Publications by authors named "Richard Gilbert"

270 Publications

Real-time impedance feedback to enhance cutaneous gene electrotransfer in a murine skin model.

Bioelectrochemistry 2021 Jul 13;142:107885. Epub 2021 Jul 13.

Department of Chemical, Biological, and Materials Engineering, University of South Florida, 4202 E. Fowler Ave ENG 030, Tampa, FL 33620, USA; Center for Molecular Delivery at USF, University of South Florida, 4202 E. Fowler Ave ENG 030, Tampa, FL 33620, USA; Department of Medical Engineering, University of South Florida, 4202 E. Fowler Avenue ENG 030, Tampa, FL 33620, USA. Electronic address:

Electric field mediated gene delivery methods have the ability to efficiently transfect cells in vivo with an excellent safety profile. The method has historically used a fixed number of electric pulses with identical characteristics in induce delivery. Electrical treatment does not typically compensate for subject-to-subject variation and other differences. This study was designed to investigate if delivery/expression could be increased using a novel electropulsation method that compensated for variation using real-time electrical impedance measurements. The method involved delivering plasmid DNA encoding luciferase to murine skin. Tissue impedance in a 1-3 KHz range was measured before electric pulses were applied. Impedance was also measured after each successive pulse. Pulsation was stopped when impedance values were reduced by either 80% or 95% relative to prepulse values. Standard/fixed pulsing parameters were also used for comparison. The results indicated that up to 15-fold increases in luciferase expression could be obtained when electrical treatment was ceased based upon impedance reductions. Furthermore, peak expression levels of all treatment groups pulsed using the novel pulsing method were statistically higher than those that employed standard pulsing. These results strongly suggest that applying pulses until a defined impedance-based endpoint results in higher expression.
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http://dx.doi.org/10.1016/j.bioelechem.2021.107885DOI Listing
July 2021

Impact of sodium glucose linked cotransporter-2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus.

Physiol Rep 2021 Jun;9(12):e14890

Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.

Background: The mechanisms whereby inhibitors of sodium-glucose linked cotransporter-2 (SGLT2) exert their nephroprotective effects in patients with diabetes are incompletely understood but have been hypothesized to include improved tissue oxygen tension within the renal cortex. The impact of SGLT2 inhibition is likely complex and region specific within the kidney. We hypothesize that SGLT2 inhibitors have differential effects on renal tissue oxygen delivery and consumption in specific regions of the diabetic kidney, including the superficial cortex, containing SGLT2-rich components of proximal tubules, versus the deeper cortex and outer medulla, containing predominantly SGLT1 receptors.

Methods: We measured glomerular filtration rate (GFR), microvascular kidney oxygen tension (P O ), erythropoietin (EPO) mRNA, and reticulocyte count in diabetic rats (streptozotocin) treated with the SGLT2 inhibitor, dapagliflozin. Utilizing phosphorescence quenching by oxygen and an intravascular oxygen sensitive probe (Oxyphor PdG4); we explored the effects of SGLT2 inhibition on P O in a region-specific manner, in vivo, in diabetic and non-diabetic rats. Superficial renal cortical or deeper cortical and outer medullary P O were measured utilizing excitations with blue and red light wavelengths, respectively.

Results: In diabetic rats treated with dapagliflozin, measurement within the superficial cortex (blue light) demonstrated no change in P O . By contrast, measurements in the deeper cortex and outer medulla (red light) demonstrated a significant reduction in P O in dapagliflozin treated diabetic rats (p = 0.014). Consistent with these findings, GFR was decreased, hypoxia-responsive EPO mRNA levels were elevated and reticulocyte counts were increased with SGLT2 inhibition in diabetic rats (p < 0.05 for all).

Conclusions: These findings indicate that microvascular kidney oxygen tension is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of SGLT-2 inhibition on tissue metabolism. This reduction in deeper P O had biological impact as demonstrated by increased renal EPO mRNA levels and circulating reticulocyte count.
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http://dx.doi.org/10.14814/phy2.14890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239445PMC
June 2021

Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility.

J Mol Cell Cardiol 2021 Jul 26;156:33-44. Epub 2021 Mar 26.

Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL 60153, USA; Heart, Lung and Vascular Institute, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA. Electronic address:

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N')-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C), displayed dilated cardiomyopathy, underscoring the importance of the N'-region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N'-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.
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http://dx.doi.org/10.1016/j.yjmcc.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217138PMC
July 2021

Intraoperative Red Blood Cell Transfusion Decision-making: A Systematic Review of Guidelines.

Ann Surg 2021 07;274(1):86-96

Department of Surgery, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.

Objectives: The objective of this work was to carry out a systematic review of clinical practice guidelines (CPGs) pertaining to intraoperative red blood cell (RBC) transfusions, in terms of indications, decision-making, and supporting evidence base.

Summary Of Background Data: RBC transfusions are common during surgery and there is evidence of wide variability in practice.

Methods: Major electronic databases (MEDLINE, EMBASE, and CINAHL), guideline clearinghouses and Google Scholar were systematically searched from inception to January 2019 for CPGs pertaining to indications for intraoperative RBC transfusion. Eligible guidelines were retrieved and their quality assessed using AGREE II. Relevant recommendations were abstracted and synthesized to allow for a comparison between guidelines.

