Extracellular discontinuities in cardiac muscle: evidence for capillary effects on the action potential foot.

It has become of fundamental importance to understand variations in the shape of the upstroke of the action potential in order to identify structural loading effects. One component of this goal is a detailed experimental analysis of the time course of the foot of the cardiac action potential (Vm foot) during propagation in different directions in anisotropic cardiac muscle. To this end, we performed phase-plane analysis of transmembrane action potentials during anisotropic propagation in adult working myocardium. The results showed that during longitudinal propagation there was initial slowing of Vm foot that resulted in deviations from a simple exponential; corollary changes occurred at numerous sites during transverse propagation. We hypothesized that the effect on Vm foot observed in the experimental data was created by the microscopic structure, especially the capillaries. This hypothesis predicts that the phase-plane trajectory of Vm foot will deviate from linearity in the presence of a high density of capillaries, and that a linear trajectory will occur in the absence of capillaries. Comparison of the results of Fast and Kléber (Circ Res. 1993;73:914-925) in a monolayer of neonatal cardiac myocytes, which is devoid of capillaries, and our results in newborn ventricular muscle, which is rich in capillaries, showed drastic differences in Vm foot as predicted. Because this comparison provided experimental support for the capillary hypothesis, we explored the underlying biophysical mechanisms due to interstitial electrical field effects, using a "2-domain" model of myocytes and capillaries separated by interstitial space. The model results show that a propagating interstitial electrical field induces an inward capacitive current in the inactive capillaries that causes a feedback effect on the active membrane (source) that slows the initial rise of its action potential. The results show unexpected mechanisms related to extracellular structural loading that may play a role in selected conduction disturbances, such as in a reperfused ischemic region surrounded by normal myocardium.

[1]  J. T. Wearn,et al.  Quantitative changes in the capillary-muscle relationship in human hearts during normal growth and hypertrophy , 1941 .

[2]  A. Hodgkin,et al.  A quantitative description of membrane current and its application to conduction and excitation in nerve , 1952, The Journal of physiology.

[3]  D. Spiro,et al.  THE ULTRASTRUCTURE OF MAMMALIAN CARDIAC MUSCLE , 1961, The Journal of biophysical and biochemical cytology.

[4]  H. Jenerick,et al.  PHASE PLANE TRAJECTORIES OF THE MUSCLE SPIKE POTENTIAL. , 1963, Biophysical journal.

[5]  B. Hoffman,et al.  Two Components of the Cardiac Action Potential , 1966, Nature.

[6]  R Plonsey,et al.  A mathematical study of nerve fiber interaction. , 1970, Biophysical journal.

[7]  G Ludwig,et al.  Capillary pattern of the myocardium. , 1971, Methods and achievements in experimental pathology.

[8]  V. Markin.  Electrical interaction of parallel non-myelinated nerve fibres-III. Interaction in bundles , 1973 .

[9]  V. Markin.  Electrical interaction of parallel non-myelinated nerve fibres-IV. Role of anatomical inhomogeneities of nerve trunks , 1973 .

[10]  J B Bassingthwaighte,et al.  Microvasculature of the dog left ventricular myocardium. , 1974, Microvascular research.

[11]  G. Langer,et al.  THE MYOCARDIAL INTERSTITIUM: ITS STRUCTURE AND ITS ROLE IN IONIC EXCHANGE , 1974, The Journal of cell biology.

[12]  L. Clerc.  Directional differences of impulse spread in trabecular muscle from mammalian heart. , 1976, The Journal of physiology.

[13]  R. Jennings,et al.  Experimental myocardial ischemic injury. II. Effect of in vivo ischemia on dog heart slice function in vitro. , 1976, Journal of molecular and cellular cardiology.

[14]  G. W. Beeler,et al.  Reconstruction of the action potential of ventricular myocardial fibres , 1977, The Journal of physiology.

[15]  P. Anversa,et al.  Absolute morphometric study of myocardial hypertrophy in experimental hypertension. II. Ultrastructure of myocytes and interstitium. , 1978, Laboratory investigation; a journal of technical methods and pathology.

[16]  D Durrer,et al.  Mechanism and Time Course of S‐T and T‐Q Segment Changes during Acute Regional Myocardial Ischemia in the Pig Heart Determined by Extracellular and Intracellular Recordings , 1978, Circulation research.

[17]  E. Johnson,et al.  Fast sodium current in cardiac muscle. A quantitative description. , 1980, Biophysical journal.

[18]  J W Moore,et al.  Effects of cellular geometry on current flow during a propagated action potential. , 1980, Biophysical journal.

[19]  D. Geselowitz,et al.  The Discontinuous Nature of Propagation in Normal Canine Cardiac Muscle: Evidence for Recurrent Discontinuities of Intracellular Resistance that Affect the Membrane Currents , 1981, Circulation research.

