Cardiac alternans in embryonic mouse ventricles.
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 pharmacological and autonomic interventions. Immunohistochemistry confirmed minimal sarcoplasmic-endoplasmic reticulum Ca-ATPase 2a expression in embryonic mouse hearts at embryonic day (E) 10.5 to E12.5, compared with neonatal or adult mouse hearts. We optically mapped voltage and/or intracellular Ca (Ca(i)) in 99 embryonic mouse hearts (dual mapping in 64 hearts) at these ages. Under control conditions, ventricular action potential duration (APD) and Ca(i) 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 Ca(i) cycling with thapsigargin plus ryanodine 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 Ca(i) transients (n = 9). Thapsigargin plus ryanodine had no major effects on Ca(i)-transient amplitude or its half time of recovery in E10.5 hearts, but significantly depressed Ca(i)-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 Ca(i) cycling.
de Diego
Carlos
C
Division of Cardiology, David Geffen School of Medicine at UCLA, University of California-Los Angeles, CA 90095, USA.
Chen
Fuhua
F
Xie
Lai-Hua
LH
Dave
Amish S
AS
Thu
Mya
M
Rongey
Christine
C
Weiss
James N
JN
Valderrábano
Miguel
M
D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000196:embryology* / Q000378:metabolism / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D018679:Cholinergic Agonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005865:Gestational Age; D006321:Heart / Q000187:drug effects / Q000196:embryology*; D006352:Heart Ventricles / Q000196:embryology / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D002121:Calcium Channel Blockers; D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D012433:Ryanodine; D019284:Thapsigargin; D002217:Carbachol; D014700:Verapamil; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D007545:Isoproterenol