Mechanisms of Altered Excitation-Contraction Coupling in Canine Tachycardia-Induced Heart Failure, II

Abstract

Abstract-Ca2ϩ transients measured in failing human ventricular myocytes exhibit reduced amplitude, slowed relaxation, and blunted frequency dependence. In the companion article (O'Rourke B, Kass DA, Tomaselli GF, Kääb S, Tunin R, Marbán E. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart, I: experimental studies. Circ Res. 1999;84:562-570 Key Words: excitation-contraction coupling Ⅲ heart failure Ⅲ midmyocardial ventricular action potential Ⅲ Ca 2ϩ transient R ecent studies using the canine tachycardia pacinginduced model of heart failure 1-8 demonstrate that changes in cellular electrophysiological and excitationcontraction (E-C) coupling processes are qualitatively similar to those observed in cells isolated from failing human heart. In human heart failure, I K1 current density measured at hyperpolarized membrane potentials is reduced by Ϸ50%, 9,10 and density of the transient outward current I to1 is reduced by Ϸ75% in subepicardial 11 and Ϸ40% in midmyocardial ventricular cells 9 and is unchanged in subendocardial ventricular cells. 11 The magnitude of I K1 is reduced by Ϸ40%, and that of I to1 by Ϸ70% in failing canine midmyocardial cells. 5 Expression of proteins involved in E-C coupling is also altered in human heart failure. Sarcoplasmic reticulum (SR) Ca 2ϩ ATPase mRNA level, 12-16 protein level, 12,17,18 and uptake rate 19 are reduced by Ϸ50% in end-stage heart failure. Na ϩ /Ca 2ϩ exchanger (NCX) mRNA levels are increased by Ϸ55% to 79%, 12,20 and NCX protein levels increase 36% to 160%. 12,20 -22

Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study

“…Since the model is capable of reproducing the complex interaction between I to and I Ca,L as described by Greenstein et al 18 for ventricular models, we conclude that the model is representative for cardiomyocytes in general. By adjusting I Ca,L gating variable d, our model is capable of reproducing a larger I Ca,L current and slower decrease of I Ca,L during the plateau phase, which results in an increased APD and plateau height and is in agreement with the experimental results of Plotnikov et al 49 Although we obtain qualitative agreement, fitting I Ca,L kinetics to the data provided by Plotnikov et al 49 may require a recent ventricular model such as the Winslow-Rice-Jafri model of the canine ventricle 71 (including the new formulation of I to1 by Greenstein et al 18 ) or the model by Ten Tusscher et al 66 Ca 2+ -Force Relation Cardiac electromechanical behavior in our model is described by combining the models of Courtemanche et al 12 and Rice et al 53,54 To model the Ca 2+ -force relation, we apply model 4 of Rice et al, 53,54 which approximates the contractile force measured during isosarcometric twitches from RV rat trabeculae. 25 In model 4, the affinity of troponin for Ca 2+ does not increase in the presence of strongly bound cross bridges.…”

Intracellular calcium and the relationship to contractility in an avian model of heart failure

“…We have not, to date, studied the sodium-calcium exchange activity in these hearts. In a recent report in human myocardium, sodium-calcium exchange activity has been implicated in the prolongation of the calcium transient seen in human heart failure (Dipla et al 1999), as well as in other animal models Winslow et al 1999).…”

Excitation-contraction coupling and mitochondrial energetics

“…Computational modeling predicted a temporarily and spatially limited increase of the Ca 2+ -concentration ([Ca 2+ ]) in the range from ∼10 µM to ∼7 mM within the first couple of ms after opening of the RyR2 [14,15,102,133,151,152,158,174,217]. This high junctional [Ca 2+ ] decays rapidly by diffusion into the submembrane space and then further into the bulk cytosol, where it peaks later and at much lower concentrations than in the cleft (at ∼1.5 µM in the submembrane space and ∼0.5 µM in the bulk cytosol [174,209]).…”

“…The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process termed Ca 2+ -induced Ca 2+ -release (CICR) [14,15,63,64]. The Ca 2+ released from RyRs floods the space between the SR and the cell membrane (i. e., the dyadic or junctional cleft), a gap of typically ∼10 nm and covering a volume with a radius of ∼200 nm [102,151].Computational modeling predicted a temporarily and spatially limited increase of the Ca 2+ -concentration ([Ca 2+ ]) in the range from ∼10 µM to ∼7 mM within the first couple of ms after opening of the RyR2 [14,15,102,133,151,152,158,174,217]. This high junctional [Ca 2+ ] decays rapidly by diffusion into the submembrane space and then further into the bulk cytosol, where it peaks later and at much lower concentrations than in the cleft (at ∼1.5 µM in the submembrane space and ∼0.5 µM in the bulk cytosol [174,209]).…”