TY - JOUR
T1 - Acidosis and ischemia increase cellular Ca2+ transient alternans and repolarization alternans susceptibility in the intact rat heart
AU - Kapur, Sunil
AU - Wasserstrom, J. Andrew
AU - Kelly, James E.
AU - Kadish, Alan H.
AU - Aistrup, Gary L.
PY - 2009/5
Y1 - 2009/5
N2 - Cardiac cellular Ca2+ transient (CaT) alternans and electrocardiographic T-wave alternans (TWA) often develop in myocardial ischemia, but the mechanisms for this relationship have not been elucidated. Acidosis is a major component of ischemia, but there is no direct evidence linking acidosis-induced cellular CaT alternans to ischemia-induced CaT alternans and TWA in whole heart. We used laser-scanning confocal microscopy to measure intracellular Ca2+ (Cai2+) cycling in individual myocytes of fluo-4 AM-loaded rat hearts and simultaneously recorded pseudo-ECGs to investigate changes in CaTs and late-phase repolarization, respectively, during baseline and rapid pacing under control and either globally acidic or globally ischemic conditions. Acidosis (hypercapnia; pH 6.6) increased diastolic Cai2+ levels, prolonged CaT duration, and shifted to slower heart rates both the development of pacing-induced acidosis-induced CaT alternans (both concordant and discordant) and of repolarization alternans (RPA, a measure of TWA in rat ECGs). The magnitudes of these shifts were equivalent for both CaT alternans and RPA, suggesting a close association between them. Nearly identical results were found in low-flow global ischemia. Additionally, ischemic preconditioning reduced the increased propensity for CaT alternans and RPA development and was mimicked by preconditioning by acidosis alone. Our results demonstrate that global acidosis or ischemia modifies Cai2+ cycling in myocytes such that the diastolic Cai2+ rises and the cellular CaT duration is prolonged, causing spatially concordant as well as spatially discordant cellular CaT alternans to develop at slower heart rates than in controls. Since RPA also developed at slower heart rates, our results suggest that acidosis is a major contributor to CaT alternans, which underlies the proarrhythmic state induced by myocardial ischemia and therefore may play a role in its modulation and prevention.
AB - Cardiac cellular Ca2+ transient (CaT) alternans and electrocardiographic T-wave alternans (TWA) often develop in myocardial ischemia, but the mechanisms for this relationship have not been elucidated. Acidosis is a major component of ischemia, but there is no direct evidence linking acidosis-induced cellular CaT alternans to ischemia-induced CaT alternans and TWA in whole heart. We used laser-scanning confocal microscopy to measure intracellular Ca2+ (Cai2+) cycling in individual myocytes of fluo-4 AM-loaded rat hearts and simultaneously recorded pseudo-ECGs to investigate changes in CaTs and late-phase repolarization, respectively, during baseline and rapid pacing under control and either globally acidic or globally ischemic conditions. Acidosis (hypercapnia; pH 6.6) increased diastolic Cai2+ levels, prolonged CaT duration, and shifted to slower heart rates both the development of pacing-induced acidosis-induced CaT alternans (both concordant and discordant) and of repolarization alternans (RPA, a measure of TWA in rat ECGs). The magnitudes of these shifts were equivalent for both CaT alternans and RPA, suggesting a close association between them. Nearly identical results were found in low-flow global ischemia. Additionally, ischemic preconditioning reduced the increased propensity for CaT alternans and RPA development and was mimicked by preconditioning by acidosis alone. Our results demonstrate that global acidosis or ischemia modifies Cai2+ cycling in myocytes such that the diastolic Cai2+ rises and the cellular CaT duration is prolonged, causing spatially concordant as well as spatially discordant cellular CaT alternans to develop at slower heart rates than in controls. Since RPA also developed at slower heart rates, our results suggest that acidosis is a major contributor to CaT alternans, which underlies the proarrhythmic state induced by myocardial ischemia and therefore may play a role in its modulation and prevention.
KW - Arrhythmia
KW - Calcium cycling
UR - http://www.scopus.com/inward/record.url?scp=66149117734&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=66149117734&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00539.2008
DO - 10.1152/ajpheart.00539.2008
M3 - Article
C2 - 19286955
AN - SCOPUS:66149117734
SN - 0363-6135
VL - 296
SP - H1491-H1512
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 5
ER -