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Lundby A.,Novo Nordisk AS | Lundby A.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Lundby A.,The Broad Institute of MIT and Harvard | Lage K.,Novo Nordisk AS | And 12 more authors.
Cell Reports | Year: 2012

The local interaction of F-actin with myosin-II motor filaments and crosslinking proteins is crucial for the force generation, dynamics, and reorganization of the intracellular cytoskeleton. By using a bottom-up approach, we are able to show that the contractility of reconstituted active actin systems is tightly controlled by the local pH. The pH-dependent intrinsic crossbridge strength of myosin-II is identified to account for a sharp transition of the actin/myosin-II activity from noncontractile to contractile by a change in pH of only 0.1. This pH-dependent contractility is a generic feature, which is observed in all studied crosslinked actin/myosin-II systems. The specific type and concentration of crosslinking protein allows one to sensitively adjust the range of pH where contraction occurs, which can recover the behavior found in Xenopus laevis oocyte extracts. Small variations in pH provide a mechanism of controlling the contractility of cytoskeletal structures, which can be expected to have broad implications in our understanding of cytoskeletal regulation

Smajilovic S.,Copenhagen University | Chattopadhyay N.,Central Drug Research Institute | Tfelt-Hansen J.,Copenhagen University | Tfelt-Hansen J.,The Danish National Research Foundation Center for Cardiac Arrhythmia
Open Heart Failure Journal | Year: 2010

Calcium is a crucial signal molecule in the cardiovascular system. Calcium (Ca 2+) acts as a second messenger via changes in intracellular Ca 2+ levels through the actions of calcium channels and pumps. However, it is now well known that calcium may also be an extracellular first messenger through a G-protein-coupled receptor that senses extracellular Ca 2+ concentration, the calcium-sensing receptor (CaR). The CaR is one of the key players in extracellular calcium homeostasis, but besides being expressed in the major organs involved in calcium homeostasis, the parathyroid gland, kidney and intestine, the CaR has also been found to be functionally expressed in other tissues. Although several studies demonstrated the CaR in heart and blood vessels, exact roles of the receptor in the cardiovascular system still remain to be elucidated. This review will summarize the current knowledge on the expression and possible functions of the CaR in the cardiac tissue. © Smajilovic et al.; Licensee Bentham Open.

Haarmark C.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Haarmark C.,Copenhagen University | Graff C.,University of Aalborg | Andersen M.P.,University of Aalborg | And 10 more authors.
Journal of Electrocardiology | Year: 2010

Introduction: Reference values for T-wave morphology analysis and evaluation of the relationship with age, sex, and heart rate are lacking in the literature. In this study, we characterized T-wave morphology in a large sample of healthy individuals. Method: A total of 1081 healthy subjects (83% men; range, 17-81 years) were included. T-wave morphology variables describing the duration, area, slopes, amplitude, and distribution were calculated using 10-second digital electrocardiogram recordings. Multivariate regression was used to test for dependence of T-wave variables with the subject age, sex, and heart rate. Results: Lead V5 (men vs women) T-wave variables were as follows: amplitude, 444 versus 317 μV; area, 48.4 versus 33.2 ms * mV; Tpeak-Tend interval, 94 versus 92 milliseconds; maximal descending slope, -5.15 versus -3.69 μV/ms; skewness, -0.24 versus -0.22; and kurtosis, -0.36 versus -0.35. Tpeak-Tend interval, skewness, and kurtosis were independent of age, sex, and heart rate (r 2 < 0.05), whereas Bazett-corrected QT-interval was more dependent (r 2 = 0.40). Conclusion: A selection of T-wave morphology variables is found to be clinically independent of age, sex, and heart rate, including Tpeak-Tend interval, skewness, and kurtosis. © 2010 Elsevier Inc. All rights reserved.

Nielsen M.W.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Nielsen M.W.,Copenhagen University | Holst A.G.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Holst A.G.,Copenhagen University | And 3 more authors.
Frontiers in Physiology | Year: 2013

Brugada syndrome (BrS) is a clinical entity first described in 1992. BrS is characterized by ST-segment elevations in the right precordial leads and susceptibility to ventricular arrhythmias and sudden cardiac death. It affects young subjects, predominantly males, with structurally normal hearts. The prevalence varies with ethnicity ranging from 1:2,000 to 1:100,000 in different parts of the world. Today, hundreds of variants in 17 genes have been associated with BrS of which mutations in SCN5A, coding for the cardiac voltage-gated sodium channel, accounts for the vast majority. Despite this, approximately 70% of BrS cases cannot be explained genetically with the current knowledge. Moreover, the monogenic role of some of the variants previously described as being associated with BrS has been questioned by their occurrence in about 4% (1:23) of the general population as found in NHLBI GO Exome Sequencing Project (ESP) currently including approximately 6500 individuals. If we add the variants described in the five newest identified genes associated with BrS, they appear at an even higher prevalence in the ESP (1:21). The current standard treatment of BrS is an implantable cardioverter-defibrillator (ICD). The risk stratification and indications for ICD treatment are based on the ECG and on the clinical and family history. In this review we discuss the genetic basis of BrS. © 2013 Nielsen, Holst, Olesen and Olesen.

Olesen M.S.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Olesen M.S.,Copenhagen University | Bentzen B.H.,The Danish National Research Foundation Center for Cardiac Arrhythmia | Bentzen B.H.,Copenhagen University | And 15 more authors.
BMC Medical Genetics | Year: 2012

Background: Atrial fibrillation (AF) is the most common arrhythmia. The potassium current I Ksis essential for cardiac repolarization. Gain-of-function mutations in K V7.1, the pore-forming α-subunit of the I Kschannel, have been associated with AF. We hypothesized that early-onset lone AF is associated with mutations in the I Kschannel regulatory subunit KCNE1.Methods: In 209 unrelated early-onset lone AF patients (< 40 years) the entire coding sequence of KCNE1 was bidirectionally sequenced. We analyzed the identified KCNE1 mutants electrophysiologically in heterologous expression systems.Results: Two non-synonymous mutations G25V and G60D were found in KCNE1 that were not present in the control group (n = 432 alleles) and that have not previously been reported in any publicly available databases or in the exom variant server holding exom data from more than 10.000 alleles. Proband 1 (female, age 45, G25V) had onset of paroxysmal AF at the age of 39 years. Proband 2 (G60D) was diagnosed with lone AF at the age of 33 years. The patient has inherited the mutation from his mother, who also has AF. Both probands had no mutations in genes previously associated with AF. In heterologous expression systems, both mutants showed significant gain-of-function for I Ksboth with respect to steady-state current levels, kinetic parameters, and heart rate-dependent modulation.Conclusions: Mutations in K V7.1 leading to gain-of-function of I Kscurrent have previously been described in lone AF, yet this is the first time a mutation in the beta-subunit KCNE1 is associated with the disease. This finding further supports the hypothesis that increased potassium current enhances AF susceptibility. © 2012 Olesen et al; licensee BioMed Central Ltd.

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