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Oslo, Norway

Espe E.K.S.,University of Oslo | Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Eriksen G.S.,University of Oslo | And 6 more authors.
Circulation: Cardiovascular Imaging | Year: 2015

Background: Left ventricular (LV) motion and deformation is dependent on mechanical load and do therefore not reflect myocardial energy consumption directly. Regional myocardial work, however, constitutes a more complete assessment of myocardial function. Methods and Results: Strain was measured using high-resolution phase-contrast MRI in 9 adult male rats with myocardial infarction (MI) and in 5 sham-operated control animals. Timing of LV valvular events and LV dimensions were evaluated by cine MRI. A separate cohort of 14 animals (MI/sham=9/5) underwent measurement of LV pressure concurrent with identification of valvular events by Doppler-echocardiography for the purpose of generating a standard LV pressure curve, normalized to valvular events. The infarctions were localized to the anterolateral LV wall. Combining strain with timing of valvular events and a measurement of peak arterial pressure, regional myocardial work could be calculated by applying the standard LV pressure curves. Cardiac output and stroke work was preserved in the MI hearts, suggesting a compensatory redistribution of myocardial work from the infarcted region to the viable tissue. In the septum, regional work was indeed increased in MI rats compared with sham (median work per unit long-axis length in a mid-ventricular slice: 241.2 [224.1-271.2] versus 137.2 [127.0-143.8] mJ/m; P<0.001). Myocardial work in infarcted regions was zero. Additionally, eccentric work was increased in the MI hearts. Conclusions: Phase-contrast MRI, in combination with measurement of peak arterial pressure and MRI-derived timing of valvular events, represent a noninvasive approach for estimation of regional myocardial work in rodents. © 2015 American Heart Association, Inc. Source

Lunde I.G.,University of Oslo | Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Kvaloy H.,University of Oslo | And 6 more authors.
Physiological Genomics | Year: 2012

Reversible protein O-GlcNAc modification has emerged as an essential intracellular signaling system in several tissues, including cardiovascular pathophysiology related to diabetes and acute ischemic stress. We tested the hypothesis that cardiac O-GlcNAc signaling is altered in chronic cardiac hypertrophy and failure of different etiologies. Global protein O-GlcNAcylation and the main enzymes regulating O-GlcNAc, O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and glutamine-fructose-6-phosphate amidotransferase (GFAT) were measured by immunoblot and/or real-time RT-PCR analyses of left ventricular tissue from aortic stenosis (AS) patients and rat models of hypertension, myocardial infarction (MI), and aortic banding (AB), with and without failure. We show here that global O-GlcNAcylation was increased by 65% in AS patients, by 47% in hypertensive rats, by 81 and 58% post-AB, and 37 and 60% post-MI in hypertrophic and failing hearts, respectively (P < 0.05). Noticeably, protein O-GlcNAcylation patterns varied in hypertrophic vs. failing hearts, and the most extensive O-GlcNAcylation was observed on proteins of 20-100 kDa in size. OGT, OGA, and GFAT2 protein and/or mRNA levels were increased by pressure overload, while neither was regulated by myocardial infarction. Pharmacological inhibition of OGA decreased cardiac contractility in post-MI failing hearts, demonstrating a possible role of O-GlcNAcylation in development of chronic cardiac dysfunction. Our data support the novel concept that O-GlcNAc signaling is altered in various etiologies of cardiac hypertrophy and failure, including human aortic stenosis. This not only provides an exciting basis for discovery of new mechanisms underlying pathological cardiac remodeling but also implies protein O-GlcNAcylation as a possible new therapeutic target in heart failure. © 2012 the American Physiological Society. Source

Espe E.K.S.,University of Oslo | Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Skrbic B.,University of Oslo | And 5 more authors.
Magnetic Resonance in Medicine | Year: 2013

Phase-contrast MRI (PC-MRI) velocimetry is a noninvasive, high-resolution motion assessment tool. However, high motion sensitivity requires strong motion-encoding magnetic gradients, making phase-contrast-MRI prone to baseline shift artifacts due to the generation of eddy currents. In this study, we propose a novel nine-point balanced velocity-encoding strategy, designed to be more accurate in the presence of strong and rapidly changing gradients. The proposed method was validated using a rotating phantom, and its robustness and precision were explored and compared with established approaches through computer simulations and in vivo experiments. Computer simulations yielded a 39-57% improvement in velocity-noise ratio (corresponding to a 27-33% reduction in measurement error), depending on which method was used for comparison. Moreover, in vivo experiments confirmed this by demonstrating a 26-53% reduction in accumulated velocity error over the R-R interval. The nine-point balanced phase-contrast-MRI-encoding strategy is likely useful for settings where high spatial and temporal resolution and/or high motion sensitivity is required, such as in high-resolution rodent myocardial tissue phase mapping. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc. Source

