Richard B. Thompson
University of Alberta
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Featured researches published by Richard B. Thompson.
Journal of Cardiovascular Magnetic Resonance | 2017
Daniel Messroghli; James C. Moon; Vanessa M. Ferreira; Lars Grosse-Wortmann; Taigang He; Peter Kellman; Julia Mascherbauer; Reza Nezafat; Michael Salerno; Erik B. Schelbert; Andrew J. Taylor; Richard B. Thompson; Martin Ugander; Ruud B. van Heeswijk; Matthias G. Friedrich
Parametric mapping techniques provide a non-invasive tool for quantifying tissue alterations in myocardial disease in those eligible for cardiovascular magnetic resonance (CMR). Parametric mapping with CMR now permits the routine spatial visualization and quantification of changes in myocardial composition based on changes in T1, T2, and T2*(star) relaxation times and extracellular volume (ECV). These changes include specific disease pathways related to mainly intracellular disturbances of the cardiomyocyte (e.g., iron overload, or glycosphingolipid accumulation in Anderson-Fabry disease); extracellular disturbances in the myocardial interstitium (e.g., myocardial fibrosis or cardiac amyloidosis from accumulation of collagen or amyloid proteins, respectively); or both (myocardial edema with increased intracellular and/or extracellular water). Parametric mapping promises improvements in patient care through advances in quantitative diagnostics, inter- and intra-patient comparability, and relatedly improvements in treatment. There is a multitude of technical approaches and potential applications. This document provides a summary of the existing evidence for the clinical value of parametric mapping in the heart as of mid 2017, and gives recommendations for practical use in different clinical scenarios for scientists, clinicians, and CMR manufacturers.
Journal of Clinical Oncology | 2017
Edith Pituskin; Mackey; Sheri L. Koshman; Jassal D; Pitz M; Mark J. Haykowsky; Joseph J Pagano; Kelvin Chow; Richard B. Thompson; Vos Lj; Ghosh S; Gavin Y. Oudit; Justin A. Ezekowitz; David I. Paterson
Purpose The primary toxicity of trastuzumab therapy for human epidermal growth factor receptor 2-overexpressing (HER2-positive) breast cancer is dose-independent cardiac dysfunction. Angiotensin-converting enzyme inhibitors and β-blockers are recommended first-line agents for heart failure. We hypothesized that angiotensin-converting enzyme inhibitors and β-blockers could prevent trastuzumab-related cardiotoxicity. Patients and Methods In this double-blinded, placebo-controlled trial, patients with HER2-positive early breast cancer were randomly assigned to receive treatment with perindopril, bisoprolol, or placebo (1:1:1) for the duration of trastuzumab adjuvant therapy. Patients underwent cardiac magnetic resonance imaging at baseline and post-cycle 17 for the determination of left ventricular volumes and left ventricular ejection fraction (LVEF). Cardiotoxicity was evaluated as the change in indexed left ventricular end diastolic volume and LVEF. Results Thirty-three patients received perindopril, 31 received bisoprolol, and 30 received placebo. Baseline demographic, cancer, and cardiovascular profiles were similar between groups. Study drugs were well tolerated with no serious adverse events. After 17 cycles of trastuzumab, indexed left ventricular end diastolic volume increased in patients treated with perindopril (+7 ± 14 mL/m2), bisoprolol (+8 mL ± 9 mL/m2), and placebo (+4 ± 11 mL/m2; P = .36). In secondary analyses, trastuzumab-mediated decline in LVEF was attenuated in bisoprolol-treated patients (-1 ± 5%) relative to the perindopril (-3 ± 4%) and placebo (-5 ± 5%) groups ( P = .001). Perindopril and bisoprolol use were independent predictors of maintained LVEF on multivariable analysis. Conclusion Perindopril and bisoprolol were well tolerated in patients with HER2-positive early breast cancer who received trastuzumab and protected against cancer therapy-related declines in LVEF; however, trastuzumab-mediated left ventricular remodeling-the primary outcome-was not prevented by these pharmacotherapies.
