Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue
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...
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Frontiers Media S.A.
2019-03-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2019.00239/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nico Kresin Nico Kresin Sabrina Stücker Sabrina Stücker Elisabeth Krämer Elisabeth Krämer Frederik Flenner Frederik Flenner Giulia Mearini Giulia Mearini Julia Münch Monica Patten Charles Redwood Lucie Carrier Lucie Carrier Felix W. Friedrich Felix W. Friedrich |
spellingShingle |
Nico Kresin Nico Kresin Sabrina Stücker Sabrina Stücker Elisabeth Krämer Elisabeth Krämer Frederik Flenner Frederik Flenner Giulia Mearini Giulia Mearini Julia Münch Monica Patten Charles Redwood Lucie Carrier Lucie Carrier Felix W. Friedrich Felix W. Friedrich Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue Frontiers in Physiology myofilament Ca2+ sensitivity hypertrophic cardiomyopathy MYBPC3 epigallocatechin-3-gallate NanoString nCounter |
author_facet |
Nico Kresin Nico Kresin Sabrina Stücker Sabrina Stücker Elisabeth Krämer Elisabeth Krämer Frederik Flenner Frederik Flenner Giulia Mearini Giulia Mearini Julia Münch Monica Patten Charles Redwood Lucie Carrier Lucie Carrier Felix W. Friedrich Felix W. Friedrich |
author_sort |
Nico Kresin |
title |
Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue |
title_short |
Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue |
title_full |
Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue |
title_fullStr |
Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue |
title_full_unstemmed |
Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue |
title_sort |
analysis of contractile function of permeabilized human hypertrophic cardiomyopathy multicellular heart tissue |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2019-03-01 |
description |
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 in 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, and FHL2 and higher NPPA, NPPB, COL1A1, CTGF, and POSTN marker levels in HCM than in NF tissues. NPPA, NPPB, ACTA1, CTGF, COL1A1, and 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). |
topic |
myofilament Ca2+ sensitivity hypertrophic cardiomyopathy MYBPC3 epigallocatechin-3-gallate NanoString nCounter |
url |
https://www.frontiersin.org/article/10.3389/fphys.2019.00239/full |
work_keys_str_mv |
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doaj-9afd9321f0244aeeaedb90d00b1f6ea02020-11-25T02:46:23ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-03-011010.3389/fphys.2019.00239417825Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart TissueNico Kresin0Nico Kresin1Sabrina Stücker2Sabrina Stücker3Elisabeth Krämer4Elisabeth Krämer5Frederik Flenner6Frederik Flenner7Giulia Mearini8Giulia Mearini9Julia Münch10Monica Patten11Charles Redwood12Lucie Carrier13Lucie Carrier14Felix W. Friedrich15Felix W. Friedrich16Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, GermanyInstitute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, GermanyInstitute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, GermanyInstitute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, GermanyInstitute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, GermanyUniversity Heart Center Hamburg, Hamburg, GermanyUniversity Heart Center Hamburg, Hamburg, GermanyRadcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United KingdomInstitute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, GermanyInstitute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, GermanyBackground: 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 in 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, and FHL2 and higher NPPA, NPPB, COL1A1, CTGF, and POSTN marker levels in HCM than in NF tissues. NPPA, NPPB, ACTA1, CTGF, COL1A1, and 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).https://www.frontiersin.org/article/10.3389/fphys.2019.00239/fullmyofilamentCa2+ sensitivityhypertrophic cardiomyopathyMYBPC3epigallocatechin-3-gallateNanoString nCounter |