Submitted on October 8, 2007
Accepted on November 7, 2007
Cardiac alternans in embryonic mouse ventricles
Carlos De Diego1, Fuhua Chen2, Lai-Hua Xie2, Amish S Dave2, Mya Thu2, Christine Rongey2, James N. Weiss3*, and Miguel Valderrabano1
1 Cardiology, UCLA, Los Angeles, California, United States
2 Los Angeles, California, United States; Cardiology, UCLA, Los Angeles, California, United States
3 Division of Cardiology, University of California School of Medicine, Los Angeles, California, United States; Cardiology, UCLA, Los Angeles, California, United States
* To whom correspondence should be addressed. E-mail: jweiss{at}mednet.ucla.edu.
T-wave alternans, an important arrhythmogenic factor has recently been described in human fetuses. Here we sought to determine whether alternans can be induced in the embryonic mouse hearts despite its underdeveloped sarcoplasmic reticulum (SR), and, if so, to analyze the response to pharmacologic and autonomic interventions. Immunohistochemistry confirmed minimal sarcoplasmic-endoplasmic reticulum Ca ATPase 2a (SERCA2a) expression in embryonic mouse hearts at E10.5-E12.5, compared to neonatal or adult mouse hearts. We optically mapped voltage and/or intracellular Ca (Cai) in 99 embryonic mouse hearts (dual mapping in 64 hearts) at these ages. Under control conditions, ventricular action potential duration (APD) and Cai transient alternans occurred during rapid pacing at an average cycle length of 212 ± 34 ms in 57% (n=15/26) of E10.5-E12.5 hearts. Maximum APD restitution slope was steeper in hearts developing alternans than those that did not (2.2 ± 0.6 vs. 0.8 ± 0.4, P<0.001). Disabling SR Cai cycling with thapsigargin plus ryanodine (Tg+Ry) did not significantly reduce alternans incidence (44%, n=8/18, p=0.5), whereas isoproterenol (n=14) increased the incidence to 100% (p<0.05) coincident with steepening APD restitution slope. Verapamil abolished Cai transients (n=9). Tg+Ry had no major effects on Cai transient amplitude or its half-time of recovery in E10.5 hearts, but significantly depressed Cai transient amplitude (by 47±8 %) and prolonged its half-time of recovery (by 18±3%) in E11.5 and older hearts. Embryonic mouse ventricles can develop cardiac alternans, which generally is well correlated with APD restitution slope and does not depend on fully functional SR Cai cycling.
