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Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 16, 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. Palpanta, Sharlene M. Daya,b, Todd J. Herrona, Kimber L. Conversoc and Joseph M. Metzgera,b

a Departments of Molecular and Integrative Physiology University of Michigan Medical School, Ann Arbor, Michigan, 48109
b Internal Medicine University of Michigan Medical School, Ann Arbor, Michigan, 48109
c Pediatrics University of Michigan Medical School, Ann Arbor, Michigan, 48109

Correspondence directed to: Joseph M. Metzger University of Michigan Medical School Dept. of Molecular and Integrative Physiology 1301 E. Catherine St. 7727 Medical Science II Ann Arbor, MI 48109-0622 Phone: (734) 763-0560 Fax: (734) 647-6461 E-mail: metzgerj{at}umich.edu

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

Methods: 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.

Results: Serial echocardiography revealed that Tg hearts showed significantly improved systolic function at four months, which was sustained for two years based on ejection fraction and velocity of circumferential fiber 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 to nontransgenic mice.

Conclusion: This is the first study to show 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; aging; cardiac function; hypoxia

Time for primary review: 19 days


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