Ca 2+ Handling and Sarcoplasmic Reticulum Ca 2+ Content in Isolated Failing and Nonfailing Human Myocardium

Abstract

Abstract —Disturbed sarcoplasmic reticulum (SR) Ca 2+ content may underlie the altered force-frequency and postrest contractile behavior in failing human myocardium. We used rapid cooling contractures (RCCs) to assess SR Ca 2+ 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°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 Ca 2+ uptake and Na + /Ca 2+ exchange to cytosolic Ca 2+ removal during relaxation. SR Ca 2+ uptake (relative to the Na + /Ca 2+ 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 Ca 2+ content to increase sufficiently at high frequencies and thus cannot overcome the frequency-dependent refractoriness of SR Ca 2+ release. The rest-dependent decay in twitch force in failing myocardium is due to rest-dependent decline in SR Ca 2+ content. These alterations could be secondary to depressed SR Ca 2+ -ATPase combined with enhanced cytosolic Ca 2+ extrusion via Na + /Ca 2+ exchange.