Results: Ten guidelines published between 1992 and 2018 provided indications for intraoperative transfusions. No guideline addressed intraoperative transfusion decision-making as its primary focus. Six guidelines provided criteria for transfusion based on hemoglobin (range 6.0-10.0 g/dL) or hematocrit (<30%) triggers. In the absence of objective transfusion rules, CPGs recommended considering other parameters such as blood loss (n = 7), signs of end organ ischemia (n = 5), and hemodynamics (n = 4). Evidence supporting intraoperative recommendations was extrapolated primarily from the nonoperative setting. There was wide variability in the quality of included guidelines based on AGREE II scores.

Conclusion: This review has identified several clinical practice guidelines providing recommendations for intraoperative transfusion. The existing guidelines were noted to be highly variable in their recommendations and to lack a sufficient evidence base from the intraoperative setting. This represents a major knowledge gap in the literature.
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http://dx.doi.org/10.1097/SLA.0000000000004710DOI Listing
July 2021

Empagliflozin Reduces Myocardial Extracellular Volume in Patients With Type 2 Diabetes and Coronary Artery Disease.

JACC Cardiovasc Imaging 2021 Jun 13;14(6):1164-1173. Epub 2021 Jan 13.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Division of Cardiology, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address:

Objectives: This study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD).

Background: Empagliflozin has been shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown.

Methods: This was a prespecified substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes) CardioLink-6 trial in which 97 participants were randomized to receive empagliflozin 10 mg daily or placebo for 6 months. Data from 74 participants were included: 39 from the empagliflozin group and 35 from the placebo group. The main outcome was change in left ventricular ECV from baseline to 6 months determined by cardiac magnetic resonance (CMR). Other outcomes included change in LVMi, indexed intracellular compartment volume (iICV) and indexed extracellular compartment volume (iECV), and the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase (MMP)-2.

Results: Baseline ECV was elevated in the empagliflozin group (29.6 ± 4.6%) and placebo group (30.6 ± 4.8%). Six months of empagliflozin therapy reduced ECV compared with placebo (adjusted difference: -1.40%; 95% confidence interval [CI]: -2.60 to -0.14%; p = 0.03). Empagliflozin therapy reduced iECV (adjusted difference: -1.5 ml/m; 95% CI: -2.6 to -0.5 ml/m; p = 0.006), with a trend toward reduction in iICV (adjusted difference: -1.7 ml/m; 95% CI: -3.8 to 0.3 ml/m; p = 0.09). Empagliflozin had no impact on MMP-2 or sST2.

Conclusions: In individuals with T2DM and CAD, 6 months of empagliflozin reduced ECV, iECV, and LVMi. No changes in MMP-2 and sST2 were seen. Further investigation into the mechanisms by which empagliflozin causes reverse remodeling is required. (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes [EMPA-HEART]; NCT02998970).
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http://dx.doi.org/10.1016/j.jcmg.2020.10.017DOI Listing
June 2021

Late intervention in the remnant kidney model attenuates proteinuria but not glomerular filtration rate decline.

Nephrology (Carlton) 2021 Mar 11;26(3):270-279. Epub 2021 Jan 11.

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

Aim: The use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting.

Methods: We used the remnant kidney (subtotal nephrectomy [SNX]) rat model that develops a decline in GFR in conjunction with heavy proteinuria and hypertension along with the histological hallmarks of CKD in humans, glomerulosclerosis and tubulointerstitial fibrosis. Using agents that had been shown to improve GFR as well as proteinuria in the prevention setting, angiotensin-converting enzyme (ACE) inhibition with enalapril and SIRT1 activation with SRT3025, treatment was initiated 6 weeks after SNX.

Results: While enalapril reduced blood pressure, proteinuria and histological injury, it did not improve GFR, as measured by inulin clearance. SRT3025 improved neither GFR nor structural damage despite a reduction in proteinuria.

Conclusion: These findings demonstrate that neither a reduction in proteinuria nor a reversal of structural damage in the kidney will necessarily translate to a restoration of kidney function.
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http://dx.doi.org/10.1111/nep.13828DOI Listing
March 2021

Renal microvascular oxygen tension during hyperoxia and acute hemodilution assessed by phosphorescence quenching and excitation with blue and red light.

Can J Anaesth 2021 Feb 10;68(2):214-225. Epub 2020 Nov 10.

Department of Anesthesia, St. Michael's Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada.

Purpose: The kidney plays a central physiologic role as an oxygen sensor. Nevertheless, the direct mechanism by which this occurs is incompletely understood. We measured renal microvascular partial pressure of oxygen (PO) to determine the impact of clinically relevant conditions that acutely change PO including hyperoxia and hemodilution.

Methods: We utilized two-wavelength excitation (red and blue spectrum) of the intravascular phosphorescent oxygen sensitive probe Oxyphor PdG4 to measure renal tissue PO in anesthetized rats (2% isoflurane, n = 6) under two conditions of altered arterial blood oxygen content (CO): 1) hyperoxia (fractional inspired oxygen 21%, 30%, and 50%) and 2) acute hemodilutional anemia (baseline, 25% and 50% acute hemodilution). The mean arterial blood pressure (MAP), rectal temperature, arterial blood gases (ABGs), and chemistry (radiometer) were measured under each condition. Blue and red light enabled measurement of PO in the superficial renal cortex and deeper cortical and medullary tissue, respectively.

Results: PO was higher in the superficial renal cortex (~ 60 mmHg, blue light) relative to the deeper renal cortex and outer medulla (~ 45 mmHg, red light). Hyperoxia resulted in a proportional increase in PO values while hemodilution decreased microvascular PO in a linear manner in both superficial and deeper regions of the kidney. In both cases (blue and red light), PO correlated with CO but not with MAP.

