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Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a beneficial effect on diastole.

ABSTRACT: 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.Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20(?RRM)mice). 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 (+/-) Rbm20(?RRM)mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20(?RRM) hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20(?RRM) mice, at both the cardiomyocyte and left ventricular chamber levels. Exercise tests revealed an increase in exercise capacity in +/- mice.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.

SUBMITTER: Methawasin M

PROVIDER: S-EPMC4032222 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a beneficial effect on diastole.

Methawasin Mei M Hutchinson Kirk R KR Lee Eun-Jeong EJ Smith John E JE Saripalli Chandra C Hidalgo Carlos G CG Ottenheijm Coen A C CA Granzier Henk H

Circulation 20140305 19

<h4>Background</h4>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 echocar ...[more]

PMID: 24599837

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Project description:BACKGROUND:Left ventricular (LV) stiffening contributes to heart failure with preserved ejection fraction (HFpEF), a syndrome with no effective treatment options. Increasing the compliance of titin in the heart has become possible recently through inhibition of the splicing factor RNA binding motif-20. Here, we investigated the effects of increasing the compliance of titin in mice with diastolic dysfunction. METHODS:Mice in which the RNA recognition motif (RRM) of one of the RNA binding motif-20 alleles was floxed and that expressed the MerCreMer transgene under control of the ?MHC promoter (referred to as cRbm20?RRM mice) were used. Mice underwent transverse aortic constriction (TAC) surgery and deoxycorticosterone acetate (DOCA) pellet implantation. RRM deletion in adult mice was triggered by injecting raloxifene (cRbm20?RRM-raloxifene), with dimethyl sulfoxide (DMSO)-injected mice (cRbm20?RRM-DMSO) as the control. Diastolic function was investigated with echocardiography and pressure-volume analysis; passive stiffness was studied in LV muscle strips and isolated cardiac myocytes before and after elimination of titin-based stiffness. Treadmill exercise performance was also studied. Titin isoform expression was evaluated with agarose gels. RESULTS:cRbm20?RRM-raloxifene mice expressed large titins in the hearts, called supercompliant titin (N2BAsc), which, within 3 weeks after raloxifene injection, made up ?45% of total titin. TAC/DOCA cRbm20?RRM-DMSO mice developed LV hypertrophy and a marked increase in LV chamber stiffness as shown by both pressure-volume analysis and echocardiography. LV chamber stiffness was normalized in TAC/DOCA cRbm20?RRM-raloxifene mice that expressed N2BAsc. Passive stiffness measurements on muscle strips isolated from the LV free wall revealed that extracellular matrix stiffness was equally increased in both groups of TAC/DOCA mice (cRbm20?RRM-DMSO and cRbm20?RRM-raloxifene). However, titin-based muscle stiffness was reduced in the mice that expressed N2BAsc (TAC/DOCAcRbm20?RRM-raloxifene). Exercise testing demonstrated significant improvement in exercise tolerance in TAC/DOCA mice that expressed N2BAsc. CONCLUSIONS:Inhibition of the RNA binding motif-20-based titin splicing system upregulates compliant titins, which improves diastolic function and exercise tolerance in the TAC/DOCA model. Titin holds promise as a therapeutic target for heart failure with preserved ejection fraction.

Project description:BackgroundWith larger blood volume flowing into a cardiac chamber, by stretching muscle fibers, increased contraction force could be detected. This phenomenon is called Frank-Starling mechanism, allowing the output of a cardiac chamber to be synchronized without external regulation. The purpose of the present study was to investigate the Frank-Starling mechanism in the right atrium (RA) represented by its volumes, volume-based functional properties and strains respecting the cardiac cycle in healthy adults by three-dimensional (3D) speckle-tracking echocardiography (3DSTE).MethodsThe present single center retrospective cohort study comprised 179 healthy adult volunteers (mean age: 33.2±12.0 years, 92 males), in whom complete two-dimensional Doppler echocardiography with 3DSTE was performed. Subjects were divided into 3 groups according to the mean value of maximum RA volume (Vmax) ± standard deviation: Vmax <30 mL, 30 mL ≤ Vmax <60 mL and Vmax ≥60 mL.ResultsAll RA volumes respecting the cardiac cycle of all subjects and calculated separately for females and males and their indexed equivalents increased with Vmax. RA stroke volumes increased with Vmax regardless of the phase it was measured in. While total atrial emptying fraction representing the reservoir phase remained unchanged with the increase of Vmax, a significant increase in passive atrial emptying fraction representing the conduit phase could be detected, in case of Vmax >60 mL (28.9%±15.1% vs. 32.5%±12.6%, P<0.05). Active atrial emptying fraction representing the booster pump function did not change with the increase of Vmax. Most global and mean segmental peak RA strains did not show significant changes with increasing RA volumes except for the RA area strain, it was the largest when Vmax was larger than 60 mL (64.7%±44.9% vs. 83.3%±49.4%, P<0.05). RA circumferential, longitudinal and area strains at atrial contraction decreased with increasing Vmax, RA radial and 3D strains did not change significantly with increasing Vmax.ConclusionsIncreasing RA volumes do not cause significant increase in RA contractility represented by strains, but reduction in strains in longitudinal and circumferential directions could be detected in end-diastolic booster pump function. In contrast to the left atrium, obvious signs of Frank-Starling mechanism could not be detected in case of the RA.

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Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a beneficial effect on diastole.

Publications

Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a beneficial effect on diastole.

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