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 myocard ium We used rapid cooling contractures (RCCs) to assess Sq Ca2+ content in ventricular muscle strips isolated from nonfailing:and end-stage failing hu man 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+/-5 3%; P<0.05), In contrast, in failing myocardium (n=30), postrest twitch for ce decreased at long rest intervals and RCC amplitude declined monotonicall y with rest (by 25+/-9% and 53+/-9%, respectively; P<0.05). With an increas e in stimulation frequencies (0.25 to 3 Hz), twitch force increased continu ously in-nonfailing human myocardium (n=7) by 71+/-17% (at 3 Hz; P<0.05) an d RCC amplitude increased in parallel by 247+/-55% (P<0.05). In contrast, i n failing myocardium (n=26), twitch force declined by 29+/-7% (P<0.05) and RCC amplitude increased only slightly by 36+/-4% (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 bu t not in failing human myocardium as stimulation rates increased. We conclu de that the negative force-frequency relation in failing,a human myocardium is due to an inability of SR Ca2+ content to increase sufficiently at high frequencies and thus cannot overcome the frequency-dependent refractorines s of:SR Ca2+ release. The rest-dependent decay in twitch force in failing m yocardium is due to rest-dependent decline in SR Ca2+ content. These altera tions could be secondary to depressed SR Ca2+-ATPase combined with enhanced cytosolic Ca2+ extrusion:via Na+/Ca2+ exchange.