We present an integrated thermokinetic model describing control of cardiac mitochondrial bioenergetics. The model describes the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and mitochondrial Ca(2+) handling. The kinetic component of the model includes effectors of the TCA cycle enzymes regulating production of NADH and FADH(2), which in turn are used by the electron transport chain to establish a proton motive force (Delta mu(H)), driving the F(1)F(0)-ATPase. In addition, mitochondrial matrix Ca(2+), determined by Ca(2+) uniporter and Na(+)/Ca(2+) exchanger activities, regulates activity of the TCA cycle enzymes isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase. The model is described by twelve ordinary differential equations for the time rate of change of mitochondrial membrane potential (Delta Psi(m)), and matrix concentrations of Ca(2+), NADH, ADP, and TCA cycle intermediates. The model is used to predict the response of mitochondria to changes in substrate delivery, metabolic inhibition, the rate of adenine nucleotide exchange, and Ca(2+). The model is able to reproduce, qualitatively and semiquantitatively, experimental data concerning mitochondrial bioenergetics, Ca(2+) dynamics, and respiratory control. Significant increases in oxygen consumption (V(O(2))), proton efflux, NADH, and ATP synthesis, in response to an increase in cytoplasmic Ca(2+), are obtained when the Ca(2+)-sensitive dehydrogenases are the main rate-controlling steps of respiratory flux. These responses diminished when control is shifted downstream (e.g., the respiratory chain or adenine nucleotide translocator). The time-dependent behavior of the model, under conditions simulating an increase in workload, closely reproduces experimentally observed mitochondrial NADH dynamics in heart trabeculae subjected to changes in pacing frequency. The steady-state and time-dependent behavior of the model support the hypothesis that mitochondrial matrix Ca(2+) plays an important role in matching energy supply with demand in cardiac myocytes.

Diffusion tensor magnetic resonance imaging (MRI) is a possible new means of elucidating the anatomic structure of the myocardium. It enjoys several advantages over traditional histological approaches, including the ability to rapidly measure fiber organization in isolated, perfused, arrested hearts, thereby avoiding fixation and sectioning of artifacts. However, quantitative validation of this MRI method has been lacking. Here, fiber orientations estimated in the same locations in the same heart using both diffusion tensor MRI and histology are compared in a total of two perfused rabbit hearts. Fiber orientations were statistically similar for both methods and differed on average by 12° at any single location. This is similar to the 10° uncertainty in fiber orientation achieved with histology. In addition, imaging studies performed in a total of seven hearts support a level of organization beyond the myofiber, the recently described laminar organization of the ventricular myocardium.

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