[20]  T. W. Keenan,et al.  Localization of xanthine oxidase in mammary-gland epithelium and capillary endothelium , 1981, Cell.

[21]  C. Crone,et al.  Electrical resistance of a capillary endothelium , 1981, The Journal of general physiology.

[22]  S. Olesen,et al.  Electrical resistance of brain microvascular endothelium , 1982, Brain Research.

[23]  J. C. Bailey,et al.  Effects of Extracellular Calcium Ions, Verapamil, and Lanthanum on Active and Passive Properties of Canine Cardiac Purkinje Fibers , 1982, Circulation research.

[24]  P A Lachenbruch,et al.  Quantitative Changes in the Capillary Bed during Developing, Peak, and Stabilized Cardiac Hypertrophy in the Spontaneously Hypertensive Rat , 1982, Circulation research.

[25]  M. Lieberman,et al.  Normal and abnormal conduction in the heart : biophysics, physiology, pharmacology, and ultrastructure , 1982 .

[26]  M. Janse,et al.  Fine structural identification of individual cells subjected to microelectrode recording in perfused cardiac preparations. , 1982, Journal of molecular and cellular cardiology.

[27]  N. Sperelakis.  Physiology and Pathophysiology of the Heart , 1984, Developments in Cardiovascular Medicine.

[28]  M. Suenson.  Ephaptic impulse transmission between ventricular myocardial cells in vitro. , 1984, Acta physiologica Scandinavica.

[29]  M. Suenson.  Interaction between ventricular cells during the early part of excitation in the ferret heart. , 1985, Acta physiologica Scandinavica.

[30]  J. Toyama,et al.  Anisotropic conduction properties of canine ventricular muscles. Influence of high extracellular K+ concentration and stimulation frequency. , 1985, Japanese circulation journal.

[31]  M. Spach,et al.  Relating the Sodium Current and Conductance to the Shape of Transmembrane and Extracellular Potentials by Simulation: Effects of Propagation Boundaries , 1985, IEEE Transactions on Biomedical Engineering.

[32]  S. Olesen,et al.  Substances that rapidly augment ionic conductance of endothelium in cerebral venules. , 1986, Acta physiologica Scandinavica.

[33]  H. Fozzard,et al.  The Heart and cardiovascular system : scientific foundations , 1986 .

[34]  J. Spear,et al.  The effects of procainamide on conduction in anisotropic canine ventricular myocardium. , 1986, Circulation.

[35]  M S Spach,et al.  Thin collagenous septa in cardiac muscle , 1987, The Anatomical record.

[36]  M S Spach,et al.  Propagating depolarization in anisotropic human and canine cardiac muscle: apparent directional differences in membrane capacitance. A simplified model for selective directional effects of modifying the sodium conductance on Vmax, tau foot, and the propagation safety factor. , 1987, Circulation research.

[37]  Yoram Rudy,et al.  A Model Study of the Effects of the Discrete Cellular Structure on Electrical Propagation in Cardiac Tissue , 1987, Circulation research.

[38]  R. Barr,et al.  Interstitial potentials and their change with depth into cardiac tissue. , 1987, Biophysical journal.

[39]  D. Roden,et al.  Frequency- and orientation-dependent effects of mexiletine and quinidine on conduction in the intact dog heart. , 1987, Circulation.

[40]  M Delmar,et al.  Effects of increasing intercellular resistance on transverse and longitudinal propagation in sheep epicardial muscle. , 1987, Circulation research.

[41]  J. Daut,et al.  Passive electrical properties and electrogenic sodium transport of cultured guinea‐pig coronary endothelial cells. , 1988, The Journal of physiology.

[42]  J. Francis Heidlage,et al.  Influence of the Passive Anisotropic Properties on Directional Differences in Propagation Following Modification of the Sodium Conductance in Human Atrial Muscle: A Model of Reentry Based on Anisotropic Discontinuous Propagation , 1988, Circulation research.

[43]  E. Sonnenblick,et al.  Coiled Perimysial Fibers of Papillary Muscle in Rat Heart: Morphology, Distribution, and Changes in Configuration , 1988, Circulation research.

[44]  N. Sperelakis.  Physiology and Pathophysiology of the Heart , 1989, Developments in Cardiovascular Medicine.

[45]  J. Saffitz,et al.  Quantitative Analysis of Intercellular Connections by Immunohistochemistry of the Cardiac Gap Junction Protein Connexin43 , 1989, Circulation research.

[46]  H Korn,et al.  Electrical field effects: their relevance in central neural networks. , 1989, Physiological reviews.

