Institute of Cardiovascular science

Winnipeg, Canada

Institute of Cardiovascular science

Winnipeg, Canada
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Mitnitski A.,Dalhousie University | Howlett S.E.,Dalhousie University | Howlett S.E.,Institute of Cardiovascular science | Rockwood K.,Dalhousie University | Rockwood K.,University of Manchester
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2017

Understanding the heterogeneity in health of older adults is a compelling question in the biology of aging. We analyzed the performance of five measures of health heterogeneity, judging them by their ability to predict mortality. Using clinical and biomarker data on 1,013 participants of the Canadian Study of Health and Aging who were followed for up to 6 years, we calculated two indices of biological age using the Klemera and Doubal method, which controversially includes using chronological age as a 'biomarker,' and three frailty indices (FIs) that do not include chronological age: a standard clinical FI, an FI from standard laboratory blood tests and blood pressure, and their combination (FI-combined). Predictive validity was tested using Cox proportional hazards analysis and discriminative ability by the area under the receiver-operating characteristic curves. All five measures showed moderate performance that was improved by combining measures to evaluate larger numbers of items. The greatest addition in explanatory power came from the FI-combined that showed the best mortality prediction in an age-adjusted model. More extensive comparisons across different databases are required, but these results do not support including chronological age as a biomarker. © The Author 2016.

Majhi B.,Institute of Cardiovascular science | Pal N.,CMSDH
Journal of Cardiovascular Echography | Year: 2017

A young male patient presented at a tertiary care hospital with cold and bluish left upper limb accompanied with digital gangrene arousing suspicion of peripheral vascular disease. History did not reveal any high-risk behavior. Clinical examination and subsequent investigations lead to the diagnosis of acute infective endocarditis of native aortic valve along with peripheral embolism caused by methicillin-resistant Staphylococcus aureus. Fogarty's balloon embolectomy was done following which patient developed pseudoaneurysm of the left subclavian artery. These iatrogenic sequelae were managed with the resection of the pseudoaneurysm and prolonged antibiotic therapy as per the culture and sensitivity report. © 2017 Journal of Cardiovascular Echography | Published by Wolters Kluwer - Medknow.

Greensmith D.J.,Institute of Cardiovascular Science
Computer Methods and Programs in Biomedicine | Year: 2014

Here I present an Excel based program for the analysis of intracellular Ca transients recorded using fluorescent indicators. The program can perform all the necessary steps which convert recorded raw voltage changes into meaningful physiological information. The program performs two fundamental processes. (1) It can prepare the raw signal by several methods. (2) It can then be used to analyze the prepared data to provide information such as absolute intracellular Ca levels. Also, the rates of change of Ca can be measured using multiple, simultaneous regression analysis. I demonstrate that this program performs equally well as commercially available software, but has numerous advantages, namely creating a simplified, self-contained analysis workflow. © 2013 The Author.

Horn M.A.,Institute of Cardiovascular science | Trafford A.W.,Institute of Cardiovascular science
Journal of Molecular and Cellular Cardiology | Year: 2015

Cardiovascular disease is a leading cause of death worldwide and there is a pressing need for new therapeutic strategies to treat such conditions. The risk of developing cardiovascular disease increases dramatically with age, yet the majority of experimental research is executed using young animals. The cardiac extracellular matrix (ECM), consisting predominantly of fibrillar collagen, preserves myocardial integrity, provides a means of force transmission and supports myocyte geometry. Disruptions to the finely balanced control of collagen synthesis, post-synthetic deposition, post-translational modification and degradation may have detrimental effects on myocardial functionality. It is now well established that the aged heart is characterized by fibrotic remodelling, but the mechanisms responsible for this are incompletely understood. Furthermore, studies using aged animal models suggest that interstitial remodelling with disease may be age-dependent. Thus with the identification of new therapeutic strategies targeting fibrotic remodelling, it may be necessary to consider age-dependent mechanisms. In this review, we discuss remodelling of the cardiac collagen matrix as a function of age, whilst highlighting potential novel mediators of age-dependent fibrotic pathways. © 2015 The Authors.