Science Translational Medicine | 2017
Evangelos D. Michelakis; Vikram Gurtu; Linda Webster; Gareth Barnes; Geoffrey Watson; Luke Howard; John Cupitt; Ian Paterson; Richard B. Thompson; Kelvin Chow; Declan P. O’Regan; Lan Zhao; John Wharton; David G. Kiely; Adam Kinnaird; Aristeidis Boukouris; C.W. White; Darren H. Freed; Stephen J. Wort; J. Simon R. Gibbs; Martin R. Wilkins
Metabolic modulation with dichloroacetate improves hemodynamics in genetically susceptible patients with idiopathic pulmonary arterial hypertension. Progress for PAH In addition to thickening and occlusion of the pulmonary arteries, mitochondrial respiration is suppressed in pulmonary arterial hypertension (PAH). Michelakis et al. treated lungs from patients with PAH with dichloroacetate (DCA), a drug used to treat cancer and congenital mitochondrial disease that inhibits the mitochondrial enzyme pyruvate dehydrogenase kinase. DCA increased mitochondrial function; however, the response was variable, and this variable response was mirrored in a phase 1 trial, with some patients showing improved hemodynamics and functional capacity. The authors determined that patients with inactivating mutations in two genes encoding mitochondrial proteins were less responsive to DCA. This work highlights the importance of considering patient genotype in clinical trial design and identifies a drug target for PAH. Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.
Canadian Journal of Cardiology | 2017
Haran Yogasundaram; Daniel Kim; Omar Oudit; Richard B. Thompson; Frank Weidemann; Gavin Y. Oudit
Anderson-Fabry disease (AFD) is an X-linked recessive, multisystem disease of lysosomal storage. A mutation in the gene encoding the hydrolase enzyme α-galactosidase A results in its deficiency, or complete absence of activity. Subsequent progressive intracellular accumulation of glycosphingolipids, predominantly globotriaosylceramide, in various tissues, results in progressive organ dysfunction and failure, most commonly affecting the kidneys, nervous system, skin, eyes, vascular endothelium, and the heart. Cardiac involvement in AFD represents a leading cause of morbidity and mortality. Globotriaosylceramide accumulation affects cardiomyocytes, smooth muscle cells, vascular endothelial cells, and fibroblasts leading to various pathologies including valvular regurgitation, conduction disease and arrhythmias, coronary microvascular dysfunction, and right and left ventricular hypertrophy (LVH) leading to early diastolic dysfunction and late-stage systolic impairment. Diagnosis is on the basis of decreased plasma α-galactosidase activity in men and positive genetic testing in women. Contemporary large-scale screening studies have revealed a prevalence of 1%-5% in patients with unexplained LVH in multiple cohorts. Cardiac magnetic resonance imaging, with its unique tissue characterization capabilities, is the most important imaging modality to assess for cardiomyopathy in patients with AFD. Enzyme replacement therapy is indicated in AFD patients with significant organ involvement, and has been shown to clear sphingolipids from endothelial cells in other organs, as well as to reduce left ventricular mass as early as 6 months after starting treatment. There is increasing evidence that enzyme replacement therapy might be more effective if given at earlier stages of disease, before the development of LVH and myocardial fibrosis.
PLOS ONE | 2016
Joseph J Pagano; Kelvin Chow; Aneal Khan; Evangelos D. Michelakis; Ian Paterson; Gavin Y. Oudit; Richard B. Thompson
Aims Anderson-Fabry disease (AFD) is characterized by progressive multiorgan accumulation of intracellular sphingolipids due to α-galactosidase A enzyme deficiency, resulting in progressive ventricular hypertrophy, heart failure, arrhythmias, and death. Decreased native (non-contrast) left ventricular (LV) T1 (longitudinal relaxation time) with MRI discriminates AFD from healthy controls or other presentations of concentric hypertrophy, but the right ventricle (RV) has not been studied. The aims of the current study were to evaluate native RV T1 values in AFD, with a goal of better understanding the pathophysiology of RV involvement. Methods and Results Native T1 values were measured in the inferior RV wall (RVI), interventricular septum (IVS), and inferior LV (LVI) in patients with AFD, patients with pulmonary hypertension, who provided an alternative RV pathological process for comparison, and healthy controls. A minimum wall thickness of 4 mm was selected to minimize partial volume errors in tissue T1 analysis. T1 analysis was performed in 6 subjects with AFD, 6 subjects with PH, and 21 controls. Native T1 values were shorter (adjusted p<0.05 for all comparisons), independent of location, in subjects with AFD (RVI-T1 = 1096±49 ms, IVS-T1 = 1053±41 ms, LVI-T1 = 1072±44 ms) compared to both PH (RVI-T1 = 1239±41 ms, IVS-T1 = 1280±123 ms, LVI-T1 = 1274±57 ms) and HC (IVS-T1 = 1180±60 ms, LVI-T1 = 1183±45 ms). RVI measurements were not possible in controls due to insufficient wall thickness. Conclusion Native T1 values appear similarly reduced in the left and right ventricles of individuals with AFD and RV wall thickening, suggesting a common pathology. In contrast, individuals with PH and thickened RVs showed increased native T1 values in both ventricles, suggestive of fibrosis.
