-018-0272-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565365PMC
January 2019

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.

Diabetes Obes Metab 2019 03 11;21(3):499-508. Epub 2018 Nov 11.

Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario, Canada.

Aims: To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon-like peptide-1 receptor agonist.

Materials And Methods: PIONEER 6 is a multinational, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once-daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non-fatal myocardial infarction or non-fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event-driven, with follow-up continuing until accrual of at least 122 primary outcome events. There is no pre-defined minimal duration.

Results: Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD.

Conclusions: PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.
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http://dx.doi.org/10.1111/dom.13553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587508PMC
March 2019

c-Myb regulates transcriptional activation of miR-143/145 in vascular smooth muscle cells.

PLoS One 2018 31;13(8):e0202778. Epub 2018 Aug 31.

Ted Rogers Centre for Heart Research, University Health Network, Toronto, Canada.

Background: MicroRNAs (miR) are small non-coding RNAs that regulate diverse biological functions. The bicistronic gene miR-143/145 determines cell fate and phenotype of vascular smooth muscle cells (VSMC), in part, by destabilizing Elk-1 mRNA. The transcription factor c-Myb also regulates differentiation and proliferation of VSMC, and here we test whether these effects may be mediated by miR-143/145.

Methods & Results: Flow cytometry of cardiovascular-directed d3.75 embryoid bodies (EBs) isolated smooth muscle progenitors with specific cell surface markers. In c-myb knockout (c-myb -/-) EB, these progenitors manifest low levels of miR-143 (19%; p<0.05) and miR-145 (6%; p<0.01) expression as compared to wild-type (wt) EB. Primary VSMC isolated from transgenic mice with diminished expression (c-myblx/lx) or reduced activity (c-mybh/h) of c-Myb also manifest low levels of miR-143 (c-myblx/lx: 50%; c-mybh/h: 41%), and miR-145 (c-myblx/lx: 49%; c-mybh/h: 56%), as compared to wt (P<0.05). Sequence alignment identified four putative c-Myb binding sites (MBS1-4) in the proximal promoter (PP) of the miR-143/145 gene. PP-reporter constructs revealed that point mutations in MBS1 and MBS4 abrogated c-Myb-dependent transcription from the miR-143/145 PP (P<0.01). Chromatin immunoprecipitation (ChIP) revealed preferential c-Myb binding at MBS4 (p<0.001). By conjugating Elk-1 3'-untranslated region (UTR) to a reporter and co-transducing wt VSMC with this plus a miR-143-antagomir, and co-transducing c-myblx/lx VSMC with this plus a miR-143-mimic, we demonstrate that c-Myb's ability to repress Elk-1 is mediated by miR-143.

Conclusion: c-Myb regulates VSMC gene expression by transcriptional activation of miR-143/145.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202778PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118359PMC
February 2019

Molecular Mechanisms Underlying the Cardiovascular Benefits of SGLT2i and GLP-1RA.

Curr Diab Rep 2018 06 9;18(7):45. Epub 2018 Jun 9.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.

Purpose Of Review: In addition to their effects on glycemic control, two specific classes of relatively new anti-diabetic drugs, namely the sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have demonstrated reduced rates of major adverse cardiovascular events (MACE) in subjects with type 2 diabetes (T2D) at high risk for cardiovascular disease (CVD). This review summarizes recent experimental results that inform putative molecular mechanisms underlying these benefits.

Recent Findings: SGLT2i and GLP-1RA exert cardiovascular effects by targeting in both common and distinctive ways (A) several mediators of macro- and microvascular pathophysiology: namely (A1) inflammation and atherogenesis, (A2) oxidative stress-induced endothelial dysfunction, (A3) vascular smooth muscle cell reactive oxygen species (ROS) production and proliferation, and (A4) thrombosis. These agents also exhibit (B) hemodynamic effects through modulation of (B1) natriuresis/diuresis and (B2) the renin-angiotensin-aldosterone system. This review highlights that while GLP-1RA exert direct effects on vascular (endothelial and smooth muscle) cells, the effects of SGLT2i appear to include the activation of signaling pathways that prevent adverse vascular remodeling. Both SGLT2i and GLP-1RA confer hemodynamic effects that counter adverse cardiac remodeling.
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http://dx.doi.org/10.1007/s11892-018-1011-7DOI Listing
June 2018

Aortic Sca-1 Progenitor Cells Arise from the Somitic Mesoderm Lineage in Mice.

Stem Cells Dev 2018 07 31;27(13):888-897. Epub 2018 May 31.

1 Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network , Toronto, Canada .