Kishore A.,Institute of Cardiovascular science | Kishore A.,Greater Manchester Comprehensive Stroke Center | Vail A.,University of Manchester | Majid A.,Greater Manchester Comprehensive Stroke Center | And 6 more authors.
Stroke | Year: 2014

Background and Purpose - Atrial fibrillation (AF) confers a high risk of recurrent stroke, although detection methods and definitions of paroxysmal AF during screening vary. We therefore undertook a systematic review and meta-analysis to determine the frequency of newly detected AF using noninvasive or invasive cardiac monitoring after ischemic stroke or transient ischemic attack. Methods - Prospective observational studies or randomized controlled trials of patients with ischemic stroke, transient ischemic attack, or both, who underwent any cardiac monitoring for a minimum of 12 hours, were included after electronic searches of multiple databases. The primary outcome was detection of any new AF during the monitoring period. We prespecified subgroup analysis of selected (prescreened or cryptogenic) versus unselected patients and according to duration of monitoring. Results - A total of 32 studies were analyzed. The overall detection rate of any AF was 11.5% (95% confidence interval, 8.9%- 14.3%), although the timing, duration, method of monitoring, and reporting of diagnostic criteria used for paroxysmal AF varied. Detection rates were higher in selected (13.4%; 95% confidence interval, 9.0%-18.4%) than in unselected patients (6.2%; 95% confidence interval, 4.4%-8.3%). There was substantial heterogeneity even within specified subgroups. Conclusions - Detection of AF was highly variable, and the review was limited by small sample sizes and marked heterogeneity. Further studies are required to inform patient selection, optimal timing, methods, and duration of monitoring for detection of AF/paroxysmal AF. © 2014 American Heart Association, Inc.

Moody W.E.,Institute of Cardiovascular Science | Ferro C.J.,University of Birmingham | Edwards N.C.,Institute of Cardiovascular Science | Chue C.D.,Institute of Cardiovascular Science | And 5 more authors.
Hypertension | Year: 2016

There is a robust inverse graded association between glomerular filtration rate (GFR) and cardiovascular risk, but proof of causality is lacking. Emerging data suggest living kidney donation may be associated with increased cardiovascular mortality although the mechanisms are unclear. We hypothesized that the reduction in GFR in living kidney donors is associated with increased left ventricular mass, impaired left ventricular function, and increased aortic stiffness. This was a multicenter, parallel group, blinded end point study of living kidney donors and healthy controls (n=124), conducted from March 2011 to August 2014. The primary outcome was a change in left ventricular mass assessed by magnetic resonance imaging (baseline to 12 months). At 12 months, the decrease in isotopic GFR in donors was-30±12 mL/min/1.73m2. In donors compared with controls, there were significant increases in left ventricular mass (+7±10 versus-3±8 g; P<0.001) and mass:volume ratio (+0.06±0.12 versus-0.01±0.09 g/mL; P<0.01), whereas aortic distensibility (-0.29±1.38 versus +0.28±0.79×10-3 mm Hg-1; P=0.03) and global circumferential strain decreased (-1.1±3.8 versus +0.4±2.4%; P=0.04). Donors had greater risks of developing detectable highly sensitive troponin T (odds ratio, 16.2 [95% confidence interval, 2.6-100.1]; P<0.01) and microalbuminuria (odds ratio, 3.8 [95% confidence interval, 1.1-12.8]; P=0.04). Serum uric acid, parathyroid hormone, fibroblast growth factor-23, and high-sensitivity C-reactive protein all increased significantly. There were no changes in ambulatory blood pressure. Change in GFR was independently associated with change in left ventricular mass (R2=0.28; P=0.01). These findings suggest that reduced GFR should be regarded as an independent causative cardiovascular risk factor. © 2016 The Authors.

Dibb K.M.,Institute of Cardiovascular science | Clarke J.D.,Institute of Cardiovascular science | Eisner D.A.,Institute of Cardiovascular science | Richards M.A.,Institute of Cardiovascular science | Trafford A.W.,Institute of Cardiovascular science
Journal of Molecular and Cellular Cardiology | Year: 2013

Mammalian ventricular myocytes are characterised by the presence of an extensive transverse (t-) tubule network which is responsible for the synchronous rise of intracellular Ca2+ concentration ([Ca2+]i) during systole. Disruption to the ventricular t-tubule network occurs in various cardiac pathologies and leads to heterogeneous changes of [Ca2+]i which are thought to contribute to the reduced contractility and increased susceptibility to arrhythmias of the diseased ventricle. Here we review evidence that, despite the long-held dogma of atrial cells having no or very few t-tubules, there is indeed an extensive and functionally significant t-tubule network present in atrial myocytes of large mammals including human. Moreover, the atrial t-tubule network is highly plastic in nature and undergoes far more extensive remodelling in heart disease than is the case in the ventricle with profound consequences for the resulting systolic Ca2+ transient. In addition to considering the functional role of the t-tubule network in the healthy and diseased atria we also provide an overview of recent data concerning the putative factors controlling the formation of t-tubules and conclude by posing some important questions that currently remain to be addressed and whether or not targeting t-tubules offers potential novel therapeutic possibilities for heart disease. This article is part of a Special Issue entitled "Calcium Signaling in Heart". © 2012 Elsevier Ltd.