[47]  M. Spach,et al.  Properties of Discontinuous Anisotropic Propagation at a Microscopic Level a , 1990, Annals of the New York Academy of Sciences.

[48]  D. Chialvo,et al.  Directional differences in excitability and margin of safety for propagation in sheep ventricular epicardial muscle. , 1990, Circulation research.

[49]  J. Jalife,et al.  Cardiac Electrophysiology: From Cell to Bedside , 1990 .

[50]  R. Lux,et al.  Conduction velocity depression and drug-induced ventricular tachyarrhythmias. Effects of lidocaine in the intact canine heart. , 1990, Circulation.

[51]  B. Roth,et al.  Action potential propagation in a thick strand of cardiac muscle. , 1991, Circulation research.

[52]  C. Luo,et al.  A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction. , 1991, Circulation research.

[53]  F A Roberge,et al.  Directional characteristics of action potential propagation in cardiac muscle. A model study. , 1991, Circulation research.

[54]  C. Green,et al.  Gap junction distribution in adult mammalian myocardium revealed by an anti-peptide antibody and laser scanning confocal microscopy. , 1991, Journal of cell science.

[55]  R C Barr,et al.  Electrophysiological interaction through the interstitial space between adjacent unmyelinated parallel fibers. , 1992, Biophysical journal.

[56]  C. Henriquez,et al.  Cardiac propagation simulation. , 1992, Critical reviews in biomedical engineering.

[57]  Spach Ms,et al.  A multidimensional model of cellular effects on the spread of electrotonic currents and on propagating action potentials. , 1992 .

[58]  C F Starmer,et al.  Cellular Vmax reflects both membrane properties and the load presented by adjoining cells. , 1992, The American journal of physiology.

[59]  M S Spach,et al.  Distribution of gap junctions in dog and rat ventricle studied with a double-label technique. , 1992, Journal of molecular and cellular cardiology.

[60]  M S Spach,et al.  A multidimensional model of cellular effects on the spread of electrotonic currents and on propagating action potentials. , 1992, Critical reviews in biomedical engineering.

[61]  K Rakusan,et al.  Morphometry of Human Coronary Capillaries During Normal Growth and the Effect of Age in Left Ventricular Pressure‐Overload Hypertrophy , 1992, Circulation.

[62]  M S Spach,et al.  Conventional and confocal fluorescence microscopy of collagen fibers in the heart. , 1993, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[63]  J. Gavin,et al.  The myocardial vasculature during ischemia and reperfusion: a target for injury and protection. , 1993, Journal of molecular and cellular cardiology.

[64]  V. Fast,et al.  Microscopic conduction in cultured strands of neonatal rat heart cells measured with voltage-sensitive dyes. , 1993, Circulation research.

[65]  K R Foster,et al.  Myocardial Electrical Impedance Mapping of Ischemic Sheep Hearts and Healing Aneurysms , 1993, Circulation.

[66]  D. Roden,et al.  Effect of Hypercapnic Acidemia on Anisotropic Propagation in the Canine Ventricle , 1994, Circulation.

[67]  V. Fast,et al.  Anisotropic conduction in monolayers of neonatal rat heart cells cultured on collagen substrate. , 1994, Circulation research.

[68]  M. Spach,et al.  The stochastic nature of cardiac propagation at a microscopic level. Electrical description of myocardial architecture and its application to conduction. , 1995, Circulation research.

[69]  V. Fast,et al.  Block of impulse propagation at an abrupt tissue expansion: evaluation of the critical strand diameter in 2- and 3-dimensional computer models. , 1995, Cardiovascular research.

[70]  J. Fleischhauer,et al.  Electrical resistances of interstitial and microvascular space as determinants of the extracellular electrical field and velocity of propagation in ventricular myocardium. , 1995, Circulation.

[71]  P. Hunter,et al.  Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog. , 1995, The American journal of physiology.

[72]  D. Zipes,et al.  Reperfusion Arrhythmias: Role of Early Afterdepolarizations Studied by Monophasic Action Potential Recordings in the Intact Canine Heart During Autonomically Denervated and Stimulated States , 1995, Journal of cardiovascular electrophysiology.

[73]  V. Fast,et al.  Anisotropic activation spread in heart cell monolayers assessed by high-resolution optical mapping. Role of tissue discontinuities. , 1996, Circulation research.

[74]  J M Kootsey,et al.  A quasi-one-dimensional theory for anisotropic propagation of excitation in cardiac muscle. , 1996, Biophysical journal.

[75]  C. Henriquez,et al.  Anisotropy, Fiber Curvature, and Bath Loading Effects on Activation in Thin and Thick Cardiac Tissue Preparations: , 1996, Journal of cardiovascular electrophysiology.

[76]  Ronald W. Joyner,et al.  Discontinuous conduction in the heart , 1998 .