title: Remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy.
abstract: Sarcomeres are the basic contractile units of cardiac myocytes. Recent studies demonstrated remodeling of sarcomeric proteins in several diseases, including genetic defects and heart failure. Here we investigated remodeling of sarcomeric α-actinin in two models of heart failure, synchronous (SHF) and dyssynchronous heart failure (DHF), as well as a model of cardiac resynchronization therapy (CRT). We applied three-dimensional confocal microscopy and quantitative methods of image analysis to study isolated cells from our animal models. 3D Fourier analysis revealed a decrease of the spatial regularity of the α-actinin distribution in both SHF and DHF versus control cells. The spatial regularity of α-actinin in DHF cells was reduced when compared with SHF cells. The spatial regularity of α-actinin was partially restored after CRT. We found longitudinal depositions of α-actinin in SHF, DHF and CRT cells. These depositions spanned adjacent Z-disks and exhibited a lower density of α-actinin than in the Z-disk. Differences in the occurrence of depositions between the SHF, CRT and DHF models versus control were significant. Also, CRT cells exhibited a higher occurrence of depositions versus SHF, but not DHF cells. Other sarcomeric proteins did not accumulate in the depositions to the same extent as α-actinin. We did not find differences in the expression of α-actinin protein and its encoding gene in our animal models. In summary, our studies indicate that HF is associated with two different types of remodeling of α-actinin and only one of those was reversed after CRT. We suggest that these results can guide us to an understanding of remodeling of structures and function associated with sarcomeres.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Lichter
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Carruth
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Mitchell
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Barth
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aiba
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Bridge
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: fs@cvrti.utah.edu.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Sachse
mesh_terms: D000185:Actinin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D058406:Cardiac Resynchronization Therapy; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D004285:Dogs; D015870:Gene Expression; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D020257:Ventricular Remodeling
chemical_list: D000185:Actinin
keywords: Alpha actinin; Cardiac recovery; Cardiac resynchronization therapy; Heart failure; Remodeling