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- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 2. |
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| 3. |
- Siebenmann, C, et al.
(författare)
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Hemoglobin mass and intravascular volume kinetics during and after exposure to 3,454-m altitude
- 2015
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 119:10, s. 1194-1201
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Tidskriftsartikel (refereegranskat)abstract
- Siebenmann C, Cathomen A, Hug M, Keiser S, Lundby AK, Hilty MP, Goetze JP, Rasmussen P, Lundby C. Hemoglobin mass and intravascular volume kinetics during and after exposure to 3,454 m altitude. J Appl Physiol 119: 1194-1201, 2015. First published March 6, 2015; doi:10.1152/japplphysiol.01121.2014.-High altitude (HA) exposure facilitates a rapid contraction of plasma volume (PV) and a slower occurring expansion of hemoglobin mass (Hbmass). The kinetics of the Hbmass expansion has never been examined by multiple repeated measurements, and this was our primary study aim. The second aim was to investigate the mechanisms mediating the PV contraction. Nine healthy, normally trained sea-level (SL) residents (8 males, 1 female) sojourned for 28 days at 3,454 m. Hbmass was measured and PV was estimated by carbon monoxide rebreathing at SL, on every 4th day at HA, and 1 and 2 wk upon return to SL. Four weeks at HA increased Hbmass by 5.26% (range 2.5-11.1%; P < 0.001). The individual Hbmass increases commenced with up to 12 days of delay and reached a maximal rate of 4.04±1.02 g/day after 14.9±5.2 days. The probability for Hbmass to plateau increased steeply after 20-24 days. Upon return to SL Hbmass decayed by-2.46 ± 2.3 g/day, reaching values similar to baseline after 2 wk. PV, aldosterone concentration, and renin activity were reduced at HA (P < 0.001) while the total circulating protein mass remained unaffected. In summary, the Hbmass response to HA exposure followed a sigmoidal pattern with a delayed onset and a plateau after ∼3 wk. The decay rate of Hbmass upon descent to SL did not indicate major changes in the rate of erythrolysis. Moreover, our data support that PV contraction at HA is regulated by the renin-angiotensin-aldosterone axis and not by changes in oncotic pressure. © 2015 The American Physiological Society.
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| 4. |
- Lundby, Carsten, et al.
(författare)
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Physiological, biochemical, anthropometric, and biomechanical influences on exercise economy in humans
- 2017
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Ingår i: Scandinavian Journal of Medicine & Science in Sports. - : Wiley. - 0905-7188. ; 27:12, s. 1627-1637
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Tidskriftsartikel (refereegranskat)abstract
- Interindividual variation in running and cycling exercise economy (EE) remains unexplained although studied for more than a century. This study is the first to comprehensively evaluate the importance of biochemical, structural, physiological, anthropometric, and biomechanical influences on running and cycling EE within a single study. In 22 healthy males (VO(2)max range 45.5-72.1mLmin-1kg-1), no factor related to skeletal muscle structure (% slow-twitch fiber content, number of capillaries per fiber), mitochondrial properties (volume density, oxidative capacity, or mitochondrial efficiency), or protein content (UCP3 and MFN2 expression) explained variation in cycling and running EE among subjects. In contrast, biomechanical variables related to vertical displacement correlated well with running EE, but were not significant when taking body weight into account. Thus, running EE and body weight were correlated (R-2=.94; P<.001), but was lower for cycling EE (R-2=.23; P<.023). To separate biomechanical determinants of running EE, we contrasted individual running and cycling EE considering that during cycle ergometer exercise, the biomechanical influence on EE would be small because of the fixed movement pattern. Differences in cycling and running exercise protocols, for example, related to biomechanics, play however only a secondary role in determining EE. There was no evidence for an impact of structural or functional skeletal muscle variables on EE. Body weight was the main determinant of EE explaining 94% of variance in running EE, although more than 50% of the variability of cycling EE remains unexplained.
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| 5. |
- Lundby, A. K. M., et al.
(författare)
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Kidney-synthesized erythropoietin is the main source for the hypoxia-induced increase in plasma erythropoietin in adult humans
- 2014
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Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6319 .- 1439-6327. ; 114:6, s. 1107-1111
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Tidskriftsartikel (refereegranskat)abstract
- Erythropoietin (EPO) is mainly synthesized within renal peritubular fibroblasts, and also other tissues such as the liver possess the ability. However, to what extent non-kidney produced EPO contributes to the hypoxia-induced increase in circulating EPO in adult humans remains unclear. We aimed to quantify this by assessing the distribution of EPO glycoforms which are characterized by posttranslational glycosylation patterns specific to the synthesizing cell. The analysis was performed on samples obtained in seven healthy volunteers before, during and after 1 month of sojourn at 3,454 m altitude. Umbilical cord (UC) plasma served as control. As expected a peak (p < 0.05) in urine (2.3 +/- A 0.5-fold) and plasma (3.3 +/- A 0.5-fold) EPO was observed on day 1 of high-altitude exposure, and thereafter the concentration decreased for the urine sample obtained after 26 days at altitude, but remained elevated (p < 0.05) by 1.5 +/- A 0.2-fold above the initial sea level value for the plasma sample. The EPO glycoform heterogeneity, in the urine samples collected at altitude, did not differ from values at sea level, but were markedly lower (p < 0.05) than the mean percent migrated isoform (PMI) for the umbilical cord samples. Our studies demonstrate (1) UC samples express a different glycoform distribution as compared to adult humans and hence illustrates the ability to synthesis EPO in non-kidney cells during fetal development (2) as expected hypoxia augments circulating EPO in adults and the predominant source here for remains being kidney derived.
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