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Takumi Washio, Seiryo Sugiura, Ryo Kanada, Jun-Ichi Okada, Toshiaki Hisada
High-performance computing approaches that combine molecular-scale and macroscale continuum mechanics have long been anticipated in various fields. Such approaches may enrich our understanding of the links between microscale molecular mechanisms and macroscopic properties in the continuum. However, there have been few successful examples to date owing to various difficulties associated with overcoming the large spatial (from 1 nm to 10 cm) and temporal (from 1 ns to 1 ms) gaps between the two scales. In this paper, we propose an efficient parallel scheme to couple a microscopic model using Langevin dynamics for a protein motor with a finite element continuum model of a beating heart...
2018: Frontiers in Physiology
Conrad P Hodgkinson, Richard E Pratt, Imke Kirste, Sophie Dal-Pra, John P Cooke, Victor J Dzau
The process by which committed precursors mature into cardiomyocytes is poorly understood. We found that TLR3 inhibition blocked cardiomyocyte maturation; precursor cells committed to the cardiomyocyte lineage failed to express maturation genes and sarcomeres did not develop. Using various approaches we found that the effects of TLR3 upon cardiomyocyte maturation were dependent upon the RelA subunit of NFκB. Importantly, under conditions that promote the development of mature cardiomyocytes NFκB became significantly enriched at the promoters of cardiomyocyte maturation genes...
April 19, 2018: Stem Cells
Arnold D Gomez, Nahla Elsaid, Maureen L Stone, Jiachen Zhuo, Jerry L Prince
Mechanical modeling of tongue deformation plays a significant role in the study of breathing, swallowing, and speech production. In the absence of internal joints, fiber orientations determine the direction of sarcomeric contraction and have great influence over real and simulated tissue motion. However, subject-specific experimental observations of fiber distribution are difficult to obtain; thus, models of fiber distribution are generally used in mechanical simulations. This paper describes modeling of fiber distribution using solutions of Laplace equations and compares the effectiveness of this approach against tractography from diffusion tensor magnetic resonance imaging...
April 19, 2018: Biomechanics and Modeling in Mechanobiology
Annette Kronenbitter, Florian Funk, Katarzyna Hackert, Simone Gorreßen, Dennis Glaser, Peter Boknik, Gereon Poschmann, Kai Stühler, Malgorzata Isić, Martina Krüger, Joachim P Schmitt
Changes in the nonischemic remote myocardium of the heart contribute to left ventricular dysfunction after ischemia and reperfusion (I/R). Understanding the underlying mechanisms early after I/R is crucial to improve the adaptation of the viable myocardium to increased mechanical demands. Here, we investigated the role of myocyte Ca2+ handling in the remote myocardium 24 h after 60 min LAD occlusion. Cardiomyocytes isolated from the basal noninfarct-related parts of wild type mouse hearts demonstrated depressed beat-to-beat Ca2+ handling...
April 16, 2018: Journal of Molecular and Cellular Cardiology
Fengyan Fan, Yang Yu, Liping Sun, Shufang Wang, Rui Wang, Leiying Zhang, Cuiying Li, Deqing Wang
BACKGROUND/AIMS: Preserved red blood cells (RBCs) in vitro undergo a series of morphological, functional and metabolic changes during storage. RBC metabolites accumulate over time during storage, the toxicity of the supernatants of RBCs (SSRBCs) on tissue cells is largely unknown. Here, we aimed to study cardiomyocyte toxicity by supernatant of long term-stored RBCs in vitro and to discover elements involved in the mechanism. METHODS: Using human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) and real-time cell analyzing (RTCA), we analyzed the cardiotoxicity of d0, d14 and d35 SSRBCs...
April 16, 2018: Cellular Physiology and Biochemistry
Antheia Kissopoulou, Cecilia Trinks, Anna Green, Jan-Erik Karlsson, Jon Jonasson, Cecilia Gunnarsson
Hypertrophic cardiomyopathy (HCM) is a primary autosomal-dominant disorder of the myocardium with variable expressivity and penetrance. Occasionally, homozygous sarcomere genetic variants emerge while genotyping HCM patients. In these cases, a more severe HCM phenotype is generally seen. Here, we report a case of HCM that was diagnosed clinically at 39 years of age. Initial symptoms were shortness of breath during exertion. Successively, he developed a wide array of severe clinical manifestations, which progressed to an ominous end-stage heart failure that resulted in heart transplantation...
April 16, 2018: ESC Heart Failure
Francine Parker, Matthew Batchelor, Marcin Wolny, Ruth Hughes, Peter J Knight, Michelle Peckham
Over 20 mutations in β-cardiac myosin heavy chain (β-MHC), expressed in cardiac and slow muscle fibres, cause Laing early onset distal myopathy (MPD-1), a skeletal muscle myopathy. Most of these mutations are in the coiled-coil tail, and commonly involve a mutation to a proline, or a single residue deletion, both of which are predicted to strongly affect the secondary structure of the coiled coil. To test this, we characterised the effects of two MPD-1 causing mutations: A1603P and K1617del in vitro and in cells...
