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

Abstract

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.

Cardiac disease in mucopolysaccharidosis type I attributed to catecholaminergic and hemodynamic deficiencies

“…In addition, the obligatory parental heterozygotes of MPS-I patients are phenotypically normal. In terms of assays described in this study, hemodynamic performance of IDUA ϩ/Ϫ mice are similar to that of C57BL/6 mice as previously reported by Palpant and colleagues (21,22).…”

Influence of genetic background on ex vivo and in vivo cardiac function in several commonly used inbred mouse strains

“…Measurements of real-time in vivo cardiovascular hemodynamics were obtained using conductance micromanometry as previously described (34,35,53,54). Mice were anesthetized and ventilated via a tracheal cannulation and ventilated via a pressure controlled ventilator with 2% isoflurane at a peak inspiratory pressure of 15 cm H2O and a respiratory rate of 60 breaths/min.…”

Cell Biology of Sarcomeric Protein Engineering: Disease Modeling and Therapeutic Potential

“…In an effort to confer the pH resiliency to cTnI, Day et al (2006) made the opposite substitution, creating A164H cTnI. A164H cTnI transgenic mice conferred protection from ischemia/ reperfusion injury, hypoxia, and age-related cardiac dysfunction (Day et al, 2006;Palpant et al, 2008Palpant et al, , 2009). Importantly they also showed no deleterious effects under physiologic conditions.…”