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Front. Physiol. | doi: 10.3389/fphys.2019.00239

Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue

 Nico Kresin1, 2, 3,  Sabrina Stücker1, 2, 3, Elisabeth Kraemer1, 2, 3, Frederik Flenner1, 2, 3,  Giulia Mearini1, 2, 3, Julia Muench4, Monika Patten4, Charles Redwood5, 6, 7,  Lucie Carrier1, 2, 3 and  Felix W. Friedrich1, 2, 3*
  • 1Institut für Experimentelle Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Germany
  • 2Herz Kreislauf Forschung, Universitätsklinikum Hamburg-Eppendorf, Germany
  • 3Partner site Hamburg/Kiel/Lübeck, DZHK, German Centre for Cardiovascular Research, Germany
  • 4Universitäres Herzzentrum Hamburg GmbH (UHZ), Germany
  • 5Radcliffe Department of Medicine, University of Oxford, United Kingdom
  • 6University of Oxford, United Kingdom
  • 7John Radcliffe Hospital, United Kingdom

Background. Many forms of hypertrophic cardiomyopathy (HCM) show an increased myofilament Ca2+ sensitivity. This observation has been mainly made in HCM mouse models, myofilament systems, and cardiomyocytes. Studies of multicellular tissues from patients with different HCM-associated gene mutations are scarce. We investigated Ca2+ sensitivity in multicellular cardiac muscle strips of HCM patients. We furthermore evaluated the use of epigallocatechin-3-gallate (EGCg), a Ca2+ desensitizer.
Methods. After strip isolation from cardiac tissues with single (MYBPC3, MYH7) or double heterozygous mutations (MYBPC3/FLNC, MYH7/LAMP2, MYBPC3/MYH7) and permeabilization we performed contractility measurements ±EGCg. We furthermore evaluated gene expression with a customized heart failure gene panel using the NanoString technology.
Results. Fmax tended to be higher in HCM than non-failing (NF) control strips and in single than in double heterozygous strips. Ca2+ sensitivity was higher by trend in most HCM vs. NF strips and by trend in tissues with double vs. single heterozygous mutations. EGCg desensitized myofilaments to Ca2+ in most of the strips and tended to induce a more pronounced shift in strips with truncating than missense or single than double heterozygous mutations. Gene expression analysis revealed lower ATP2A2, PPP1R1A, FHL2, and higher NPPA, NPPB, COL1A1, CTGF, POSTN marker levels in HCM than in NF tissues. NPPA, NPPB, ACTA1, CTGF, COL1A1, POSTN levels were higher in tissues with missense than truncating mutations.
Conclusion. We report an increased myofilament Ca2+ sensitivity in native multicellular cardiac HCM strips, which by trend was more pronounced in samples with double heterozygous mutations. EGCg could have differential effects depending on the underlying genetic status (single vs. double heterozygous) and type (missense vs. truncating).

Keywords: Myofilament, calcium sensitivity, hypertrophic cardiomyopathy, MYBPC3, Epigallocatechin 3-gallate, NanoString nCounter

Received: 03 Aug 2018; Accepted: 22 Feb 2019.

Edited by:

Francisco H. Andrade, University of Kentucky, United States

Reviewed by:

Stuart Campbell, Yale University, United States
Kenneth S. Campbell, University of Kentucky, United States  

Copyright: © 2019 Kresin, Stücker, Kraemer, Flenner, Mearini, Muench, Patten, Redwood, Carrier and Friedrich. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Felix W. Friedrich, Institut für Experimentelle Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany, f.friedrich@uke.de