Greensmith D.J.,Institute of Cardiovascular Science | Galli G.L.J.,Institute of Cardiovascular Science | Trafford A.W.,Institute of Cardiovascular Science | Eisner D.A.,Institute of Cardiovascular Science
Cardiovascular Research | Year: 2014

Aims Most of the calcium that activates contraction is released from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RyR). It is controversial whether activators of the RyR produce a maintained increase in the amplitude of the systolic Ca transient.We therefore aimed to examine the effects of activation of the RyR in large animals under conditions designed to be as physiological as possible while simultaneously measuring SR and cytoplasmic Ca. Methods and results Experimentswere performed on ventricular myocytes fromcanine and ovine hearts. Cytoplasmic Cawas measured with fluo-3 and SR Ca with mag-fura-2. Application of caffeine resulted in a brief increase in the amplitude of the systolic Ca transient accompanied by an increase of action potential duration. These effects disappeared with a rate constant of ̃3 s-1. Similar effects were seen in cells taken from sheep in which heart failure had been induced by rapid pacing. The decrease of Ca transient amplitude was accompanied by a decrease of SR Ca content. During this phase, the maximum (end-diastolic) SR Ca content fell while the minimum systolic increased. Conclusions This study shows that, under conditions designed to be as physiological as possible, potentiation of RyR opening has no maintained effect on the systolic Ca transient. This result makes it unlikely that potentiation of the RyR has a maintained role in positive inotropy. © The Author 2014.

Dhingra R.,University of Manitoba | Gang H.,University of Manitoba | Wang Y.,University of Manitoba | Biala A.K.,University of Manitoba | And 5 more authors.
Circulation: Heart Failure | Year: 2013

Background-Tumor necrosis factor-á and other proinflammatory cytokines activate the canonical Nuclear Factor (NF)-κB pathway through the kinase IKKâ. Previously, we established that IKKβ is also critical for Akt-mediated NF-κB activation in ventricular myocytes. Akt activates the kinase mammalian target of rapamycin (mTOR), which mediates important processes such as cardiac hypertrophy. However, whether mTOR regulates cardiac myocyte cell survival is unknown. Methods and Results-Herein, we demonstrate bidirectional regulation between NF-êB signaling and mTOR, the balance which determines ventricular myocyte survival. Overexpression of IKKâ resulted in mTOR activation and conversely overexpression of mTOR lead to NF-êB activation. Loss of function approaches demonstrated that endogenous levels of IKKâ and mTOR also signal through this pathway. NF-κB activation by mTOR was mediated by phosphorylation of the NF-κB p65 subunit increasing p65 nuclear translocation and activation of gene transcription. This circuit was also important for NF-êB activation by the canonical tumor necrosis factor-α pathway. Our previous work has shown that NF-κB signaling suppresses transcription of the death gene Bnip3 resulting in ventricular myocyte survival. Inhibition of mTOR with rapamycin decreased NF-κB activation resulting in increased Bnip3 expression and cell death. Conversely, mTOR overexpression suppressed Bnip3 levels and cell death of ventricular myocytes in response to hypoxia. Conclusions-To our knowledge, these data provide the first evidence for a bidirectional link between NF-κB signaling and mTOR that is critical in the regulation of Bnip3 expression and cardiac myocyte death. Hence, modulation of this axis may be cardioprotective during ischemia. © 2013 American Heart Association, Inc.

Majumder B.,Institute of Cardiovascular science
Indian heart journal | Year: 2010

A 56 year gentleman referred to our hospital for evaluation of syncope. He was seen previously at a local clinic and treated for cardiac failure with diuretics and was doing well on medication. He started having recurrent episode of syncope. He had his last visit to the local physician three days prior to admission when he had palpitation and was prescribed digoxin in addition to the usual medicine. Patient started having syncope from 3rd day and was referred to our hospital for evaluation. Patient's electrocardiogram as well as echocardiography was a classical finding of cardiac amyloidosis and a fat pad biopsy confirmed the diagnosis. After withdrawing digoxin and after two days on pacemaker, the patient regained normal heart rate and was discharged on diuretics.

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