Sca-1 progenitor cells in the adult mouse aorta are known to generate vascular smooth muscle cells (VSMCs), but their embryological origins and temporal abundance are not known. Using tamoxifen-inducible Myf5-Cre mice, we demonstrate that Sca-1 adult aortic cells arise from the somitic mesoderm beginning at E8.5 and continue throughout somitogenesis. Myf5 lineage-derived Sca-1 cells greatly expand in situ, starting at 4 weeks of age, and become a major source of aortic Sca-1 cells by 6 weeks of age. Myf5-derived adult aortic cells are capable of forming multicellular sphere-like structures in vitro and express the pluripotency marker Sox2. Exposure to transforming growth factor-β3 induces these spheres to differentiate into calponin-expressing VSMCs. Pulse-chase experiments using tamoxifen-inducible Sox2-Cre mice at 8 weeks of age demonstrate that ∼35% of all adult aortic Sca-1 cells are derived from Sox2 cells. The present study demonstrates that aortic Sca-1 progenitor cells are derived from the somitic mesoderm formed at the earliest stages of somitogenesis and from Sox2-expressing progenitors in adult mice.
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http://dx.doi.org/10.1089/scd.2018.0038DOI Listing
July 2018

Cardiac-specific inducible overexpression of human plasma membrane Ca ATPase 4b is cardioprotective and improves survival in mice following ischemic injury.

Clin Sci (Lond) 2018 03 26;132(6):641-654. Epub 2018 Mar 26.

Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G-2C4, Canada

Heart failure (HF) is associated with reduced expression of plasma membrane Ca-ATPase 4 (PMCA4). Cardiac-specific overexpression of human PMCA4b in mice inhibited nNOS activity and reduced cardiac hypertrophy by inhibiting calcineurin. Here we examine temporally regulated cardiac-specific overexpression of hPMCA4b in mouse models of myocardial ischemia reperfusion injury (IRI) , and HF following experimental myocardial infarction (MI) Doxycycline-regulated cardiomyocyte-specific overexpression and activity of hPMCA4b produced adaptive changes in expression levels of Ca-regulatory genes, and induced hypertrophy without significant differences in Ca transients or diastolic Ca concentrations. Total cardiac NOS and nNOS-specific activities were reduced in mice with cardiac overexpression of hPMCA4b while nNOS, eNOS and iNOS protein levels did not differ. hMPCA4b-overexpressing mice also exhibited elevated systolic blood pressure vs. controls, with increased contractility and lusitropy In isolated hearts undergoing IRI, hPMCA4b overexpression was cardioprotective. NO donor-treated hearts overexpressing hPMCA4b showed reduced LVDP and larger infarct size versus vehicle-treated hearts undergoing IRI, demonstrating that the cardioprotective benefits of hPMCA4b-repressed nNOS are lost by restoring NO availability. Finally, both pre-existing and post-MI induction of hPMCA4b overexpression reduced infarct expansion and improved survival from HF. Cardiac PMCA4b regulates nNOS activity, cardiac mass and contractility, such that PMCA4b overexpression preserves cardiac function following IRI, heightens cardiac performance and limits infarct progression, cardiac hypertrophy and HF, even when induced late post-MI. These data identify PMCA4b as a novel therapeutic target for IRI and HF.
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http://dx.doi.org/10.1042/CS20171337DOI Listing
March 2018

A CD103 Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis.

Immunity 2017 11;47(5):974-989.e8

Toronto General Hospital Research Institute, University Health Network (UHN), Toronto ON, M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto ON, M5S 1A1, Canada; Department of Immunology, University of Toronto, Toronto ON, M5S 1A1, Canada; Peter Munk Cardiac Centre, Toronto ON, M5G 1L7, Canada; Ted Rogers Centre for Heart Research, Toronto ON, M5G 1L7, Canada. Electronic address:

Innate and adaptive immune cells modulate heart failure pathogenesis during viral myocarditis, yet their identities and functions remain poorly defined. We utilized a combination of genetic fate mapping, parabiotic, transcriptional, and functional analyses and demonstrated that the heart contained two major conventional dendritic cell (cDC) subsets, CD103 and CD11b, which differentially relied on local proliferation and precursor recruitment to maintain their tissue residency. Following viral infection of the myocardium, cDCs accumulated in the heart coincident with monocyte infiltration and loss of resident reparative embryonic-derived cardiac macrophages. cDC depletion abrogated antigen-specific CD8 T cell proliferative expansion, transforming subclinical cardiac injury to overt heart failure. These effects were mediated by CD103 cDCs, which are dependent on the transcription factor BATF3 for their development. Collectively, our findings identified resident cardiac cDC subsets, defined their origins, and revealed an essential role for CD103 cDCs in antigen-specific T cell responses during subclinical viral myocarditis.
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http://dx.doi.org/10.1016/j.immuni.2017.10.011DOI Listing
November 2017

HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner.

