Abstract 1572: 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. The purpose of this study was to determine whether titrating myofilament calcium sensitivity could protect the whole animal physiological response to acidosis in vivo. We hypothesized that single histidine substituted cardiac troponin I (A164H) transgenic (Tg) mice would confer cardio-protection during a severe respiratory acidosis challenge in vivo. Severe hypercapnic acidosis was induced in mice by ventilation with 40% CO2. Echocardiographic analysis showed that systolic function and ventricular geometry were maintained in Tg mice. By contrast, nontransgenic (Ntg) littermates experienced marked deterioration in systolic performance and significant LV dilation during this same challenge (ejection fraction during hypercapnia: [Ntg, n =5] 23.6 ± 4.9 vs. [Tg, n=7] 67.8 ± 4.5% P < 0.05; volume at systole during hypercapnia: [Ntg, n = 5] 40.6 ± 5.1 vs. [Tg, n = 7] 14.4 ± 3.4 mm3 P < 0.05). Using radio-telemetry to monitor blood pressure in freely moving animals, Tg mice maintained significantly higher peripheral arterial blood pressures compared to Ntg mice during a long term acidosis challenge (change in mean arterial pressure: [Ntg, n = 4] −81.5 ± 18.4 vs. [Tg, n = 7] −37.7 ± 6.3 mmHg P < 0.05). For detailed hemodymanic assessment, pressure-conductance analysis was performed. To specifically isolate cardiac performance, animals were treated with a beta blocker, esmolol, during a 40% CO2 challenge. Survival and load independent measures of contractility were significantly greater in Tg vs. Ntg mice (preload recruitable stroke work: [Ntg, n = 6] 78.6 ± 9.5 vs. [Tg, n = 7] 147.2 ± 9.6 P < 0.05). Furthermore, hemodynamic analysis during beta blockade and hypercapnia showed that Ntg mice underwent marked cardiac decompensation and death within five minutes of acidosis compared to Tg mice that maintained contractility and survived the challenge (survival curve [Ntg, n = 6; Tg n = 7], P < 0.0002). This study shows that, independent of any beta adrenergic compensation, myofilament-based molecular manipulation of inotropy by histidine-modified troponin I maintains contractile function and improves survival during severe hypercapnic acidosis in vivo.
This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).