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Cardiovascular Research Advance Access first published online on July 16, 2008
This version [Corrected Proof] published online on August 27, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn198
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Single histidine-substituted cardiac troponin I confers protection from age-related systolic and diastolic dysfunction

Nathan J. Palpant1, Sharlene M. Day1,2, Todd J. Herron1, Kimber L. Converso3 and Joseph M. Metzger1,2,*

1 Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1301 E. Catherine Street, 7727 Medical Science II, Ann Arbor, MI 48109-0622, USA
2 Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
3 Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA

* Corresponding author. Tel: +1 734 763 0560; fax: +1 734 647 6461. E-mail address: metzgerj{at}umich.edu

Aims: Contractile dysfunction associated with myocardial ischaemia is a significant cause of morbidity and mortality in the elderly. Strategies to protect the aged heart from ischaemia-mediated pump failure are needed. We hypothesized that troponin I-mediated augmentation of myofilament calcium sensitivity would protect cardiac function in aged mice.

Methods and results: To address this, we investigated transgenic (Tg) mice expressing a histidine-substituted form of adult cardiac troponin I (cTnI A164H), which increases myofilament calcium sensitivity in a pH-dependent manner. Serial echocardiography revealed that Tg hearts showed significantly improved systolic function at 4 months, which was sustained for 2 years based on ejection fraction and velocity of circumferential fibre shortening. Age-related diastolic dysfunction was also attenuated in Tg mice as assessed by Doppler measurements of the mitral valve inflow and lateral annulus Doppler tissue imaging. During acute hypoxia, cardiac contractility significantly improved in aged Tg mice made evident by increased stroke volume, end systolic pressure, and +dP/dt compared with non-transgenic mice.

Conclusion: This study shows that increasing myofilament function by means of a pH-responsive histidine button engineered into cTnI results in enhanced baseline heart function in Tg mice over their lifetime, and during acute hypoxia improves survival in aged mice by maintaining cardiac contractility.

KEYWORDS Troponin I; Ageing; Cardiac function; Hypoxia

Time for primary review: 19 days


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