Clinical Cardiology | 2017
Michael D. Nelson; Behzad Sharif; Jaime L. Shaw; Galen Cook-Wiens; Janet Wei; Chrisandra Shufelt; Puja K. Mehta; Louise Thomson; Daniel Berman; Richard B. Thompson; Eileen Handberg; Carl J. Pepine; Debiao Li; C. Noel Bairey Merz
Patients with coronary microvascular dysfunction (CMD) often have diastolic dysfunction, representing an important therapeutic target. Ranolazine—a late sodium current inhibitor—improves diastolic function in animal models and subjects with obstructive coronary artery disease (CAD).
Scientific Reports | 2018
Calvin Kruger; Margaret L. McNeely; Robert J Bailey; Milad Yavari; Juan G. Abraldes; Michelle Carbonneau; Kim Newnham; Vanessa DenHeyer; Mang Ma; Richard B. Thompson; Ian Paterson; Mark J. Haykowsky; Puneeta Tandon
Cirrhosis patients have reduced peak aerobic power (peak VO2) that is associated with reduced survival. Supervised exercise training increases exercise tolerance. The effect of home-based exercise training (HET) in cirrhosis is unknown. The objective was to evaluate the safety and efficacy of 8 weeks of HET on peak VO2, 6-minute walk distance (6MWD), muscle mass, and quality of life in cirrhosis. Random assignment to 8 weeks of HET (moderate to high intensity cycling exercise, 3 days/week) or usual care. Exercise adherence defined as completing ≥80% training sessions. Paired t-tests and analysis of covariance used for comparisons. Forty patients enrolled: 58% male, mean age 57u2009y, 70% Child Pugh-A. Between group increases in peak VO2 (1.7, 95% CI: −0.33 to 3.7u2009ml/kg/min, pu2009=u20090.09) and 6MWD (33.7, 95% CI: 5.1 to 62.4u2009m, pu2009=u20090.02) were greater after HET versus usual care. Improvements even more marked in adherent subjects for peak VO2 (2.8, 95% CI: 0.5–5.2u2009mL/kg/min, pu2009=u20090.02) and 6MWD (46.4, 95% CI: 12.4–80.5u2009m, pu2009=u20090.009). No adverse events occurred during testing or HET. Eight weeks of HET is a safe and effective intervention to improve exercise capacity in cirrhosis, with maximal benefits occurring in those who complete ≥80% of the program.
Journal of Applied Physiology | 2017
Zainisha Vasanji; Ronald J. Sigal; Neil D. Eves; Debra Isaac; Matthias G. Friedrich; Kelvin Chow; Richard B. Thompson
Individuals with type 1 diabetes (T1D) characteristically have high glycemic levels that over time can result in reactive fibrosis and abnormalities in myocardial function. T1 mapping with magnetic resonance imaging (MRI) can estimate the extent of reactive fibrosis by measurement of the extracellular volume fraction (ECV). The extent of alterations in the ECV and associated changes in left ventricular (LV) function and morphology in individuals with T1D is unknown. Fourteen individuals with long-term T1D and 14 sex-, age-, and body mass index-matched controls without diabetes underwent MRI measurement of myocardial T1 and ECV values as well as LV function and morphology. Ventricular mass, volumes, and global function (LVEF and circumferential/longitudinal/radial strain) were similar in those with T1D and controls. However, those with T1D had larger myocardial ECV (22.1 ± 1.8 vs. 20.1 ± 2.1, P = 0.008) and increased native (noncontrast) myocardial T1 values (1,211 ± 44 vs. 1,172 ± 43 ms, P < 0.001) as compared with controls. Both the ECV and native T1 values significantly correlated with several components of torsion and circumferential-longitudinal shear strain (Ecl, the shear strain component associated with twist). Individuals with T1D had increased systolic torsion (P = 0.035), systolic torsion rate (P = 0.032), peak Ecl (P = 0.001), and rates of change of systolic (P = 0.007) and diastolic (P = 0.007) Ecl Individuals with T1D, with normal structure, LVEF, and strain, have increased extracellular volume and increased native T1 values with associated augmented torsion and Ecl These measures may be useful in detecting the early stages of diabetic cardiomyopathy and warrant larger prospective studies.NEW & NOTEWORTHY Individuals with type 1 diabetes, with normal left ventricular structure and function (ejection fraction and strain), have signs of interstitial fibrosis, measured with MRI as increased extracellular volume fraction and increased native myocardial T1, which significantly correlated with a number of measures of augmented left ventricular twist function. These measures may be useful in detecting the early stages of diabetic cardiomyopathy.