April 13, 2018: Journal of Molecular Biology
Jeffrey B Geske, Steve R Ommen, Bernard J Gersh
Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, manifesting as left ventricular hypertrophy in the absence of a secondary cause. The genetic underpinnings of HCM arise largely from mutations of sarcomeric proteins; however, the specific underlying mutation often remains undetermined. Patient presentation is phenotypically diverse, ranging from asymptomatic to heart failure or sudden cardiac death. Left ventricular hypertrophy and abnormal ventricular configuration result in dynamic left ventricular outflow obstruction in most patients...
April 5, 2018: JACC. Heart Failure
Amin Damanafshan, Ies Elzenaar, Benoit Samson-Couterie, Ingeborg van der Made, Meriem Bourajjaj, Maarten M van den Hoogenhof, Henk A van Veen, Daisy I Picavet, Abdelaziz Beqqali, Elisabeth Ehler, Leon J De Windt, Yigal M Pinto, Ralph J van Oort
Aim: The pathology of heart failure is characterized by poorly contracting and dilated ventricles. At the cellular level, this is associated with lengthening of individual cardiomyocytes and loss of sarcomeres. While it is known that the transcription factor myocyte enhancer factor -2 (MEF2) is involved in this cardiomyocyte remodeling, the underlying mechanism remains to be elucidated. Here, we aim to mechanistically link MEF2 target genes with loss of sarcomeres during cardiomyocyte remodeling...
April 10, 2018: Cardiovascular Research
Anna Axelsson Raja, Hoshang Farhad, Anne Marie Valente, John-Paul Couce, John Lynn Jefferies, Henning Bundgaard, Kenneth Zahka, Harry Lever, Anne M Murphy, Euan Ashley, Sharlene M Day, Mark V Sherrid, Ling Shi, David A Bluemke, Charles E Canter, Steven D Colan, Carolyn Y Ho
Background -Late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is believed to represent dense replacement fibrosis. It is seen in ~60% of adult patients with hypertrophic cardiomyopathy (HCM). However, the prevalence of LGE in children and adolescents with HCM is not well established. Additionally, longitudinal studies describing the development and evolution of LGE in pediatric HCM are lacking. This study assesses the prevalence, progression, and clinical correlations of LGE in children and adolescents with, or genetically predisposed to, HCM...
April 5, 2018: Circulation
Daria M Adamczak, Zofia Oko-Sarnowska
Hypertrophic cardiomyopathy (HCM) is a heart disease characterized by hypertrophy of the left ventricular myocardium and is most often caused by mutations in sarcomere genes. The structural and functional abnormalities are not explained by flow-limiting coronary artery disease or loading conditions. The disease affects at least 0.2% of the population worldwide and is the most common cause of sudden cardiac death in young people and competitive athletes because of fatal ventricular arrhythmia. In some patients, however, HCM has a benign course...
May 2018: Cardiology in Review
Sandra G Velleman, Daniel L Clark, Jeffrey R Tonniges
The wooden breast (WB) has been classically identified by the phenotypic presence of a wood-like pectoralis major (p. major) muscle. The WB-affected p. major muscle is characterized by necrotic muscle fibers and the replacement of muscle with connective tissue, water, and fat. The objective of the current study was to determine the effect of the WB myopathy on sarcomere organization by transmission electron microscopy. Sarcomere structure and organization were examined in two broiler lines with a high incidence of WB (Lines A and B) and another broiler line without WB (Line C)...
March 2018: Avian Diseases
Kacey Ronaldson-Bouchard, Stephen P Ma, Keith Yeager, Timothy Chen, LouJin Song, Dario Sirabella, Kumi Morikawa, Diogo Teles, Masayuki Yazawa, Gordana Vunjak-Novakovic
Cardiac tissues generated from human induced pluripotent stem cells (iPSCs) can serve as platforms for patient-specific studies of physiology and disease1-6 . However, the predictive power of these models is presently limited by the immature state of the cells1, 2, 5, 6 . Here we show that this fundamental limitation can be overcome if cardiac tissues are formed from early-stage iPSC-derived cardiomyocytes soon after the initiation of spontaneous contractions and are subjected to physical conditioning with increasing intensity over time...
April 4, 2018: Nature
Andrea Leonard, Alessandro Bertero, Joseph D Powers, Kevin M Beussman, Shiv Bhandari, Michael Regnier, Charles E Murry, Nathan J Sniadecki
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) grown in engineered heart tissue (EHT) can be used for drug screening, disease modeling, and heart repair. However, the immaturity of hiPSC-CMs currently limits their use. Because mechanical loading increases during development and facilitates cardiac maturation, we hypothesized that afterload would promote maturation of EHTs. To test this we developed a system in which EHTs are suspended between a rigid post and a flexible one, whose resistance to contraction can be modulated by applying braces of varying length...
