Pause-dependent augmentation of J waves was confirmed in about one-half of the patients with idiopathic VF after sudden R-R prolongation. Such dynamicity of J waves was specific to idiopathic VF and may be used for risk stratification.
Starling's Law and the well-known end-systolic pressure-volume relationship (ESPVR) of the left ventricle reflect the effect of sarcomere length (SL) on stress (sigma) development and shortening by myocytes in the uniform ventricle. We show here that tetanic contractions of rat cardiac trabeculae exhibit a sigma-SL relationship at saturating [Ca2+] that depends on sarcomere geometry in a manner similar to skeletal sarcomeres and the existence of opposing forces in cardiac muscle shortened below slack length. The sigma-SL-[Ca2+]free relationships (sigma-SL-CaR) at submaximal [Ca2+] in intact and skinned trabeculae were similar, albeit that the sensitivity for Ca2+ of intact muscle was higher. We analyzed the mechanisms underlying the sigma-SL-CaR using a kinetic model where we assumed that the rates of Ca2+ binding by Troponin-C (Tn-C) and/or cross-bridge (XB) cycling are determined by SL, [Ca2+] or stress. We analyzed the correlation between the model results and steady state stress measurements at varied SL and [Ca2+] from skinned rat cardiac trabeculae to test the hypotheses that: (i) the dominant feedback mechanism is SL, stress or [Ca2+]-dependent; and (ii) the feedback mechanism regulates: Tn-C-Ca2+ affinity, XB kinetics or, unitary XB-force. The analysis strongly suggests that feedback of the number of strong XBs to cardiac Tn-C-Ca2+ affinity is the dominant mechanism that regulates XB recruitment. Application of this concept in a mathematical model of twitch-stress accurately reproduced the sigma-SL-CaR and the time course of twitch-stress as well as the time course of intracellular [Ca2+]i. Modeling of the response of the cardiac twitch to rapid stress changes using the above feedback model uniquely predicted the occurrence of [Ca2+]i transients as a result of accelerated Ca2+ dissociation from Tn-C. The above concept has important repercussions for the non-uniformly contracting heart in which arrhythmogenic Ca2+ waves arise from weakened areas in cardiac muscle. These Ca2+ waves can reversibly be induced in muscle with non-uniform excitation contraction coupling (ECC) by the cycle of stretch and release in the border zone between the damaged and intact regions. Stimulus trains induced propagating Ca2+ waves and reversibly induced arrhythmias. We hypothesize that rapid force loss by sarcomeres in the border zone during relaxation causes Ca2+ release from Tn-C and initiates Ca2+ waves propagated by the sarcoplasmic reticulum (SR). These observations suggest the unifying hypothesis that force feedback to Ca2+ binding by Tn-C is responsible for Starling's Law and the ESPVR in uniform myocardium and leads in non-uniform myocardium to a surge of Ca2+ released by the myofilaments during relaxation, which initiates arrhythmogenic propagating Ca2+ release by the SR.
Although changes in intracellular Ca2+ concentration ([Ca2+]i) are spatially heterogeneous during spontaneous contraction in mammalian cardiac muscle, it has not yet been observed how [Ca2+]i changes spatially within cardiac myocytes during delayed (DADs) and early (EADs) afterdepolarizations. The aim of this study is to characterize the spatial features of the increase in [Ca2+]i during such afterdepolarizations and to understand the ionic mechanisms responsible for them. Myocytes were enzymatically isolated from guinea pig ventricles and loaded with fura 2-acetoxymethylester, the Ca2+ fluorescence indicator dye. Membrane potential was recorded with a conventional microelectrode technique, and spatiotemporal changes in fura 2 fluorescence and cell length were recorded using a digital television system. After superfusion with potassium-free Tyrode solution, DADs and EADs were induced. During DADs, fluorescence transients were heterogeneous within myocytes (n = 11). Furthermore, they often propagated within myocytes as if they were "waves." In contrast, during EADs, fluorescence transients showed no waves within myocytes but rather showed synchronous changes throughout the myocytes (n = 15). The results of this study suggest that the spatial features of the increase in [Ca2+]i differ between the DADs and EADs. We concluded from these differing features that the ionic mechanisms responsible for the two triggered activities are different.
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