European Journal of Echocardiography | 2018
Stefania Rosmini; Heerajnarain Bulluck; Gabriella Captur; Thomas A. Treibel; Amna Abdel-Gadir; Anish N. Bhuva; Veronica Culotta; Ahmed Merghani; Marianna Fontana; Viviana Maestrini; Anna S. Herrey; Kelvin Chow; Richard B. Thompson; Stefan K. Piechnik; Peter Kellman; Charlotte Manisty; James C. Moon
Abstract Aims To determine how native myocardial T1 and extracellular volume (ECV) change with age, both to understand aging and to inform on normal reference ranges. Methods and results Ninety-four healthy volunteers with no a history or symptoms of cardiovascular disease or diabetes underwent cardiovascular magnetic resonance at 1.5u2009T. Mid-ventricular short axis native and post-contrast T1 maps by Shortened MOdified Look-Locker Inversion-recovery (ShMOLLI), MOdified Look-Locker Inversion Recovery (MOLLI) [pre-contrast: 5s(3s)3s, post-contrast: 4s(1s)3s(1s)2s] and saturation recovery single-shot acquisition (SASHA) were acquired and ECV by these three techniques were derived for the mid anteroseptum. Mean age was 50u2009±u200914u2009years (range 20–76), male 52%, with no age difference between genders (males 51u2009±u200914u2009years; females 49u2009±u200915u2009years, Pu2009=u20090.55). Quoting respectively ShMOLLI, MOLLI, SASHA throughout, mean myocardial T1 was 957u2009±u200930u2009ms, 1025u2009±u200938u2009ms, 1144u2009±u200945u2009ms (Pu2009<u20090.0001) and ECV 28.4u2009±u20093.0% [95% confidence interval (CI) 27.8–29.0], 27.3u2009±u20092.7 (95% CI 26.8–27.9), 24.1u2009±u20092.9% (95% CI 23.5–24.7) (Pu2009<u20090.0001), with all values higher in females for all techniques (T1 +18u2009ms, +35u2009ms, +51u2009ms; ECV +2.7%, +2.6%, +3.4%). Native myocardial T1 reduced slightly with age (R2u2009=u20090.042, Pu2009=u20090.048; R2u2009=u20090.131, Pu2009<u20090.0001—on average by 8–11u2009ms/decade—but not for SASHA (R2u2009=u20090.033 and Pu2009=u20090.083). ECV did not change with age (R2u2009=u20090.003, Pu2009=u20090.582; R2u2009=u20090.002, Pu2009=u20090.689; R2u2009=u20090.003, Pu2009=u20090.615). Heart rate decreased slightly with age (R2u2009=u20090.075, coefficientu2009=u2009−0.273, Pu2009=u20090.008), but there was no relationship between age and other blood T1 influences (haematocrit, iron, high density lipoprotein-cholesterol). Conclusion Gender influences native T1 and ECV with women having a higher native T1 and ECV. Native T1 measured by MOLLI and ShMOLLI was slightly lower with increasing age but not with SASHA and ECV was independent of age for all techniques.
Journal of the American College of Cardiology | 2017
Richard B. Thompson; Joseph J Pagano; Kelvin Chow; Viktor Sekowski; Ian Paterson; Justin A. Ezekowitz; Todd J. Anderson; Jason R. B. Dyck; Mark J. Haykowsky
A cardinal feature of heart failure (HF) is reduced exercise tolerance (peak oxygen uptake [Vo2]) that is associated with dyspnea and increased left ventricular (LV) filling pressure [(1)][1]. Elevated resting LV filling pressures in patients with HF have been shown to bexa0associated with increased