Contractile Dysfunction Irrespective of the Mutant Protein in Human Hypertrophic Cardiomyopathy With Normal Systolic Function

Sabine J. van Dijk; E. Rosalie Paalberends; Aref Najafi; Michelle Michels; Sakthivel Sadayappan; Lucie Carrier; Nicky M. Boontje; Diederik W. D. Kuster; Marjon van Slegtenhorst; Dennis Dooijes; Cris dos Remedios; Folkert J. ten Cate; Ger J. M. Stienen; Jolanda van der Velden

doi:10.1161/CIRCHEARTFAILURE.111.963702

Contractile Dysfunction Irrespective of the Mutant Protein in Human Hypertrophic Cardiomyopathy With Normal Systolic Function

Sabine J. van Dijk, E. Rosalie Paalberends, Aref Najafi, Michelle Michels, Sakthivel Sadayappan, Lucie Carrier, Nicky M. Boontje, Diederik W. D. Kuster, Marjon van Slegtenhorst, Dennis Dooijes, Cris dos Remedios, Folkert J. ten Cate, Ger J. M. Stienen, Jolanda van der Velden^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background-Hypertrophic cardiomyopathy (HCM), typically characterized by asymmetrical left ventricular hypertrophy, frequently is caused by mutations in sarcomeric proteins. We studied if changes in sarcomeric properties in HCM depend on the underlying protein mutation.

Methods and Results-Comparisons were made between cardiac samples from patients carrying a MYBPC3 mutation (MYBPC3(mut); n = 17), mutation negative HCM patients without an identified sarcomere mutation (HCMmn; n = 11), and nonfailing donors (n = 12). All patients had normal systolic function, but impaired diastolic function. Protein expression of myosin binding protein C (cMyBP-C) was significantly lower in MYBPC3(mut) by 33 +/- 5%, and similar in HCMmn compared with donor. cMyBP-C phosphorylation in MYBPC3(mut) was similar to donor, whereas it was significantly lower in HCMmn. Troponin I phosphorylation was lower in both patient groups compared with donor. Force measurements in single permeabilized cardiomyocytes demonstrated comparable sarcomeric dysfunction in both patient groups characterized by lower maximal force generating capacity in MYBPC3(mut) and HCMmn, compared with donor (26.4 +/- 2.9, 28.0 +/- 3.7, and 37.2 +/- 2.3 kN/m(2), respectively), and higher myofilament Ca2+-sensitivity (EC50 = 2.5 +/- 0.2, 2.4 +/- 0.2, and 3.0 +/- 0.2 mu mol/L, respectively). The sarcomere length-dependent increase in Ca2+-sensitivity was significantly smaller in both patient groups compared with donor (Delta EC50: 0.46 +/- 0.04, 0.37 +/- 0.05, and 0.75 +/- 0.07 mu mol/L, respectively). Protein kinase A treatment restored myofilament Ca2+-sensitivity and length-dependent activation in both patient groups to donor values.

Conclusions-Changes in sarcomere function reflect the clinical HCM phenotype rather than the specific MYBPC3 mutation. Hypocontractile sarcomeres are a common deficit in human HCM with normal systolic left ventricular function and may contribute to HCM disease progression. (Circ Heart Fail. 2012; 5: 36-46.)

Original language	English
Pages (from-to)	36-U126
Number of pages	16
Journal	Circulation. Heart Failure
Volume	5
Issue number	1
DOIs	https://doi.org/10.1161/CIRCHEARTFAILURE.111.963702
Publication status	Published - Jan 2012

Keywords

cardiomyopathy
myofilament proteins
mutation
myocardial contraction
HUMAN HEART-MUSCLE
LENGTH-DEPENDENT ACTIVATION
BETA-BLOCKER THERAPY
C PHOSPHORYLATION
TROPONIN-I
KINASE-A
MAGNETIC-RESONANCE
CARDIAC-FUNCTION
HUMAN MYOCARDIUM
MUTATIONS

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10.1161/CIRCHEARTFAILURE.111.963702

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van Dijk, S. J., Paalberends, E. R., Najafi, A., Michels, M., Sadayappan, S., Carrier, L., Boontje, N. M., Kuster, D. W. D., van Slegtenhorst, M., Dooijes, D., dos Remedios, C., ten Cate, F. J., Stienen, G. J. M., & van der Velden, J. (2012). Contractile Dysfunction Irrespective of the Mutant Protein in Human Hypertrophic Cardiomyopathy With Normal Systolic Function. Circulation. Heart Failure, 5(1), 36-U126. https://doi.org/10.1161/CIRCHEARTFAILURE.111.963702

