The Mechanism of Reflection Type Reentry: A Simulation Study.

INTRODUCTION: Reflection is a special type of reentry in which an electrical wave front travels in a forward direction through tissue that is then re-excited by a wave front that propagates backward. This type of reentry has been studied computationally in 1-dimensional fibers and verified experimentally. Different hypotheses explaining reflected reentry have been proposed based on the structure and heterogeneity of the tissue properties, but the mechanism remains uncertain. METHODS AND RESULTS: We used the bidomain model to represent cardiac tissue and the Luo-Rudy model to describe the active membrane properties. We consider an ischemic region in a volume of ventricular myocardium. Our results show that a slow depolarization in the ischemic border zone caused by electrotonic coupling to depolarized tissue in the normal region creates a delay between proximal and distal regions that produces enough electrotonic current in the distal region to re-excite the proximal region. CONCLUSION: Our simulation shows that an early afterdepolarization (EAD) is not the source of the reflection. It depends on the pacing interval and stimulus strength necessary to maintain enough time delay between proximal and distal regions.

Intracellular calcium and the mechanism of the dip in the anodal strength-interval curve in cardiac tissue.

BACKGROUND: The strength-interval (SI) curve is an important measure of refractoriness in cardiac tissue. The anodal SI curve contains a "dip" in which the S2 threshold increases with interval. Two explanations exist for this dip: (1) electrotonic interaction between regions of depolarization and hyperpolarization; and (2) the sodium-calcium exchange (NCX) current. The goal of this study is to use mathematical modeling to determine which explanation is correct. METHODS AND RESULTS: The bidomain model represents cardiac tissue and the Luo-Rudy model describes the active membrane. The SI curve is determined by applying a threshold stimulus at different time intervals after a previous action potential. During space-clamped and equal-anisotropy-ratios simulations, anodal excitation does not occur. During unequal-anisotropy-ratios simulations, electrotonic currents, not membrane currents, are present during the few milliseconds before excitation. The dip disappears with no NCX current, but is present with 50% or 75% reduction of it. The calcium-induced-calcium-release (CICR) current has little effect on the dip. CONCLUSIONS: These results indicate that neither the NCX nor the CICR current is responsible for the dip in the anodal SI curve. It is caused by the electrotonic interaction between regions of depolarization and hyperpolarization following the S2 stimulus.

Substrate-dependent differential regulation of mitochondrial bioenergetics in the heart and kidney cortex and outer medulla.

The kinetics and efficiency of mitochondrial oxidative phosphorylation (OxPhos) can depend on the choice of respiratory substrates. Furthermore, potential differences in this substrate dependency among different tissues are not well-understood. Here, we determined the effects of different substrates on the kinetics and efficiency of OxPhos in isolated mitochondria from the heart and kidney cortex and outer medulla (OM) of Sprague-Dawley rats. The substrates were pyruvate+malate, glutamate+malate, palmitoyl-carnitine+malate, alpha-ketoglutarate+malate, and succinate±rotenone at saturating concentrations. The kinetics of OxPhos were interrogated by measuring mitochondrial bioenergetics under different ADP perturbations. Results show that the kinetics and efficiency of OxPhos are highly dependent on the substrates used, and this dependency is distinctly different between heart and kidney. Heart mitochondria showed higher respiratory rates and OxPhos efficiencies for all substrates in comparison to kidney mitochondria. Cortex mitochondria respiratory rates were higher than OM mitochondria, but OM mitochondria OxPhos efficiencies were higher than cortex mitochondria. State 3 respiration was low in heart mitochondria with succinate but increased significantly in the presence of rotenone, unlike kidney mitochondria. Similar differences were observed in mitochondrial membrane potential. Differences in H2O2 emission in the presence of succinate±rotenone were observed in heart mitochondria and to a lesser extent in OM mitochondria, but not in cortex mitochondria. Bioenergetics and H2O2 emission data with succinate±rotenone indicate that oxaloacetate accumulation and reverse electron transfer may play a more prominent regulatory role in heart mitochondria than kidney mitochondria. These studies provide novel quantitative data demonstrating that the choice of respiratory substrates affects mitochondrial responses in a tissue-specific manner.