Conclusion: The observed linear relationship between CO and PO shows the biological function of the kidney as a quantitative sensor of anemic hypoxia and hyperoxia. A better understanding of the impact of changes in PO may inform clinical practices to improve renal oxygen delivery and prevent acute kidney injury.
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http://dx.doi.org/10.1007/s12630-020-01848-5DOI Listing
February 2021

The management of occult hemothorax in adults with thoracic trauma: A systematic review and meta-analysis.

J Trauma Acute Care Surg 2020 12;89(6):1225-1232

From the University of Ottawa (R.W.G., A.M.F., L.P., A.T.); and Trauma Services, Division of General Surgery (R.W.G., A.M.F., A.T., J.L.), Department of Surgery, The Ottawa Hospital, Ottawa, Ontario, Canada.

Background: Hemothorax is a common sequelae following thoracic trauma and is associated with significant morbidity and mortality. Current guidelines recommend all traumatic hemothoraces be considered for drainage with tube thoracostomy (TT), regardless of size. With increasing use of computed tomography, smaller hemothoraces not seen on x-ray (defined as an occult hemothorax) are frequently detected.

Methods: This systematic review was performed to gather data on patients with occult hemothorax managed with TT or without TT (termed expectant management [EM]). MEDLINE, EMBASE, and Cochrane databases from inception to October 2019 were searched for relevant articles. The primary outcome was rates of failure of expectant (conservative) management. Secondary outcomes of interest included predictors of TT insertion, predictors of failure of EM, and morbidity and mortality in patients with occult hemothorax.

Results: We screened 1,329 abstracts from which 6 articles reporting 1,405 patients with occult hemothorax were included. Of these patients, 601 (43.68%) were managed initially with TT, and 802 (56.32%) were managed expectantly. Of the 802 patients managed expectantly, 212 failed conservative management and underwent TT insertion (23.1% pooled failure rate estimate [95% confidence interval, 17.1-29.1%]). The presence of concomitant pneumothorax predicted upfront TT insertion. Of the patients who failed EM, the need for mechanical ventilation and the presence of a large hemothorax predicted failure. Mortality was similar in both groups.

Conclusions: Conservative treatment of occult hemothorax fails in 23.1% of patients. The presence of hemothorax greater than 300 mL and the need for mechanical ventilation predicted failure of conservative treatment and the need for TT. There was no difference in mortality between EM and TT cohorts. These data suggest that it may be possible to safely observe patients with occult hemothoraces less than 300 mL (1.5 cm pleural stripe) secondary to blunt trauma without upfront TT insertion.

Level Of Evidence: Systematic review and meta-analysis, level III.
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http://dx.doi.org/10.1097/TA.0000000000002936DOI Listing
December 2020

Overexpression of the Severe Acute Respiratory Syndrome Coronavirus-2 Receptor, Angiotensin-Converting Enzyme 2, in Diabetic Kidney Disease: Implications for Kidney Injury in Novel Coronavirus Disease 2019.

Can J Diabetes 2021 Mar 18;45(2):162-166.e1. Epub 2020 Jul 18.

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

Objectives: Diabetes is associated with adverse outcomes, including death, after coronavirus disease 19 (COVID-19) infection. Beyond the lungs, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiologic agent of the COVID-19 pandemic, can infect a range of other tissues, including the kidney, potentially contributing to acute kidney injury in those with severe disease. We hypothesized that the renal abundance of angiotensin-converting enzyme (ACE) 2, the cell surface receptor for SARS-CoV-2, may be modulated by diabetes and agents that block the renin-angiotensin-aldosterone system (RAAS).

Methods: The expression of ACE 2 was examined in 49 archival kidney biopsies from patients with diabetic kidney disease and from 12 healthy, potential living allograft donors using next-generation sequencing technology (RNA Seq).

Results: Mean ACE 2 messenger RNA was increased approximately 2-fold in diabetes when compared with healthy control subjects (mean ± SD, 13.2±7.9 vs 7.7±3.6 reads per million reads, respectively; p=0.001). No difference in transcript abundance was noted between recipients and nonrecipients of agents that block the RAAS (12.2±6.7 vs 16.2±10.7 reads per million reads, respectively; p=0.25).

Conclusions: Increased ACE 2 messenger RNA in the diabetic kidney may increase the risk and/or severity of kidney infection with SARS-CoV-2 in the setting of COVID-19 disease. Further studies are needed to ascertain whether this diabetes-related overexpression is generalizable to other tissues, most notably the lungs.
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http://dx.doi.org/10.1016/j.jcjd.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368650PMC
March 2021

Adaptive and innate immune mechanisms in cardiac fibrosis complicating pulmonary arterial hypertension.

Physiol Rep 2020 08;8(15):e14532

Warren Alpert Medical School of Brown University, Providence VA Medical Center, Providence, RI, USA.