March 28, 2018: Journal of Molecular and Cellular Cardiology
Young Soo Han, Niccole Schaible, Torkjel Tveita, Gary Sieck
After exposing spontaneously beating hearts as well as electrically stimulated isolated cardiomyocytes to hypothermia/rewarming (H/R), cardiac dysfunction or alterations in excitation-contraction coupling, respectively, is a consequence. In contrast, hypothermic cardiac arrest as routinely applied during cardiac surgery, will not impose any hazard to cardiac function after rewarming. We hypothesize that by maintaining asystole during H/R, cardiomyocytes will avoid Ca2+ overload due to the transient stimulation-evoked elevation of [Ca2+ ]cyto and thus, H/R-induced elevation of p-cTnI, and reduced Ca2+ sensitivity after rewarming...
March 31, 2018: Experimental Physiology
Tiago P Dias, Sandra N Pinto, Juliana I Santos, Tiago G Fernandes, Fábio Fernandes, Maria Margarida Diogo, Manuel Prieto, Joaquim M S Cabral
Human induced Pluripotent Stem Cell-derived cardiomyocytes (hiPSC-CMs) have an enormous potential for the development of drug screening and modeling cardiac disease platforms. However, early hiPSC-CMs usually exhibit low structural development, precluding the applicability of these cells. Here, we follow during 120 days the progressive structural maturation of hiPSC-CM microtissues obtained using the Wnt signaling modulation protocol. For this purpose, we designed a user friendly custom-written program to quantify cardiac fiber alignment and sarcomere length...
March 27, 2018: Biochemical and Biophysical Research Communications
Thorsteinn Bjornsson, Rosa B Thorolfsdottir, Gardar Sveinbjornsson, Patrick Sulem, Gudmundur L Norddahl, Anna Helgadottir, Solveig Gretarsdottir, Audur Magnusdottir, Ragnar Danielsen, Emil L Sigurdsson, Berglind Adalsteinsdottir, Sverrir I Gunnarsson, Ingileif Jonsdottir, David O Arnar, Hrodmar Helgason, Tomas Gudbjartsson, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Hilma Holm, Kari Stefansson
Aims: Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and confers substantial morbidity despite treatment. It is increasingly recognized as a highly heritable condition. The aim of the study was to search for sequence variants that affect the risk of CoA. Methods and results: We performed a genome-wide association study of CoA among Icelanders (120 cases and 355 166 controls) based on imputed variants identified through whole-genome sequencing...
March 24, 2018: European Heart Journal
Johan Lindqvist, Marloes van den Berg, Robbert van der Pijl, Pleuni E Hooijman, Albertus Beishuizen, Judith Elshof, Monique de Waard, Armand Girbes, Angelique Spoelstra-de Man, Zhong-Hua Shi, Charissa van den Brom, Sylvia Bogaards, Shengyi Shen, Joshua Strom, Henk Granzier, Jeroen Kole, René J P Musters, Marinus A Paul, Leo M A Heunks, Coen A C Ottenheijm
RATIONALE: Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay, and increases mortality and health care costs. The mechanisms underlying diaphragm weakness include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown. OBJECTIVES: To test the hypothesis that mechanical ventilation with positive end-expiratory pressure (PEEP) induces longitudinal atrophy by displacing the diaphragm in caudal direction and reducing the length of fibers...
March 26, 2018: American Journal of Respiratory and Critical Care Medicine
Ai-Jun Sun, Liang Qiao, Chao Huang, Xi Zhang, Yu-Quan Li, Xiang-Qun Yang
The present study aimed to compare brown adipose-derived stem cell (BASC) and white adipose-derived stem cell (WASC) differentiation into pacemaker‑like cells following T‑box (TBX)18 transduction. Mouse BASCs and WASCs were induced to differentiate into pacemaker‑like cells by adenovirus‑TBX18 transduction in vitro. The transduction rate was determined by fluorescence microscopy and cell ultrastructural changes were observed by transmission electron microscopy at 48 h post‑transduction. The mRNA and protein expression of pacemaker cell‑associated markers, including TBX18, TBX3, sarcomeric α‑actinin (Sr) and hyperpolarization‑activated cyclic nucleotide‑gated channel 4 (HCN4), were detected by reverse transcription‑quantitative polymerase chain reaction, immunofluorescence staining and western blot analysis...
March 20, 2018: Molecular Medicine Reports
Styliani Vakrou, Ryuya Fukunaga, D Brian Foster, Lars Sorensen, Yamin Liu, Yufan Guan, Kirubel Woldemichael, Roberto Pineda-Reyes, Ting Liu, Jill C Tardiff, Leslie A Leinwand, Carlo G Tocchetti, Theodore P Abraham, Brian O'Rourke, Miguel A Aon, M Roselle Abraham
Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease...
March 22, 2018: JCI Insight
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