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Physiologic force-frequency response in engineered heart muscle by electromechanical stimulation.

ABSTRACT: A hallmark of mature mammalian ventricular myocardium is a positive force-frequency relationship (FFR). Despite evidence of organotypic structural and molecular maturation, a positive FFR has not been observed in mammalian tissue engineered heart muscle. We hypothesized that concurrent mechanical and electrical stimulation at frequencies matching physiological heart rate will result in functional maturation. We investigated the role of biomimetic mechanical and electrical stimulation in functional maturation in engineered heart muscle (EHM). Following tissue consolidation, EHM were subjected to electrical field stimulation at 0, 2, 4, or 6 Hz for 5 days, while strained on flexible poles to facilitate auxotonic contractions. EHM stimulated at 2 and 4 Hz displayed a similarly enhanced inotropic reserve, but a clearly diverging FFR. The positive FFR in 4 Hz stimulated EHM was associated with reduced calcium sensitivity, frequency-dependent acceleration of relaxation, and enhanced post-rest potentiation. This was paralleled on the cellular level with improved calcium storage and release capacity of the sarcoplasmic reticulum and enhanced T-tubulation. We conclude that electro-mechanical stimulation at a physiological frequency supports functional maturation in mammalian EHM. The observed positive FFR in EHM has important implications for the applicability of EHM in cardiovascular research.

SUBMITTER: Godier-Furnemont AF

PROVIDER: S-EPMC4921199 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Physiologic force-frequency response in engineered heart muscle by electromechanical stimulation.

Godier-Furnémont Amandine F G AF Tiburcy Malte M Wagner Eva E Dewenter Matthias M Lämmle Simon S El-Armouche Ali A Lehnart Stephan E SE Vunjak-Novakovic Gordana G Zimmermann Wolfram-Hubertus WH

Biomaterials 20150515

A hallmark of mature mammalian ventricular myocardium is a positive force-frequency relationship (FFR). Despite evidence of organotypic structural and molecular maturation, a positive FFR has not been observed in mammalian tissue engineered heart muscle. We hypothesized that concurrent mechanical and electrical stimulation at frequencies matching physiological heart rate will result in functional maturation. We investigated the role of biomimetic mechanical and electrical stimulation in function ...[more]

PMID: 25985155

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Project description:ObjectivesLow-frequency electrical muscle stimulation (LF-EMS) may have the potential to reduce breathlessness and increase exercise capacity in the chronic heart failure population who struggle to adhere to conventional exercise. The study's aim was to establish if a randomised controlled trial of LF-EMS was feasible.Design and settingDouble blind (participants, outcome assessors), randomised study in a secondary care outpatient cardiac rehabilitation programme.ParticipantsPatients with severe heart failure (New York Heart Association class III-IV) having left ventricular ejection fraction <40% documented by echocardiography were eligible.InterventionsParticipants were randomised (remotely by computer) to 8 weeks (5×60 mins per week) of either LF-EMS intervention (4 Hz, continuous, n=30) or sham placebo (skin level stimulation only, n=30) of the quadriceps and hamstrings muscles. Participants used the LF-EMS straps at home and were supervised weekly OUTCOME MEASURES: Recruitment, adherence and tolerability to the intervention were measured during the trial as well as physiological outcomes (primary outcome: 6 min walk, secondary outcomes: quadriceps strength, quality of life and physical activity).ResultsSixty of 171 eligible participants (35.08%) were recruited to the trial. 12 (20%) of the 60 patients (4 LF-EMS and 8 sham) withdrew. Forty-one patients (68.3%), adhered to the protocol for at least 70% of the sessions. The physiological measures indicated no significant differences between groups in 6 min walk distance(p=0.13) and quality of life (p=0.55) although both outcomes improved more with LF-EMS.ConclusionPatients with severe heart failure can be recruited to and tolerate LF-EMS studies. A larger randomised controlled trial (RCT) in the advanced heart failure population is technically feasible, although adherence to follow-up would be challenging. The preliminary improvements in exercise capacity and quality of life were minimal and this should be considered if planning a larger trial.Trial registration numberISRCTN16749049.

Dataset Information

Physiologic force-frequency response in engineered heart muscle by electromechanical stimulation.

Publications

Physiologic force-frequency response in engineered heart muscle by electromechanical stimulation.

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