Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium.
Disturbed sarcoplasmic reticulum (SR) Ca2+ content may underlie the altered force-frequency and postrest contractile behavior in failing human myocardium. We used rapid cooling contractures (RCCs) to assess SR Ca2+ content in ventricular muscle strips isolated from nonfailing and end-stage failing human hearts. With an increase in rest intervals (1 to 240 s; 37 degrees C), nonfailing human myocardium (n=7) exhibited a parallel increase in postrest twitch force (at 240 s by 121+/-44%; P<0.05) and RCC amplitude (by 69+/-53%; P<0.05). In contrast, in failing myocardium (n=30), postrest twitch force decreased at long rest intervals and RCC amplitude declined monotonically with rest (by 25+/-9% and 53+/-9%, respectively; P<0.05). With an increase in stimulation frequencies (0.25 to 3 Hz), twitch force increased continuously in nonfailing human myocardium (n=7) by 71+/-17% (at 3 Hz; P<0.05) and RCC amplitude increased in parallel by 247+/-55% (P<0.05). In contrast, in failing myocardium (n=26), twitch force declined by 29+/-7% (P<0. 05) and RCC amplitude increased only slightly by 36+/-14% (P<0.05). Paired RCCs were evoked to investigate the relative contribution of SR Ca2+ uptake and Na+/Ca2+ exchange to cytosolic Ca2+ removal during relaxation. SR Ca2+ uptake (relative to the Na+/Ca2+ exchange) increased significantly in nonfailing but not in failing human myocardium as stimulation rates increased. We conclude that the negative force-frequency relation in failing human myocardium is due to an inability of SR Ca2+ content to increase sufficiently at high frequencies and thus cannot overcome the frequency-dependent refractoriness of SR Ca2+ release. The rest-dependent decay in twitch force in failing myocardium is due to rest-dependent decline in SR Ca2+ content. These alterations could be secondary to depressed SR Ca2+-ATPase combined with enhanced cytosolic Ca2+ extrusion via Na+/Ca2+ exchange.
Zentrum Innere Medizin, Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Göttingen, Germany.
B
B
Pieske
L S
LS
Maier
D M
DM
Bers
G
G
Hasenfuss
D000328:Adult; D002118:Calcium / Q000378:metabolism*; D002303:Cardiac Output, Low / Q000378:metabolism*; D002675:Child, Preschool; D003080:Cold Temperature; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D012016:Reference Values; D012032:Refractory Period, Electrophysiological; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D016276:Ventricular Function / Q000502:physiology
D002118:Calcium