Single histidine button in cardiac troponin I sustains heart performance in response to severe hypercapnic respiratory acidosis in vivo.
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% CO(2) 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 beta-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 beta-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
Nathan J
NJ
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
D'Alecy
Louis G
LG
Metzger
Joseph M
JM
D000142:Acidosis, Respiratory / Q000503:physiopathology*; D000818:Animals; D006321:Heart / Q000502:physiology*; D006639:Histidine / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D006935:Hypercapnia / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D011412:Propanolamines / Q000494:pharmacology; D019210:Troponin I / Q000235:genetics / Q000378:metabolism*
D011412:Propanolamines; D019210:Troponin I; D006639:Histidine; C036604:esmolol; D010100:Oxygen