Experimentally increasing titin compliance in a novel mouse model attenuates the frank-starling mechanism but has a beneficial effect on diastole

Mei Methawasin, Kirk R. Hutchinson, Eun Jeong Lee, John E. Smith, Chandra Saripalli, Carlos G. Hidalgo, Coen A C Ottenheijm, Hendrikus "Henk" Granzier

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Background: Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography. Methods and Results: Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin's spring elements. At both cardiomyocyte and left ventricular chamber levels, diastolic stiffness was reduced in heterozygous (+/-) Rbm20mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20 hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20 mice, at both the cardiomyocyte and left ventricular chamber levels. Exercise tests revealed an increase in exercise capacity in +/- mice. Conclusions: Titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness owing to the increased compliance of myocytes, but it depresses end-systolic elastance; under conditions of exercise, the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving the diastolic function in patients with heart failure.

Original languageEnglish (US)
Pages (from-to)1924-1936
Number of pages13
JournalCirculation
Volume129
Issue number19
DOIs
StatePublished - 2014

Fingerprint

Connectin
Starlings
Diastole
Compliance
Cardiac Myocytes
Muscle Cells
Fibrosis
Exercise
Doppler Echocardiography
Mechanics
Exercise Test
Exons
Heart Failure
Genome
Phenotype
Pressure

Keywords

  • Connectin
  • Diastole
  • Myocardial contraction
  • Myocytes cardiac
  • Physiology

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Experimentally increasing titin compliance in a novel mouse model attenuates the frank-starling mechanism but has a beneficial effect on diastole. / Methawasin, Mei; Hutchinson, Kirk R.; Lee, Eun Jeong; Smith, John E.; Saripalli, Chandra; Hidalgo, Carlos G.; Ottenheijm, Coen A C; Granzier, Hendrikus "Henk".

In: Circulation, Vol. 129, No. 19, 2014, p. 1924-1936.

Research output: Contribution to journalArticle

Methawasin, Mei ; Hutchinson, Kirk R. ; Lee, Eun Jeong ; Smith, John E. ; Saripalli, Chandra ; Hidalgo, Carlos G. ; Ottenheijm, Coen A C ; Granzier, Hendrikus "Henk". / Experimentally increasing titin compliance in a novel mouse model attenuates the frank-starling mechanism but has a beneficial effect on diastole. In: Circulation. 2014 ; Vol. 129, No. 19. pp. 1924-1936.
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abstract = "Background: Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography. Methods and Results: Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin's spring elements. At both cardiomyocyte and left ventricular chamber levels, diastolic stiffness was reduced in heterozygous (+/-) Rbm20mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20 hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20 mice, at both the cardiomyocyte and left ventricular chamber levels. Exercise tests revealed an increase in exercise capacity in +/- mice. Conclusions: Titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness owing to the increased compliance of myocytes, but it depresses end-systolic elastance; under conditions of exercise, the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving the diastolic function in patients with heart failure.",
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AU - Smith, John E.

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AU - Hidalgo, Carlos G.

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N2 - Background: Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography. Methods and Results: Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin's spring elements. At both cardiomyocyte and left ventricular chamber levels, diastolic stiffness was reduced in heterozygous (+/-) Rbm20mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20 hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20 mice, at both the cardiomyocyte and left ventricular chamber levels. Exercise tests revealed an increase in exercise capacity in +/- mice. Conclusions: Titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness owing to the increased compliance of myocytes, but it depresses end-systolic elastance; under conditions of exercise, the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving the diastolic function in patients with heart failure.

AB - Background: Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography. Methods and Results: Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin's spring elements. At both cardiomyocyte and left ventricular chamber levels, diastolic stiffness was reduced in heterozygous (+/-) Rbm20mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20 hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20 mice, at both the cardiomyocyte and left ventricular chamber levels. Exercise tests revealed an increase in exercise capacity in +/- mice. Conclusions: Titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness owing to the increased compliance of myocytes, but it depresses end-systolic elastance; under conditions of exercise, the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving the diastolic function in patients with heart failure.

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