Substrate- and Calcium-Dependent Differential Regulation of Mitochondrial Oxidative Phosphorylation and Energy Production in the Heart and Kidney.

Mitochondrial dehydrogenases are differentially stimulated by Ca2+. Ca2+ has also diverse regulatory effects on mitochondrial transporters and other enzymes. However, the consequences of these regulatory effects on mitochondrial oxidative phosphorylation (OxPhos) and ATP production, and the dependencies of these consequences on respiratory substrates, have not been investigated between the kidney and heart despite the fact that kidney energy requirements are second only to those of the heart. Our objective was, therefore, to elucidate these relationships in isolated mitochondria from the kidney outer medulla (OM) and heart. ADP-induced mitochondrial respiration was measured at different CaCl2 concentrations in the presence of various respiratory substrates, including pyruvate + malate (PM), glutamate + malate (GM), alpha-ketoglutarate + malate (AM), palmitoyl-carnitine + malate (PCM), and succinate + rotenone (SUC + ROT). The results showed that, in both heart and OM mitochondria, and for most complex I substrates, Ca2+ effects are biphasic: small increases in Ca2+ concentration stimulated, while large increases inhibited mitochondrial respiration. Furthermore, significant differences in substrate- and Ca2+-dependent O2 utilization towards ATP production between heart and OM mitochondria were observed. With PM and PCM substrates, Ca2+ showed more prominent stimulatory effects in OM than in heart mitochondria, while with GM and AM substrates, Ca2+ had similar biphasic regulatory effects in both OM and heart mitochondria. In contrast, with complex II substrate SUC + ROT, only inhibitory effects on mitochondrial respiration was observed in both the heart and the OM. We conclude that the regulatory effects of Ca2+ on mitochondrial OxPhos and ATP synthesis are biphasic, substrate-dependent, and tissue-specific.

ELECTRICAL INSTABILITY DUE TO REGIONAL INCREASE IN EXTRACELLULAR POTASSIUM ION CONCENTRATION.

INTRODUCTION: Ventricular tachycardia and ventricular fibrillation are the two most dangerous arrhythmias. Both are related to reentrant electrical activity in the ventricles. Many studies of arrhythmias consider a homogeneous sheet of cardiac tissue. Since normal ventricular myocardium is inhomogeneous and inhomogeneities play an important role in the induction of reentry, we investigate the effect of a localized inhomogeniety developed at the border between normal and ischemic region. METHODS: We used the bidomain model to represent the electrical properties of cardiac tissue and a modified version of the dynamic Luo-Rudy (LRd) model to represent the active properties of the membrane. To investigate the effect of a localized inhomogeneity, the extracellular potassium [K]e concentration is raised to 10 mM from normal [K]e (4 mM) on the right half of the tissue. RESULTS AND DISCUSSION: A train of cathodal stimuli are applied from the lower left corner of the tissue with different basic cycle lengths (BCL). At certain BCL, the spatial heterogeneity created with regional elevation of [K]e can lead to action potential instability (alternans) in the normal and border regions, and 2:1 conduction block in the ischemic region. We observed the reentry when local heterogeneity in [K]e is changed from 10 to 12 mM on the right half of the virtual ventricular myocardium sheet. CONCLUSION: Electrical alternans occur during high heart rates and are observed in patients suffering from ventricular tachycardia. It is an early indication of left ventricular systolic impairment. This study will help to evaluate alternans as a predictor and guide for antiarrhythmic therapy.

The strength-interval curve in cardiac tissue.

The bidomain model describes the electrical properties of cardiac tissue and is often used to simulate the response of the heart to an electric shock. The strength-interval curve summarizes how refractory tissue is excited. This paper analyzes calculations of the strength-interval curve when a stimulus is applied through a unipolar electrode. In particular, the bidomain model is used to clarify why the cathodal and anodal strength-interval curves are different, and what the mechanism of the "dip" in the anodal strength-interval curve is.