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Single histidine button in cardiac troponin I sustains heart performance in response to severe hypercapnic respiratory acidosis in vivo

Nathan J. Palpant^*, Louis G. D'Alecy^* and Joseph M. Metzger^,1

^* Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA; and

Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

¹ Correspondence: Department of Integrative Biology and Physiology, University of Minnesota Medical School, 6-125 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455, USA. E-mail: metzgerj{at}umn.edu

Intracellular acidosis is a profound negative regulator of myocardial performance. We hypothesized that titrating myofilament calcium sensitivity by a single histidine substituted cardiac troponin I (A164H) would protect the whole animal physiological response to acidosis in vivo. To experimentally induce severe hypercapnic acidosis, mice were exposed to a 40% CO₂ challenge. By echocardiography, it was found that systolic function and ventricular geometry were maintained in cTnI A164H transgenic (Tg) mice. By contrast, non-Tg (Ntg) littermates experienced rapid and marked cardiac decompensation during this same challenge. For detailed hemodymanic assessment, Millar pressure-conductance catheterization was performed while animals were treated with a β-blocker, esmolol, during a severe hypercapnic acidosis challenge. Survival and load-independent measures of contractility were significantly greater in Tg vs. Ntg mice. This assay showed that Ntg mice had 100% mortality within 5 min of acidosis. By contrast, systolic and diastolic function were protected in Tg mice during acidosis, and they had 100% survival. This study shows that, independent of any β-adrenergic compensation, myofilament-based molecular manipulation of inotropy by histidine-modified troponin I maintains cardiac inotropic and lusitropic performance and markedly improves survival during severe acidosis in vivo.—Palpant, N. J., D'Alecy, L. G., Metzger, J. M. Single histidine button in cardiac troponin I sustains heart performance in response to severe hypercapnic respiratory acidosis in vivo.

Key Words: myocardial function • myofilaments • pH