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title = "Contractile Dysfunction Irrespective of the Mutant Protein in Human Hypertrophic Cardiomyopathy With Normal Systolic Function",

abstract = "Background-Hypertrophic cardiomyopathy (HCM), typically characterized by asymmetrical left ventricular hypertrophy, frequently is caused by mutations in sarcomeric proteins. We studied if changes in sarcomeric properties in HCM depend on the underlying protein mutation.Methods and Results-Comparisons were made between cardiac samples from patients carrying a MYBPC3 mutation (MYBPC3(mut); n = 17), mutation negative HCM patients without an identified sarcomere mutation (HCMmn; n = 11), and nonfailing donors (n = 12). All patients had normal systolic function, but impaired diastolic function. Protein expression of myosin binding protein C (cMyBP-C) was significantly lower in MYBPC3(mut) by 33 +/- 5%, and similar in HCMmn compared with donor. cMyBP-C phosphorylation in MYBPC3(mut) was similar to donor, whereas it was significantly lower in HCMmn. Troponin I phosphorylation was lower in both patient groups compared with donor. Force measurements in single permeabilized cardiomyocytes demonstrated comparable sarcomeric dysfunction in both patient groups characterized by lower maximal force generating capacity in MYBPC3(mut) and HCMmn, compared with donor (26.4 +/- 2.9, 28.0 +/- 3.7, and 37.2 +/- 2.3 kN/m(2), respectively), and higher myofilament Ca2+-sensitivity (EC50 = 2.5 +/- 0.2, 2.4 +/- 0.2, and 3.0 +/- 0.2 mu mol/L, respectively). The sarcomere length-dependent increase in Ca2+-sensitivity was significantly smaller in both patient groups compared with donor (Delta EC50: 0.46 +/- 0.04, 0.37 +/- 0.05, and 0.75 +/- 0.07 mu mol/L, respectively). Protein kinase A treatment restored myofilament Ca2+-sensitivity and length-dependent activation in both patient groups to donor values.Conclusions-Changes in sarcomere function reflect the clinical HCM phenotype rather than the specific MYBPC3 mutation. Hypocontractile sarcomeres are a common deficit in human HCM with normal systolic left ventricular function and may contribute to HCM disease progression. (Circ Heart Fail. 2012; 5: 36-46.)",

keywords = "cardiomyopathy, myofilament proteins, mutation, myocardial contraction, HUMAN HEART-MUSCLE, LENGTH-DEPENDENT ACTIVATION, BETA-BLOCKER THERAPY, C PHOSPHORYLATION, TROPONIN-I, KINASE-A, MAGNETIC-RESONANCE, CARDIAC-FUNCTION, HUMAN MYOCARDIUM, MUTATIONS",

author = "{van Dijk}, {Sabine J.} and Paalberends, {E. Rosalie} and Aref Najafi and Michelle Michels and Sakthivel Sadayappan and Lucie Carrier and Boontje, {Nicky M.} and Kuster, {Diederik W. D.} and {van Slegtenhorst}, Marjon and Dennis Dooijes and {dos Remedios}, Cris and {ten Cate}, {Folkert J.} and Stienen, {Ger J. M.} and {van der Velden}, Jolanda",

year = "2012",

month = jan,

doi = "10.1161/CIRCHEARTFAILURE.111.963702",

language = "English",

volume = "5",

pages = "36--U126",

journal = "Circulation. Heart Failure",

issn = "1941-3289",

publisher = "Lippincott Williams & Wilkins",

number = "1",

}

van Dijk, SJ, Paalberends, ER, Najafi, A, Michels, M, Sadayappan, S, Carrier, L, Boontje, NM, Kuster, DWD, van Slegtenhorst, M, Dooijes, D, dos Remedios, C, ten Cate, FJ, Stienen, GJM & van der Velden, J 2012, 'Contractile Dysfunction Irrespective of the Mutant Protein in Human Hypertrophic Cardiomyopathy With Normal Systolic Function', Circulation. Heart Failure, vol. 5, no. 1, pp. 36-U126. https://doi.org/10.1161/CIRCHEARTFAILURE.111.963702

TY - JOUR

T1 - Contractile Dysfunction Irrespective of the Mutant Protein in Human Hypertrophic Cardiomyopathy With Normal Systolic Function

AU - van Dijk, Sabine J.

AU - Paalberends, E. Rosalie

AU - Najafi, Aref

AU - Michels, Michelle

AU - Sadayappan, Sakthivel

AU - Carrier, Lucie

AU - Boontje, Nicky M.

AU - Kuster, Diederik W. D.

AU - van Slegtenhorst, Marjon

AU - Dooijes, Dennis

AU - dos Remedios, Cris

AU - ten Cate, Folkert J.

AU - Stienen, Ger J. M.