Pulmonary arterial hypertension (PAH) is a syndrome diagnosed by increased mean pulmonary artery (PA) pressure and resistance and normal pulmonary capillary wedge pressure. PAH is characterized pathologically by distal pulmonary artery remodeling, increased pulmonary vascular resistance, and plexiform lesions (PLs). Right ventricular fibrosis and hypertrophy, leading to right ventricular failure, are the main determinants of mortality in PAH. Recent work suggests that right ventricular fibrosis results from resident cardiac fibroblast activation and conversion to myofibroblasts, leading to replacement of contractile cardiomyocytes with nondistensible tissue incapable of conductivity or contractility. However, the origins, triggers, and consequences of myofibroblast expansion and its pathophysiological relationship with PAH are unclear. Recent advances indicate that signals generated by adaptive and innate immune cells may play a role in right ventricular fibrosis and remodeling. This review summarizes recent insights into the mechanisms by which adaptive and innate immune signals participate in the transition of cardiac fibroblasts to activated myofibroblasts and highlights the existing gaps of knowledge as relates to the development of right ventricular fibrosis.
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http://dx.doi.org/10.14814/phy2.14532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422804PMC
August 2020

Renal histology in diabetic nephropathy predicts progression to end-stage kidney disease but not the rate of renal function decline.

BMC Nephrol 2020 07 18;21(1):285. Epub 2020 Jul 18.

Division of Nephrology, St. Michael's Hospital, Unity Health Toronto and University of Toronto, 30 Bond St, Toronto, ON, M5B 1W8, Canada.

Background: While histopathologic changes correlate with functional impairment in cross-sectional studies of diabetic nephropathy (DN), whether these findings predict future rate of kidney function loss remains uncertain. We thus sought to examine the relationship between kidney histopathology, incidence of end-stage kidney disease (ESKD), and rate of estimated glomerular filtration rate (eGFR) loss in DN.

Methods: In this longitudinal cohort study, we studied 50 adults diagnosed with biopsy-proven DN. We analyzed the histopathologic parameters of each patient's kidney biopsy, as defined by the Renal Pathology Society classification system for DN, and tracked all available eGFR measurements post-biopsy. We additionally collected baseline clinical parameters (at the time of biopsy), including eGFR, albumin-to-creatinine ratio (ACR), and hemoglobin A. Multivariable linear regression was used to assess the relationship between histologic and clinical parameters at the time of the biopsy and eGFR slope. Kaplan-Meier curves and Cox regression were used to evaluate the association between histologic and clinical parameters and ESKD incidence.

Results: Progression to ESKD was associated with worsening interstitial fibrosis score (p = 0.05), lower baseline eGFR (p = 0.02), higher ACR (p = 0.001), and faster eGFR decline (p < 0.001). The rate of eGFR decline did not associate with any histologic parameter. Baseline ACR was the only studied variable correlating with eGFR slope (rho = - 0.41).

Conclusions: Renal histology predicts ultimate progression to ESKD, but not the rate of progression. Future work is required to identify novel predictors of rapid functional decline in patients with diabetic nephropathy.
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http://dx.doi.org/10.1186/s12882-020-01943-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368674PMC
July 2020

Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3 variant.

Biophys Rev 2020 Aug 12;12(4):1065-1084. Epub 2020 Jul 12.

Division of Cardiovascular Health and Disease, Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0575, USA.

Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by ventricular enlargement, diastolic dysfunction, and increased risk for sudden cardiac death. Sarcomeric genetic defects are the predominant known cause of HCM. In particular, mutations in the myosin-binding protein C gene (MYBPC3) are associated with ~ 40% of all HCM cases in which a genetic basis has been established. A decade ago, our group reported a 25-base pair deletion in intron 32 of MYBPC3 (MYBPC3) that is uniquely prevalent in South Asians and is associated with autosomal dominant cardiomyopathy. Although our studies suggest that this deletion results in left ventricular dysfunction, cardiomyopathies, and heart failure, the precise mechanism by which this variant predisposes to heart disease remains unclear. Increasingly appreciated, however, is the contribution of secondary risk factors, additional mutations, and lifestyle choices in augmenting or modifying the HCM phenotype in MYBPC3 carriers. Therefore, the goal of this review article is to summarize the current research dedicated to understanding the molecular pathophysiology of HCM in South Asians with the MYBPC3 variant. An emphasis is to review the latest techniques currently applied to explore the MYBPC3 pathogenesis and to provide a foundation for developing new diagnostic strategies and advances in therapeutics.
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http://dx.doi.org/10.1007/s12551-020-00725-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429610PMC
August 2020

The Long-Term Effects of COVID-19 on Dysphagia Evaluation and Treatment.

Arch Phys Med Rehabil 2020 09 10;101(9):1662-1664. Epub 2020 Jun 10.

Laboratory for Biological Architecture, Research Service, Providence VAMC, Warren Alpert Medical School, Brown University, Providence, RI.

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http://dx.doi.org/10.1016/j.apmr.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286637PMC
September 2020

Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children.

Can J Cardiol 2020 05;36(5):596-624

Service de néphrologie, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Quebec, Canada.

Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.
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http://dx.doi.org/10.1016/j.cjca.2020.02.086DOI Listing
May 2020

Improving the treatment of pre-operative anemia in hepato-pancreato-biliary patients: a quality improvement initiative.

Patient Saf Surg 2020 24;14:18. Epub 2020 Apr 24.

2Department of Surgery, The Ottawa Hospital - General Campus, 501 Smyth Road, Ottawa, ON K1H 8 L6 Canada.

Background: Pre-operative anemia is a common, but treatable, condition encountered by surgical patients. It has been associated with increased perioperative complications, length of stay, and blood transfusions. The aim of this project was to increase the treatment rate of pre-operative anemia to 75% of patients consented for major hepato-pancreato-biliary (HPB) surgery.

Methods: This was an interrupted time series study and a spread initiative from a similar project in a colorectal surgery population. Interventions included an anemia screening and treatment algorithm, standardized blood work, referral to a patient blood management program, and standardized oral iron prescriptions. The primary outcome measure was the change in pre-operative anemia treatment rate and the secondary outcome measure was the post treatment increase in hemoglobin.

