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      Changes in contractile protein expression are linked to ventricular stiffness in infants with pulmonary hypertension or right ventricular hypertrophy due to congenital heart disease

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          Abstract

          Background

          The right ventricle (RV) is not designed to sustain high pressure leading to failure. There are no current medications to help RV contraction, so further information is required on adaption of the RV to such hypertension.

          Methods

          The Right Ventricle in Children (RVENCH) study assessed infants with congenital heart disease undergoing cardiac surgery with hypertensive RV. Clinical and echocardiographic data were recorded, and samples of RV were taken from matched infants, analysed for proteomics and compared between pathologies and with clinical and echocardiographic outcome data.

          Results

          Those with tetralogy of Fallot (TOF) were significantly more cyanosed than those with ventricular septal defect (median oxygen saturation 83% vs 98%, P=0.0038), had significantly stiffer RV (tricuspid E wave/A wave ratio 1.95 vs 0.84, P=0.009) and had most had restrictive physiology. Gene ontology in TOF, with enrichment analysis, demonstrated significant increase in proteins of contractile mechanisms and those of calmodulin, actin binding and others associated with contractility than inventricular septal defect. Structural proteins were also found to be higher in association with sarcomeric function: Z-disc, M-Band and thin-filament proteins. Remaining proteins associated with actin binding, calcium signalling and myocyte cytoskeletal development. Phosphopeptide enrichment led to higher levels of calcium signalling proteins in TOF.

          Conclusion

          This is the first demonstration that those with an RV, which is stiff and hypertensive in TOF, have a range of altered proteins, often in calcium signalling pathways. Information about these alterations might guide treatment options both in terms of individualised therapy or inotropic support for the Right ventricle when hypertensive due to pulmoanry hypertension or congenital heart disease.

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          Most cited references25

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          The M-band: an elastic web that crosslinks thick filaments in the center of the sarcomere.

          Irina Agarkova, Jean-Claude Perriard (2005)
          The sarcomere of striated muscle is an efficient molecular machine, characterized by perfect structural organization of contractile filaments. This order is ensured by the sarcomere cytoskeleton, an important element of which is the M-band, believed to maintain the thick filament lattice. We review here recent progress in understanding the M-band function and its structural organization. We explain how the M-band might reduce the intrinsic instability of thick filaments and help titin to maintain order in the sarcomeres. The M-band molecular structure has been clarified recently by biochemical and biophysical approaches that focused on the properties of the prominent M-band component myomesin. These have shown that antiparallel myomesin dimers might link the thick filaments in the M-band, a role analogous to that of alpha-actinin in the Z-disc. Furthermore, similar to titin, myomesin is a molecular spring with complex visco-elastic properties that can be modified by alternative splicing. M-band protein composition correlates with the expression of titin isoforms and appears to be a reliable marker for biomechanical conditions in contracting muscle. We propose that the M-band is in fact a dynamic structure that monitors the stress appearing in the thick filament lattice during contraction and quickly reorganizes to meet new physiological requirements.
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            Cardiac titin: an adjustable multi-functional spring.

            Henk Granzier, Siegfried Labeit (2002)
            The giant elastic protein titin contains a molecular spring segment that underlies the majority of myocardial passive stiffness. The mechanical characteristics of this spring may be tuned to match changing mechanical demands placed on muscle, using mechanisms that operate on different time scales and that include post-transcriptional and post-translational processes. Recent work also suggests that titin performs roles that go beyond passive stiffness generation. In contracting myocardium, titin may modulate actomyosin interaction by a titin-based alteration of the distance between myosin heads and actin. Furthermore, novel ligands have been identified that link titin to membrane channels, protein turnover and gene expression. This review highlights that titin is a versatile and adjustable spring with a range of important functions in passive and contracting myocardium.
            Article 0 comments Cited 39 times – based on 0 reviews     Review now
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              Characterization of muscle filamin isoforms suggests a possible role of gamma-filamin/ABP-L in sarcomeric Z-disc formation.

              Andor F. van den Hoven, D Furst, M Gautel … (2000)
              Filamin, also called actin binding protein-280, is a dimeric protein that cross-links actin filaments in the cortical cytoplasm. In addition to this ubiquitously expressed isoform (FLN1), a second isoform (ABP-L/gamma-filamin) was recently identified that is highly expressed in mammalian striated muscles. A monoclonal antibody was developed, that enabled us to identify filamin as a Z-disc protein in mammalian striated muscles by immunocytochemistry and immunoelectron microscopy. In addition, filamin was identified as a component of intercalated discs in mammalian cardiac muscle and of myotendinous junctions in skeletal muscle. Northern and Western blots showed that both, ABP-L/gamma-filamin mRNA and protein, are absent from proliferating cultured human skeletal muscle cells. This muscle specific filamin isoform is, however, up-regulated immediately after the induction of differentiation. In cultured myotubes, ABP-L/gamma-filamin localises in Z-discs already at the first stages of Z-disc formation, suggesting that ABP-L/gamma-filamin might play a role in Z-disc assembly. Copyright 2000 Wiley-Liss, Inc.
              Article 0 comments Cited 37 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Open Heart
                Journal ID (iso-abbrev): Open Heart
                Journal ID (hwp): openhrt
                Journal ID (publisher-id): openheart
                Title: Open Heart
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Electronic): 2053-3624
                Publication date Collection: 2018
                Publication date (Electronic): 3 January 2018
                Volume: 5
                Issue: 1
                Electronic Location Identifier: e000716
                Affiliations
                [1 ] departmentClinical Sciences , Bristol Heart Institute, Bristol Royal Infirmary , Bristol, UK
                [2 ] departmentProteomics Facility , University of Bristol , Bristol, UK
                [3 ] departmentDepartment of Congenital Heart Disease , King David Building , Bristol, UK
                Author notes
                [Correspondence to ] Professor Robert M R Tulloh; Robert.Tulloh@ 123456bristol.ac.uk
                Author information
                http://orcid.org/0000-0002-3180-6993
                Article
                Publisher ID: openhrt-2017-000716
                DOI: 10.1136/openhrt-2017-000716
                PMC ID: 5761287
                PubMed ID: 29344379
                SO-VID: 3aa75d61-cb7c-44a2-bda0-da837e0bf84a
                Copyright © © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
                License:

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                Date received : 03 September 2017
                Date revision received : 15 November 2017
                Date accepted : 18 November 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000861, Sparks;
                Categories
                Subject: Basic and Translational Research
                Subject: 1506
                Series title: Original research article
                Custom metadata
                special-feature unlocked

                Keywords: congenital heart disease,right ventricle,ventricular hypertrophy,proteomics
                Data availability:
                Keywords: congenital heart disease, right ventricle, ventricular hypertrophy, proteomics

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