AU - van der Velden, Jolanda

PY - 2012/1

Y1 - 2012/1

N2 - Background-Hypertrophic cardiomyopathy (HCM), typically characterized by asymmetrical left ventricular hypertrophy, frequently is caused by mutations in sarcomeric proteins. We studied if changes in sarcomeric properties in HCM depend on the underlying protein mutation.Methods and Results-Comparisons were made between cardiac samples from patients carrying a MYBPC3 mutation (MYBPC3(mut); n = 17), mutation negative HCM patients without an identified sarcomere mutation (HCMmn; n = 11), and nonfailing donors (n = 12). All patients had normal systolic function, but impaired diastolic function. Protein expression of myosin binding protein C (cMyBP-C) was significantly lower in MYBPC3(mut) by 33 +/- 5%, and similar in HCMmn compared with donor. cMyBP-C phosphorylation in MYBPC3(mut) was similar to donor, whereas it was significantly lower in HCMmn. Troponin I phosphorylation was lower in both patient groups compared with donor. Force measurements in single permeabilized cardiomyocytes demonstrated comparable sarcomeric dysfunction in both patient groups characterized by lower maximal force generating capacity in MYBPC3(mut) and HCMmn, compared with donor (26.4 +/- 2.9, 28.0 +/- 3.7, and 37.2 +/- 2.3 kN/m(2), respectively), and higher myofilament Ca2+-sensitivity (EC50 = 2.5 +/- 0.2, 2.4 +/- 0.2, and 3.0 +/- 0.2 mu mol/L, respectively). The sarcomere length-dependent increase in Ca2+-sensitivity was significantly smaller in both patient groups compared with donor (Delta EC50: 0.46 +/- 0.04, 0.37 +/- 0.05, and 0.75 +/- 0.07 mu mol/L, respectively). Protein kinase A treatment restored myofilament Ca2+-sensitivity and length-dependent activation in both patient groups to donor values.Conclusions-Changes in sarcomere function reflect the clinical HCM phenotype rather than the specific MYBPC3 mutation. Hypocontractile sarcomeres are a common deficit in human HCM with normal systolic left ventricular function and may contribute to HCM disease progression. (Circ Heart Fail. 2012; 5: 36-46.)

AB - Background-Hypertrophic cardiomyopathy (HCM), typically characterized by asymmetrical left ventricular hypertrophy, frequently is caused by mutations in sarcomeric proteins. We studied if changes in sarcomeric properties in HCM depend on the underlying protein mutation.Methods and Results-Comparisons were made between cardiac samples from patients carrying a MYBPC3 mutation (MYBPC3(mut); n = 17), mutation negative HCM patients without an identified sarcomere mutation (HCMmn; n = 11), and nonfailing donors (n = 12). All patients had normal systolic function, but impaired diastolic function. Protein expression of myosin binding protein C (cMyBP-C) was significantly lower in MYBPC3(mut) by 33 +/- 5%, and similar in HCMmn compared with donor. cMyBP-C phosphorylation in MYBPC3(mut) was similar to donor, whereas it was significantly lower in HCMmn. Troponin I phosphorylation was lower in both patient groups compared with donor. Force measurements in single permeabilized cardiomyocytes demonstrated comparable sarcomeric dysfunction in both patient groups characterized by lower maximal force generating capacity in MYBPC3(mut) and HCMmn, compared with donor (26.4 +/- 2.9, 28.0 +/- 3.7, and 37.2 +/- 2.3 kN/m(2), respectively), and higher myofilament Ca2+-sensitivity (EC50 = 2.5 +/- 0.2, 2.4 +/- 0.2, and 3.0 +/- 0.2 mu mol/L, respectively). The sarcomere length-dependent increase in Ca2+-sensitivity was significantly smaller in both patient groups compared with donor (Delta EC50: 0.46 +/- 0.04, 0.37 +/- 0.05, and 0.75 +/- 0.07 mu mol/L, respectively). Protein kinase A treatment restored myofilament Ca2+-sensitivity and length-dependent activation in both patient groups to donor values.Conclusions-Changes in sarcomere function reflect the clinical HCM phenotype rather than the specific MYBPC3 mutation. Hypocontractile sarcomeres are a common deficit in human HCM with normal systolic left ventricular function and may contribute to HCM disease progression. (Circ Heart Fail. 2012; 5: 36-46.)

KW - cardiomyopathy

KW - myofilament proteins

KW - mutation

KW - myocardial contraction

KW - HUMAN HEART-MUSCLE

KW - LENGTH-DEPENDENT ACTIVATION

KW - BETA-BLOCKER THERAPY

KW - C PHOSPHORYLATION

KW - TROPONIN-I

KW - KINASE-A

KW - MAGNETIC-RESONANCE

KW - CARDIAC-FUNCTION

KW - HUMAN MYOCARDIUM

KW - MUTATIONS

UR - http://www.scopus.com/inward/record.url?scp=84859632282&partnerID=8YFLogxK

U2 - 10.1161/CIRCHEARTFAILURE.111.963702

DO - 10.1161/CIRCHEARTFAILURE.111.963702

M3 - Article

C2 - 22178992

SN - 1941-3289

VL - 5

SP - 36-U126

JO - Circulation. Heart Failure

JF - Circulation. Heart Failure

IS - 1

ER -

Contractile Dysfunction Irrespective of the Mutant Protein in Human Hypertrophic Cardiomyopathy With Normal Systolic Function

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Keywords

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