Results: A total of 208 patients were included ( = 124 pre-intervention and  = 84 post-intervention). Anemia was present in 39.9% of patients. The treatment rate of pre-operative anemia increased to 44.1% from 28.6%. The mean hemoglobin increased from 110 g/L to 119 g/L in patients who were treated ( = 0.03). There was no significant increase or decrease in blood transfusions or mean number of red cell units transfused per patient. Screening rates for pre-operative anemia increased from 41.1 to 64.3% and appropriate referrals to the patient blood management program increased from 14.3 to 67.6%.

Conclusions: This study demonstrates a small scale spread initiative focused on the treatment of pre-operative anemia. Although the goal to treat 75% of anemic patients was not reached, an effective referral pathway to an existing patient blood management program was developed, and a significant increase in the mean hemoglobin in anemic patients who have been treated pre-operatively was demonstrated.
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http://dx.doi.org/10.1186/s13037-020-00239-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181477PMC
April 2020

Renal tissue Po sensing during acute hemodilution is dependent on the diluent.

Am J Physiol Regul Integr Comp Physiol 2020 04 4;318(4):R799-R812. Epub 2020 Mar 4.

Department of Anesthesia, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Sensing changes in blood oxygen content ([Formula: see text]) is an important physiological role of the kidney; however, the mechanism(s) by which the kidneys sense and respond to changes in [Formula: see text] are incompletely understood. Accurate measurements of kidney tissue oxygen tension ([Formula: see text]) may increase our understanding of renal oxygen-sensing mechanisms and could inform decisions regarding the optimal fluid for intravascular volume resuscitation to maintain renal perfusion. In some clinical settings, starch solution may be nephrotoxic, possibly due to inadequacy of tissue oxygen delivery. We hypothesized that hemodilution with starch colloid solutions would reduce [Formula: see text] to a more severe degree than other diluents. Anesthetized Sprague-Dawley rats ( = 77) were randomized to undergo hemodilution with either colloid (6% hydroxyethyl starch or 5% albumin), crystalloid (0.9% saline), or a sham procedure (control) ( = 13-18 rats/group). Data were analyzed by ANOVA with significance assigned at < 0.05. After hemodilution, mean arterial pressure (MAP) decreased marginally in all groups, while hemoglobin (Hb) and [Formula: see text] decreased in proportion to the degree of hemodilution. Cardiac output was maintained in all groups after hemodilution. [Formula: see text] decreased in proportion to the reduction in Hb in all treatment groups. At comparably reduced Hb, and maintained arterial oxygen values, hemodilution with starch resulted in larger decreases in [Formula: see text] relative to animals hemodiluted with albumin or saline ( < 0.008). Renal medullary erythropoietin (EPO) mRNA levels increased more prominently, relative to other hypoxia-regulated molecules (GLUT-1, GAPDH, and VEGF). Our data demonstrate that the kidney acts as a biosensor of reduced [Formula: see text] following hemodilution and that [Formula: see text] may provide a quantitative signal for renal cellular responsiveness to acute anemia. Evidence of a more severe reduction in [Formula: see text] following hemodilution with starch colloid solution suggests that tissue hypoxia may contribute to starch induced renal toxicity.
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http://dx.doi.org/10.1152/ajpregu.00323.2019DOI Listing
April 2020

Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction.

Cardiovasc Diabetol 2020 02 8;19(1):13. Epub 2020 Feb 8.

Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 61 Queen Street East, Toronto, M5C 2T2, ON, Canada.

Background And Aims: Sodium-glucose linked cotransporter-2 (SGLT2) inhibitors reduce the likelihood of hospitalization for heart failure and cardiovascular death in both diabetic and non-diabetic individuals with reduced ejection fraction heart failure. Because SGLT2 inhibitors lead to volume contraction with reductions in both preload and afterload, these load-dependent factors are thought to be major contributors to the cardioprotective effects of the drug class. Beyond these effects, we hypothesized that SGLT2 inhibitors may also improve intrinsic cardiac function, independent of loading conditions.

Methods: Pressure-volume (P-V) relationship analysis was used to elucidate changes in intrinsic cardiac function, independent of alterations in loading conditions in animals with experimental myocardial infarction, a well-established model of HFrEF. Ten-week old, non-diabetic Fischer F344 rats underwent ligation of the left anterior descending (LAD) coronary artery to induce myocardial infarction (MI) of the left ventricle (LV). Following confirmation of infarct size with echocardiography 1-week post MI, animals were randomized to receive vehicle, or the SGLT2 inhibitor, empagliflozin. Cardiac function was assessed by conductance catheterization just prior to termination 6 weeks later.

Results: The circumferential extent of MI in animals that were subsequently randomized to vehicle or empagliflozin groups was similar. Empagliflozin did not affect fractional shortening (FS) as assessed by echocardiography. In contrast, load-insensitive measures of cardiac function were substantially improved with empagliflozin. Load-independent measures of cardiac contractility, preload recruitable stroke work (PRSW) and end-systolic pressure volume relationship (ESPVR) were higher in rats that had received empagliflozin. Consistent with enhanced cardiac performance in the heart failure setting, systolic blood pressure (SBP) was higher in rats that had received empagliflozin despite its diuretic effects. A trend to improved diastolic function, as evidenced by reduction in left ventricular end-diastolic pressure (LVEDP) was also seen with empagliflozin. MI animals treated with vehicle demonstrated myocyte hypertrophy, interstitial fibrosis and evidence for changes in key calcium handling proteins (all p < 0.05) that were not affected by empagliflozin therapy.