Espe E.K.,University of Oslo | Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Skardal K.,University of Oslo | And 3 more authors.
Journal of Cardiovascular Magnetic Resonance | Year: 2013

Background: Phase contrast velocimetry cardiovascular magnetic resonance (PC-CMR) is a powerful and versatile tool allowing assessment of in vivo motion of the myocardium. However, PC-CMR is sensitive to motion related artifacts causing errors that are geometrically systematic, rendering regional analysis of myocardial function challenging. The objective of this study was to establish an optimized PC-CMR method able to provide novel insight in the complex regional motion and strain of the rodent myocardium, and provide a proof-of-concept in normal and diseased rat hearts with higher temporal and spatial resolution than previously reported. Methods. A PC-CMR protocol optimized for assessing the motion and deformation of the myocardium in rats with high spatiotemporal resolution was established, and ten animals with different degree of cardiac dysfunction underwent examination and served as proof-of-concept. Global and regional myocardial velocities and circumferential strain were calculated, and the results were compared to five control animals. Furthermore, the global strain measurements were validated against speckle-tracking echocardiography, and inter- and intrastudy variability of the protocol were evaluated. Results: The presented method allows assessment of regional myocardial function in rats with high level of detail; temporal resolution was 3.2 ms, and analysis was done using 32 circumferential segments. In the dysfunctional hearts, global and regional function were distinctly altered, including reduced global peak values, increased regional heterogeneity and increased index of dyssynchrony. Strain derived from the PC-CMR data was in excellent agreement with echocardiography (r = 0.95, p < 0.001; limits-of-agreement -0.02 ± 3.92%strain), and intra- and interstudy variability were low for both velocity and strain (limits-of-agreement, radial motion: 0.01 ± 0.32 cm/s and -0.06 ± 0.75 cm/s; circumferential strain: -0.16 ± 0.89%strain and -0.71 ± 1.67%strain, for intra- and interstudy, respectively). Conclusion: We demonstrate, for the first time, that PC-CMR enables high-resolution evaluation of in vivo circumferential strain in addition to myocardial motion of the rat heart. In combination with the superior geometric robustness of CMR, this ultimately provides a tool for longitudinal studies of regional function in rodents with high level of detail. © 2013 Espe et al.; licensee BioMed Central Ltd. Source

Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Swift F.,University of Oslo | Sejersted O.M.,University of Oslo
Journal of Molecular and Cellular Cardiology | Year: 2013

The excitation-contraction coupling (EC-coupling) links membrane depolarization with contraction in cardiomyocytes. Ca2+ induced opening of ryanodine receptors (RyRs) leads to Ca2+ induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) into the dyadic cleft between the t-tubules and SR. Ca2+ is removed from the cytosol by the SR Ca2+ ATPase (SERCA2) and the Na,Ca-exchanger (NCX). The NCX connects cardiac Ca2+ and Na+-transport, leading to Na+-dependent regulation of EC-coupling by several mechanisms of which some still lack firm experimental evidence. Firstly, NCX might contribute to CICR during an action potential (AP) as Na+-accumulation at the intracellular site together with depolarization will trigger reverse mode exchange bringing Ca2+ into the dyadic cleft. The controversial issue is the nature of the compartment in which Na+ accumulates. It seems not to be the bulk cytosol, but is it part of a widespread subsarcolemmal space, a localized microdomain ("fuzzy space"), or as we propose, a more localized "spot" to which only a few membrane proteins have shared access (nanodomains)? Also, there seems to be spots where the Na,K-pump (NKA) will cause local Na+ depletion. Secondly, Na+ determines the rate of cytosolic Ca2+ removal and SR Ca2+ load by regulating the SERCA2/NCX-balance during the decay of the Ca2+ transient. The aim of this review is to describe available data and current concepts of Na+-mediated regulation of cardiac EC-coupling, with special focus on subcellular microdomains and the potential roles of Na+ transport proteins in regulating CICR and Ca2+ extrusion in cardiomyocytes. We propose that voltage gated Na+ channels, NCX and the NKA α2-isoform all regulate cardiac EC-coupling through control of the "Na+ concentration in specific subcellular nanodomains in cardiomyocytes. This article is part of a Special Issue entitled "Na+ Regulation in Cardiac Myocytes.". © 2013 Elsevier Ltd. Source

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