Am J Physiol Heart Circ Physiol 2018 01 6;314(1):H31-H44. Epub 2017 Oct 6.

Medical Sciences Graduate Program, McMaster University , Hamilton, Ontario , Canada.

Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1) and wild-type mice (apoA1) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1 mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1 mice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1/2 activation in cardiomyocytes. NEW & NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.
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http://dx.doi.org/10.1152/ajpheart.00521.2016DOI Listing
January 2018

Diagnostic and prognostic significance of transient ischemic dilation (TID) in myocardial perfusion imaging: A systematic review and meta-analysis.

J Nucl Cardiol 2018 06 25;25(3):724-737. Epub 2017 Sep 25.

Division of Cardiology, Peter Munk Cardiac Center and the Joint Department of Medical Imaging, Toronto, Canada.

Background: Transient ischemic dilatation (TID) of the left ventricle is a potential marker of high risk obstructive coronary artery disease on stress myocardial perfusion imaging (MPI). There is, however, interstudy variation in the diagnostic performance of TID for identification of severe and extensive coronary disease anatomy, and varied prognostic implications in the published literature.

Methods: We searched MEDLINE, EMBASE, and COCHRANE databases for studies where TID was compared with invasive or CT coronary angiography for evaluation of coronary artery stenosis. Two reviewers independently evaluated and abstracted data from each study. A bivariate random effects model was used to derive pooled sensitivities and specificities, in order to account for correlation between TID in MPI and anatomic disease severity.

Results: A total of 525 articles were reviewed, of which 51 met inclusion criteria. Thirty-one studies contributed to the analysis, representing a total of 2037 patients in the diagnostic meta-analysis and 9003 patients in the review of prognosis. The ratio above which TID was deemed present ranged from 1.13 to 1.38. Pooled sensitivity was 44% (95% CI 30%-60%) and specificity was 88% (95% CI 83%-92%) for the detection of extensive or severe anatomic coronary artery disease. Analysis of outcome data demonstrated increased cardiac event rates in patients with TID and an abnormal MPI. In otherwise normal perfusion, TID is an indicator of poor prognosis in patients with diabetes and/or a history of coronary disease.

Conclusions: Among patients undergoing MPI, the presence of TID is specific for the detection of extensive or severe coronary artery disease.
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http://dx.doi.org/10.1007/s12350-017-1040-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966496PMC
June 2018

-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria.

Infect Immun 2017 09 18;85(9). Epub 2017 Aug 18.

Sandra Rotman Centre for Global Health, University Health Network, University of Toronto, Toronto, ON, Canada

Artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by -nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme, -nitrosoglutathione reductase (GSNOR), which exhibit enhanced -nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria. GSNOR knockout (KO) mice infected with ANKA had significantly delayed mortality compared to WT animals ( < 0.0001), despite higher parasite burdens ( < 0.01), and displayed markedly enhanced survival versus the wild type (WT) when treated with the antimalarial drug artesunate (77% versus 38%; < 0.001). Improved survival was associated with higher levels of protein-bound NO, decreased levels of CD4 and CD8 T cells in the brain, improved blood-brain barrier integrity, and improved coma scores, as well as higher levels of gamma interferon. GSNOR KO animals receiving WT bone marrow had significantly reduced survival following ANKA infection compared to those receiving KO bone barrow ( < 0.001). Reciprocal transplants established that survival benefits of GSNOR deletion were attributable primarily to the T cell compartment. These data indicate a role for GSNOR in the host response to malaria infection and suggest that strategies to disrupt its activity will improve clinical outcomes by enhancing microvascular integrity and modulating T cell tissue tropism.
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http://dx.doi.org/10.1128/IAI.00371-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563579PMC
September 2017

Paradoxical Suppression of Atherosclerosis in the Absence of microRNA-146a.

Circ Res 2017 Aug 21;121(4):354-367. Epub 2017 Jun 21.

From the Toronto General Hospital Research Institute, University Health Network, Ontario, Canada (H.S.C, R.B., A.L., Z.C., E.A.S., N.K., S.A.M., M.H., M.I.C., C.S.R., J.E.F.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada (H.S.C, R.B., A.L., Z.C., E.A.S., N.K., S.A.M., M.H., M.I.C., C.S.R., J.E.F.); Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, Ontario, Canada (H.S.C, R.B., A.L., Z.C., E.A.S., N.K., M.H., M.I.C., C.S.R., J.E.F.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Germany (M.N.-J., A.S.); INSERM, Unit 970, Paris Cardiovascular Research Center-PARCC, France (A.H., C.M.B.); University of Ottawa Heart Institute, Ontario, Canada (M.-A.N., M.G., K.J.R.); and Pharmacology and Nutritional Sciences, University of Kentucky, Lexington (L.C., T.L., R.E.T.).