Conclusion: Empagliflozin therapy improves cardiac function independent of loading conditions. These findings suggest that its salutary effects are, at least in part, due to actions beyond a direct effect of reduced preload and afterload.
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http://dx.doi.org/10.1186/s12933-020-0994-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007658PMC
February 2020

Comparison of Ligation of the Intersphincteric Fistula Tract and BioLIFT for the Treatment of Transsphincteric Anal Fistula: A Retrospective Analysis.

Dis Colon Rectum 2020 03;63(3):365-370

Department of Surgery, The Ottawa Hospital, Ottawa, Ontario, Canada.

Background: Ligation of the intersphincteric fistula tract is a sphincter-preserving technique for the treatment of anal fistulas. The BioLIFT modification involves the placement of a biologic mesh in the intersphincteric plane. Advocates of this modification state improved healing rates, however evidence for this is lacking, and this approach costs significantly more.

Objective: The purpose of this study was to compare the healing rates of the ligation of the intersphincteric fistula tract with the BioLIFT.

Design: This was a retrospective cohort study.

Settings: The study was conducted at a tertiary care hospital from April 2008 to April 2018.

Patients: All adult patients with transsphincteric anal fistulas were included. Patients were excluded if they had IBD, more than 1 fistula tract operated on simultaneously, or a previous attempt at repair.

Main Outcome Measures: The primary outcome was primary healing of the fistula tract, and secondary outcomes included overall success, complications, and time to recurrence.

Results: There were 119 cases (75 ligation of the intersphincteric fistula tract and 44 BioLIFTs). One surgeon performed 84% of the BioLIFT cases. The primary healing rate was 75.0% versus 58.7% (p = 0.08), and the complication rate was 22.7% versus 17.3% (p = 0.48; BioLIFT vs ligation of intersphincteric fistula tract). After multivariate logistic regression, the BioLIFT had a significantly better healing rate (OR = 2.38 (95% CI, 1.01-5.62); p = 0.048). Median follow-up was 9 versus 29 weeks (BioLIFT vs ligation of intersphincteric fistula tract). Kaplan-Meier analysis demonstrated no difference in the time to recurrence (p = 0.48).

Limitations: This study was limited by the retrospective nature, different lengths of follow-up, and varying case numbers between the surgeons.

Conclusions: The BioLIFT modification is safe and effective for the treatment of anal fistulas but has a higher cost. This modification warrants additional prospective studies to establish its benefits over the ligation of the intersphincteric fistula tract procedure. See Video Abstract at http://links.lww.com/DCR/B139. COMPARACIÓN DE LIFT VERSUS BIOLIFT PARA EL TRATAMIENTO DE LA FÍSTULA ANAL TRANSFINTERÉRICA: UN ANÁLISIS RETROSPECTIVO: Ligadura del tracto de la fístula interesfintérica es una técnica para preservación del esfínter en el tratamiento de las fístulas anales. La modificación BioLIFT implica la colocación de una malla biológica en el plano interesfintérico. Protagonistas de la modificación mejoraron las tasas de curación, sin embargo, carecen evidencias definitivas y la técnica eleva costos significativamente.Comparar las tasas de curación de ligadura del tracto de la fístula interesfintérica con el BioLIFT.Estudio de cohorte retrospectivo.Hospital de atención de tercer nivel desde abril de 2008 hasta abril de 2018.Se incluyeron todos los pacientes adultos con fístulas anales transfinteréricas. Los pacientes fueron excluidos si tenían enfermedad inflamatoria intestinal, más de un tracto fistuloso operado simultáneamente o con un intento previo de reparación.El resultado principal fue la curación primaria del tracto fistuloso y los resultados secundarios incluyeron el éxito en general, las complicaciones y tiempo hasta recurrencia.Se registraron 119 casos (75 ligaduras del tracto de la fístula interesfintérica y 44 BioLIFT). Un cirujano realizó el 84% de los casos de BioLIFT. La tasa de curación primaria fue del 75.0% vs 58.7%, p = 0.08, y la tasa de complicaciones fue del 22.7% vs 17.3%, p = 0.48 comparando BioLIFT vs ligadura del tracto de la fístula interesfintérica. Después de la regresión logística multivariada, el BioLIFT tuvo una tasa de curación significativamente mejor (OR 2.38 [IC 95% 1.01-5.62], p = 0.048). La mediana de seguimiento fue de 9 vs 29 semanas (BioLIFT vs ligadura del tracto de la fístula interesfintérica). El análisis de Kaplan-Meier no demostró diferencias en el tiempo hasta la recurrencia (p = 0,48).Este estudio estuvo limitado por ser retrospectivo, las diferentes duraciones de seguimiento y el número variable de casos entre los cirujanos.La modificación BioLIFT es segura y efectiva para el tratamiento de las fístulas anales pero tiene un costo más alto. Esta modificación amerita más estudios prospectivos para establecer los beneficios sobre ligadura del tracto de la fístula interesfintérica. Consulte Video Resumen en hhttp://links.lww.com/DCR/B139.
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http://dx.doi.org/10.1097/DCR.0000000000001573DOI Listing
March 2020

The safety and efficacy of hypovolemic phlebotomy on blood loss and transfusion in liver surgery: a systematic review and meta-analysis.

