Ca2+ clock malfunction in a canine model of pacing-induced heart failure.
The mechanisms of sinoatrial node (SAN) dysfunction in heart failure (HF) remain unclear. We hypothesized that impaired rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release (Ca(2+) clock) plays an important role in SAN dysfunction in HF. HF was induced in canine hearts by rapid ventricular pacing. The location of pacemaking sites was determined in vivo using computerized electrical mapping in acute open-chest preparations (normal, n = 3; and HF, n = 4). Isoproterenol (Iso, 0.2 μg·kg(-1)·min(-1)) infusion increased heart rate and shifted the pacemaking site to the superior SAN in all normal hearts. However, in failing hearts, Iso did not induce superior shift of the pacemaking site despite heart rate acceleration. Simultaneous optical recording of intracellular Ca(2+) and membrane potential was performed in Langendorff-perfused isolated right atrium (RA) preparations from normal (n = 7) and failing hearts (n = 6). Iso increased sinus rate, enhanced late diastolic Ca(2+) elevation (LDCAE), and shifted the pacemaking sites to the superior SAN in all normal but in none of the HF RAs. Caffeine (2 ml, 20 mmol/l) caused LDCAE and increased heart rate in four normal RAs but in none of the three HF RAs. Iso induced ectopic beats from lower crista terminalis in five of six HF RAs. These ectopic beats were suppressed by ZD-7288, a specific pacemaker current (I(f)) blocker. We conclude that HF results in the suppression of Ca(2+) clock, resulting in the unresponsiveness of superior SAN to Iso and caffeine. HF also increases the ectopic pacemaking activity by activating the I(f) at the latent pacemaking sites in lower crista terminalis.
Shinohara
Tetsuji
T
Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Park
Hyung-Wook
HW
Han
Seongwook
S
Shen
Mark J
MJ
Maruyama
Mitsunori
M
Kim
Daehyeok
D
Chen
Peng-Sheng
PS
Lin
Shien-Fong
SF
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D057906:Circadian Clocks / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D022062:Electrophysiologic Techniques, Cardiac; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials; D010477:Perfusion; D011743:Pyrimidines / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012849:Sinoatrial Node / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D011743:Pyrimidines; C082246:ICI D2788; D002110:Caffeine; D007545:Isoproterenol