Rationale: Inflammation is a key contributor to atherosclerosis. MicroRNA-146a (miR-146a) has been identified as a critical brake on proinflammatory nuclear factor κ light chain enhancer of activated B cells signaling in several cell types, including endothelial cells and bone marrow (BM)-derived cells. Importantly, miR-146a expression is elevated in human atherosclerotic plaques, and polymorphisms in the precursor have been associated with risk of coronary artery disease.

Objective: To define the role of endogenous miR-146a during atherogenesis.

Methods And Results: Paradoxically, (low-density lipoprotein receptor null) mice deficient in develop less atherosclerosis, despite having highly elevated levels of circulating proinflammatory cytokines. In contrast, cytokine levels are normalized in mice receiving wild-type BM transplantation, and these mice have enhanced endothelial cell activation and elevated atherosclerotic plaque burden compared with mice receiving wild-type BM, demonstrating the atheroprotective role of miR-146a in the endothelium. We find that deficiency of in BM-derived cells precipitates defects in hematopoietic stem cell function, contributing to extramedullary hematopoiesis, splenomegaly, BM failure, and decreased levels of circulating proatherogenic cells in mice fed an atherogenic diet. These hematopoietic phenotypes seem to be driven by unrestrained inflammatory signaling that leads to the expansion and eventual exhaustion of hematopoietic cells, and this occurs in the face of lower levels of circulating low-density lipoprotein cholesterol in mice lacking in BM-derived cells. Furthermore, we identify sortilin-1(), a known regulator of circulating low-density lipoprotein levels in humans, as a novel target of miR-146a.

Conclusions: Our study reveals that miR-146a regulates cholesterol metabolism and tempers chronic inflammatory responses to atherogenic diet by restraining proinflammatory signaling in endothelial cells and BM-derived cells.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.310529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542783PMC
August 2017

Skin-derived precursors from human subjects with Type 2 diabetes yield dysfunctional vascular smooth muscle cells.

Clin Sci (Lond) 2017 Aug 5;131(15):1801-1814. Epub 2017 Jul 5.

Toronto General Hospital Research Institute, University Health Network, Toronto, Canada

Objective Few methods enable molecular and cellular studies of vascular aging or Type 2 diabetes (T2D). Here, we report a new approach to studying human vascular smooth muscle cell (VSMC) pathophysiology by examining VSMCs differentiated from progenitors found in skin. Approach and results Skin-derived precursors (SKPs) were cultured from biopsies (=164, ∼1 cm) taken from the edges of surgical incisions of older adults (=158; males 72%; mean age 62.7 ± 13 years) undergoing cardiothoracic surgery, and differentiated into VSMCs at high efficiency (>80% yield). The number of SKPs isolated from subjects with T2D was ∼50% lower than those without T2D (cells/g: 0.18 ± 0.03, =58 versus 0.40 ± 0.05, =100, <0.05). Importantly, SKP-derived VSMCs from subjects with T2D had higher Fluo-5F-determined baseline cytosolic Ca concentrations (AU: 1,968 ± 160, =7 versus 1,386 ± 170, =13, <0.05), and a trend toward greater Ca cycling responses to norepinephrine (NE) (AUC: 177,207 ± 24,669, =7 versus 101,537 ± 15,881, =20, <0.08) despite a reduced frequency of Ca cycling (events s cell: 0.011 ± 0.004, =8 versus 0.021 ± 0.003, =19, <0.05) than those without T2D. SKP-derived VSMCs from subjects with T2D also manifest enhanced sensitivity to phenylephrine (PE) in an impedance-based assay (EC nM: 72.3 ± 63.6, =5 versus 3,684 ± 3,122, =9, <0.05), and impaired wound closure (% closure: 21.9 ± 3.6, =4 versus 67.0 ± 10.3, =4, <0.05). Compared with aortic- and saphenous vein-derived primary VSMCs, SKP-derived VSMCs are functionally distinct, but mirror defects of T2D also exhibited by primary VSMCs.

Conclusion: Skin biopsies from older adults yield sufficient SKPs to differentiate VSMCs, which reveal abnormal phenotypes of T2D that survive differentiation and persist even after long-term normoglycemic culture.
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http://dx.doi.org/10.1042/CS20170239DOI Listing
August 2017