HPB (Oxford) 2020 03 13;22(3):340-350. Epub 2019 Nov 13.

Liver and Pancreas Unit, Department of Surgery, The Ottawa Hospital, University of Ottawa, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Canada. Electronic address:

Background: Hypovolemic phlebotomy (HP) is a novel intervention that involves intraoperative removal of whole blood (7-10 mL/kg) without volume replacement. The subsequent central venous pressure (CVP) reduction is hypothesized to decrease blood loss and the need for blood transfusion. The objective was to conduct a systematic assessment of the safety and efficacy of HP on blood loss and transfusion in the liver surgery literature.

Methods: MEDLINE, EMBASE, and Cochrane Library databases were searched. Outcomes of interest included blood loss, allogenic red blood cell transfusion, postoperative adverse events, and CVP change. A qualitative synthesis and meta-analysis were performed as appropriate.

Results: Four cohort studies, one case series, and three randomized controlled trials involving 2255 patients were included. Meta-analysis of studies involving liver resections for any indication (n = 6) found no difference in transfusion (OR 0.38, p = 0.12) or incidence of adverse events with HP compared to non-use. Pooling of studies involving liver resections for an underlying pathology (n = 4) revealed HP was associated with significant reduction in transfusion (OR 0.25, p = 0.03) but no differences in blood loss (-173 mL, p = 0.17).

Conclusion: This review suggests HP is safe and associated with decreased transfusion in patients undergoing liver surgery. It supports further investigation.
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http://dx.doi.org/10.1016/j.hpb.2019.10.001DOI Listing
March 2020

Diabetic kidney disease 2.0: the treatment paradigm shifts.

Lancet Diabetes Endocrinol 2019 11 5;7(11):820-821. Epub 2019 Sep 5.

Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(19)30253-0DOI Listing
November 2019

Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial.

Circulation 2019 11 22;140(21):1693-1702. Epub 2019 Aug 22.

Division of Cardiology (A.T.Y., D.H.F., S.G.G., K.A.C.), Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.

Background: SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease.

Methods: Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m. The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide).

Results: Among the 97 participants (90 men [93%], mean [standard deviation] age 62.8 [9.0] years, type 2 diabetes mellitus duration 11.0 [8.2] years, estimated glomerular filtration rate 88.4 [16.9] mL/min/1.73m, LV mass indexed to body surface area 60.7 [11.9] g/m), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m and 0.01 g/m for those assigned empagliflozin and placebo, respectively (adjusted difference -3.35 g/m; 95% CI, -5.9 to -0.81g/m, =0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference -6.8mmHg, 95% CI -11.2 to -2.3mmHg, =0.003), diastolic blood pressure (adjusted difference -3.2mmHg; 95% CI, -5.8 to -0.6mmHg, =0.02) and elevation of hematocrit (=0.0003).

Conclusions: Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02998970.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042375DOI Listing
November 2019

Malignant melanoma arising from an end ileostomy.

BMJ Case Rep 2019 Aug 1;12(7). Epub 2019 Aug 1.

General Surgery, Ottawa General Hospital, Ottawa, Ontario, Canada.

A 65-year-old woman with a history of proctocolectomy and end ileostomy for ulcerative colitis was referred to our clinic with a slowly growing mass around her ileostomy. She did not report any systemic symptoms. On examination, an exophytic mass was observed around her ileostomy and hard lymph nodes palpated in her groins bilaterally. Punch biopsy of the lesion established a diagnosis of invasive melanoma. Positron emission tomography revealed regional metastatic lymphadenopathy in the right axilla and both groins. There was no evidence of distant metastatic disease. The patient then underwent wide local excision of her ileostomy with bowel resection and ileostomy re-siting, bilateral complete ilioinguinal lymphadenectomy and a right Level III axillary dissection. She is doing well postoperatively and receiving adjuvant systemic therapy with BRAF and MEK inhibitors, now 17 months later with no signs of recurrent disease.
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http://dx.doi.org/10.1136/bcr-2019-230265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677946PMC
August 2019

The potential role of neddylation in pre- and postnatal cardiac remodeling.

Am J Physiol Heart Circ Physiol 2019 Aug 5;317(2):H276-H278. Epub 2019 Jul 5.

Research Service, Providence Veterans Affairs Medical Center and Brown University , Providence, Rhode Island.

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http://dx.doi.org/10.1152/ajpheart.00260.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732480PMC
August 2019

Guidelines on the intraoperative transfusion of red blood cells: a protocol for systematic review.

BMJ Open 2019 06 17;9(6):e029684. Epub 2019 Jun 17.

Department of Surgery, The Ottawa Hospital, Ottawa, Ontario, Canada.

Introduction: A significant proportion of red blood cell (RBC) transfusions are administered intraoperatively; yet there is limited evidence to guide transfusion decisions in this setting. The objective of this systematic review is to explore the availability, quality and content of clinical practice guidelines (CPGs) reporting on the indication for allogenic RBC transfusion during surgery.

Methods: Major electronic databases (MEDLINE, EMBASE and CINAHL), guideline clearinghouses and Google Scholar, will be systematically searched from inception to January 2019 for CPGs pertaining to indications for intraoperative allogenic RBC transfusion. Characteristics of eligible guidelines will be reported in a summary table. The AGREE II instrument will be used to appraise the quality of identified guidelines. Recommendations advising on indications for intraoperative RBC transfusion will be manually extracted and presented to allow for comparison of similarities and/or discrepancies in the literature.

