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GW24-e1851 An increase of CO2 levels, enhancing late sodium current, is an independent factor of proarrhythmia in the heart
  1. Lin Wu1,
  2. Jihua Ma2,
  3. Yong Huo1,
  4. Yansheng Ding1
  1. 1Peking University First Hospital
  2. 2Wuhan University of Science and Technology

Abstract

Objectives Increased CO2 levels in the myocardium may be global due to inadequate ventilation/circulation or local due to myocardial ischaemia/infarction (by 4 times higher than the normal), and are associated with ventricular arrhythmias. We hypothesised that the increase in CO2 levels augment late sodium current (INa) and is an independent factor to induce polymorphic ventricular tachycardia.

Methods Female rabbit isolated hearts were paced at 1 Hz and exposed to solutions gassed with 5, 10 and 20% CO2. A pH value was kept at 7.4 for all solution and osmolarity was adjusted. Rabbit ventricular myocytes were isolated and exposed to solutions with different CO2 levels (pH = 7.4). Monophasic action potential duration (MAPD) and ion currents were recorded using MAP electrodes and whole-cell patch clamp, respectively.

Results When the pH value in solutions was kept at 7.4 and CO2 levels were increased from 5 (physiological) to 10 (respiratory failure) and 20% (CO2 intoxication), the amplitude of late sodium current in ventricular myocytes was increased from-0.406 ± 0.009 to-0.827 ± 0.029 and-1.253 ± 0.043 pA/pF (n = 7, p < 0.01, compared to 5% CO2) in a concentration-dependent manner. This increases in late INa were completely reversed by 2 µM TTX in the presence of either 10 or 20% CO2. MAPD90 from the whole heart was increased significantly by 20 ± 3 and 63 ± 6ms from a baseline of 189 ± 4 to 208 ± 4 and 252 ± 8 ms (n = 11, p < 0.01), respectively. At CO2 level of 5%, E-4031 (10 nM, n = 11) and ATX-II (1 nM, n = 8) prolonged MAPD90 by 27 ± 5 and 31 ± 3 ms, respectively, and caused no TdP. In the presence of either E-4031 or ATX-II, increases of CO2 to 10 and 20% cause greater increased in MAPD90 by 52 ± 8 and 42 ± 5, and 105 ± 15 and 133 ± 11 ms (n = 11 and 8. p < 0.01 compared to the values at 5% of CO2). In hearts treated with either E-4031 or ATX-II, a high concentration (20%) of CO2 caused polymorphic ventricular tachycardia in 8/11 (73%) and 7/8 (87.5%) of hearts studied, respectively.

Conclusions Increased CO2 levels is an independent factor (to acidosis) to enhance late sodium current and cause APD prolongation. These effects are expected to reduce repolarization reserve in the heart and therefore are proarrhythmic, which may explain the clinical arrhythmias in patients with obstructive sleep apnea, sudden infant death syndrome and ischaemia.

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