Ethics And Dissemination: The results of this systematic review will be disseminated through relevant conferences and peer-reviewed journals.

Trial Registration Number: CRD42018111487.
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http://dx.doi.org/10.1136/bmjopen-2019-029684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586075PMC
June 2019

Impaired SIRT1 activity leads to diminution in glomerular endowment without accelerating age-associated GFR decline.

Physiol Rep 2019 05;7(9):e14044

Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.

Glomerular filtration rate (GFR) declines with age such that the prevalence of chronic kidney disease is much higher in the elderly. SIRT1 is the leading member of the sirtuin family of NAD -dependent lysine deacetylases that mediate the health span extending properties of caloric restriction. Since reduction in energy intake has also been shown to decrease age-related kidney disease in rodents, we hypothesized that a diminution in SIRT1 activity would accelerate the GFR decline and structural injury with age. To test this hypothesis, we compared changes in the kidney structure and function in control mice and mice that carry a point mutation at a conserved histidine (H355Y) of SIRT1 that renders the enzyme catalytically inactive. Taking advantage of this mouse model along with the disector/fractionator technique for glomerular counting and direct measurements of GFR by inulin clearance, we assessed the impact of SIRT1 inactivity on kidney aging. At 14 months of age, SIRT1 catalytically inactive (Sirt1 ) mice had lower GFRs and fewer glomeruli than their wild-type (Sirt1 ) counterparts. This was not, however, due to either accelerated GFR decline or increased glomerulosclerosis and loss, but rather to reduced glomerular endowment in Sirt1 mice. Moreover, the compensatory glomerular hypertrophy and elevated single nephron GFR that customarily accompany reduction in nephron number were absent in Sirt1 mice. These findings suggest a role for SIRT1 not only in determining nephron endowment but also in orchestrating the response to it.
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http://dx.doi.org/10.14814/phy2.14044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513772PMC
May 2019

Acute kidney injury with sodium-glucose co-transporter-2 inhibitors: A meta-analysis of cardiovascular outcome trials.

Diabetes Obes Metab 2019 08 24;21(8):1996-2000. Epub 2019 May 24.

Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Three, multicentre, large-scale, randomized, placebo-controlled trials of cardiovascular outcomes with sodium-glucose co-transporter-2 (SGLT2) inhibitors have each shown substantial reductions in rates of hospitalization for heart failure and progression of chronic kidney disease in people with type 2 diabetes. However, safety concerns remain for this ostensibly paradigm-shifting drug class. In particular, the US Food and Drug Administration has highlighted the risk of acute kidney injury (AKI), a condition associated with high morbidity and mortality. To investigate this further, we conducted a meta-analysis of the three trials to compare the frequency of AKI adverse event reports between participants treated with placebo and those who had received an SGLT2 inhibitor. Rather than an increase, we noted a consistent and robust reduction in the likelihood of AKI among those participants who had been randomized to receive an SGLT2 inhibitor (hazard ratio 0.66, 95% confidence interval 0.54-0.80). We further noted that the reports of AKI were similar in frequency to those of kidney disease progression. The caveats of the non-adjudicated reporting of AKI in the trials notwithstanding, these data suggest that SGLT2 inhibitors may protect vulnerable patients with type 2 diabetes from AKI and that prospective studies to evaluate this additional aspect of kidney protection are warranted.
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http://dx.doi.org/10.1111/dom.13754DOI Listing
August 2019

Ablation of the calpain-targeted site in cardiac myosin binding protein-C is cardioprotective during ischemia-reperfusion injury.

J Mol Cell Cardiol 2019 04 9;129:236-246. Epub 2019 Mar 9.

Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL, USA; Heart, Lung and Vascular Institute, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA. Electronic address:

Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is essential for normal heart function and protects the heart from ischemia-reperfusion (I/R) injury. It is known that protein kinase-A (PKA)-mediated phosphorylation of cMyBP-C prevents I/R-dependent proteolysis, whereas dephosphorylation of cMyBP-C at PKA sites correlates with its degradation. While sites on cMyBP-C associated with phosphorylation and proteolysis co-localize, the mechanisms that link cMyBP-C phosphorylation and proteolysis during cardioprotection are not well understood. Therefore, we aimed to determine if abrogation of cMyBP-C proteolysis in association with calpain, a calcium-activated protease, confers cardioprotection during I/R injury. Calpain is activated in both human ischemic heart samples and ischemic mouse myocardium where cMyBP-C is dephosphorylated and undergoes proteolysis. Moreover, cMyBP-C is a substrate for calpain proteolysis and cleaved by calpain at residues 272-TSLAGAGRR-280, a domain termed as the calpain-target site (CTS). Cardiac-specific transgenic (Tg) mice in which the CTS motif was ablated were bred into a cMyBP-C null background. These Tg mice were conclusively shown to possess a normal basal structure and function by analysis of histology, electron microscopy, immunofluorescence microscopy, Q-space MRI of tissue architecture, echocardiography, and hemodynamics. However, the genetic ablation of the CTS motif conferred resistance to calpain-mediated proteolysis of cMyBP-C. Following I/R injury, the loss of the CTS reduced infarct size compared to non-transgenic controls. Collectively, these findings demonstrate the physiological significance of calpain-targeted cMyBP-C proteolysis and provide a rationale for studying inhibition of calpain-mediated proteolysis of cMyBP-C as a therapeutic target for cardioprotection.
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http://dx.doi.org/10.1016/j.yjmcc.2019.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222036PMC
April 2019
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