Systems Approach to Understanding Electromechanical Activity in the Human Heart: A National Heart, Lung, and Blood Institute Workshop Summary

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of cardiologists, cardiac electrophysiologists, cell biophysicists, and computational modelers on August 20 and 21, 2007, in Washington, DC, to advise the NHLBI on new research directions needed to develop integrative approaches to elucidate human cardiac function. The workshop strove to identify limitations in the use of data from nonhuman animal species for elucidation of human electromechanical function/activity and to identify what specific information on ion channel kinetics, calcium handling, and dynamic changes in the intracellular/extracellular milieu is needed from human cardiac tissues to develop more robust computational models of human cardiac electromechanical activity. This article summarizes the workshop discussions and recommendations on the following topics: (1) limitations of animal models and differences from human electrophysiology, (2) modeling ion channel structure/function in the context of whole-cell electrophysiology, (3) excitation–contraction coupling and regulatory pathways, (4) whole-heart simulations of human electromechanical activity, and (5) what human data are currently needed and how to obtain them. The recommendations can be found on the NHLBI Web site at http://www.nhlbi.nih.gov/meetings/workshops/electro.htm.

[1]  S. Waxman Channel, neuronal and clinical function in sodium channelopathies: from genotype to phenotype , 2007, Nature Neuroscience.

[2]  J. Nerbonne,et al.  Molecular physiology of cardiac repolarization. , 2005, Physiological reviews.

[3]  Kumaraswamy Nanthakumar,et al.  Optical mapping of Langendorff-perfused human hearts: establishing a model for the study of ventricular fibrillation in humans. , 2007, American journal of physiology. Heart and circulatory physiology.

[4]  Donald M Bers,et al.  Cardiac Alternans Do Not Rely on Diastolic Sarcoplasmic Reticulum Calcium Content Fluctuations , 2006, Circulation research.

[5]  Y. Rudy,et al.  Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia , 1999, Nature.

[6]  Giovanni Paternostro,et al.  Cardiac Systems Biology , 2005, Annals of the New York Academy of Sciences.

[7]  Michael J. Ackerman,et al.  Mutation of an A-kinase-anchoring protein causes long-QT syndrome , 2007, Proceedings of the National Academy of Sciences.

[8]  S. Pogwizd,et al.  Mechanisms underlying spontaneous and induced ventricular arrhythmias in patients with idiopathic dilated cardiomyopathy. , 1996, Circulation.

[9]  E. Campbell,et al.  Crystal Structure of a Mammalian Voltage-Dependent Shaker Family K+ Channel , 2005, Science.

[10]  S Nattel,et al.  Transient outward and delayed rectifier currents in canine atrium: properties and role of isolation methods. , 1996, The American journal of physiology.

[11]  J. Kjems,et al.  Polycation-based nanoparticle delivery for improved RNA interference therapeutics , 2007, Expert opinion on biological therapy.

[12]  A. Feldman,et al.  Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts , 2007, Gene Therapy.

[13]  Blanca Rodriguez,et al.  Arrhythmogenesis in the heart: Multiscale modeling of the effects of defibrillation shocks and the role of electrophysiological heterogeneity. , 2007, Chaos.

[14]  S. Priori,et al.  Role of Genetic Analyses in Cardiology: Part I: Mendelian Diseases: Cardiac Channelopathies , 2006, Circulation.

[15]  Michael J Ackerman,et al.  Mutant Caveolin-3 Induces Persistent Late Sodium Current and Is Associated With Long-QT Syndrome , 2006, Circulation.

[16]  Donald M Bers,et al.  Dynamic Regulation of Sodium/Calcium Exchange Function in Human Heart Failure , 2003, Circulation.

[17]  G. Bett,et al.  Time- and voltage-dependent components of Kv4.3 inactivation. , 2005, Biophysical journal.

[18]  T. Furukawa,et al.  Regulation of cardiac ion channels via non-genomic action of sex steroid hormones: implication for the gender difference in cardiac arrhythmias. , 2007, Pharmacology & therapeutics.

[19]  D. Harrison,et al.  Study of the normal and failing isolated human heart: decreased response of failing heart to isoproterenol. , 1983, American heart journal.

[20]  M. Ackerman,et al.  Sudden cardiac death and channelopathies: a review of implantable defibrillator therapy. , 2004, Pediatric clinics of North America.

[21]  I. Efimov,et al.  Enhanced Transmural Fiber Rotation and Connexin 43 Heterogeneity Are Associated With an Increased Upper Limit of Vulnerability in a Transgenic Rabbit Model of Human Hypertrophic Cardiomyopathy , 2007, Circulation research.

[22]  Michael J Ackerman,et al.  SCN4B-Encoded Sodium Channel &bgr;4 Subunit in Congenital Long-QT Syndrome , 2007, Circulation.

[23]  Yoram Rudy,et al.  Electrocardiographic imaging (ECGI): a new noninvasive imaging modality for cardiac electrophysiology and arrhythmia , 2006, SPIE Medical Imaging.

[24]  D M Roden,et al.  The long QT syndromes: genetic basis and clinical implications. , 2000, Journal of the American College of Cardiology.

[25]  W. Catterall,et al.  Regulation of Sodium and Calcium Channels by Signaling Complexes , 2006, Journal of receptor and signal transduction research.

[26]  G. Salama,et al.  Optical Imaging of the Heart , 2004, Circulation research.

[27]  M. Bristow,et al.  Quantitative pharmacologic responses of normal and atherosclerotic isolated human epicardial coronary arteries. , 1984, Circulation.

[28]  Y. Rudy,et al.  Basic mechanisms of cardiac impulse propagation and associated arrhythmias. , 2004, Physiological reviews.

[29]  D. Bers Calcium cycling and signaling in cardiac myocytes. , 2008, Annual review of physiology.

[30]  Lufang Zhou,et al.  Mechanistic model of cardiac energy metabolism predicts localization of glycolysis to cytosolic subdomain during ischemia. , 2005, American journal of physiology. Heart and circulatory physiology.

[31]  D. Noble Modeling the Heart--from Genes to Cells to the Whole Organ , 2002, Science.

[32]  I. Efimov Connections, connections, connexins: towards systems biology paradigm of cardiac arrhythmia. , 2006, Journal of molecular and cellular cardiology.

[33]  Y. Rudy,et al.  Activation and repolarization of the normal human heart under complete physiological conditions. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[34]  A. McCulloch,et al.  Integrating metabolomics and phenomics with systems models of cardiac hypoxia. , 2008, Progress in biophysics and molecular biology.

[35]  Denis Noble,et al.  Models of cardiac ventricular action potentials: iterative interaction between experiment and simulation , 2001, Philosophical Transactions of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences.

[36]  Steven R Houser,et al.  Is depressed myocyte contractility centrally involved in heart failure? , 2003, Circulation research.

[37]  Lili X. Peng,et al.  Systems analysis of PKA-mediated phosphorylation gradients in live cardiac myocytes , 2006, Proceedings of the National Academy of Sciences.

[38]  P. C. Viswanathan,et al.  Mutation in Glycerol-3-Phosphate Dehydrogenase 1–Like Gene (GPD1-L) Decreases Cardiac Na+ Current and Causes Inherited Arrhythmias , 2007, Circulation.

[39]  David Gavaghan,et al.  Three‐Dimensional Models of Individual Cardiac Histoanatomy: Tools and Challenges , 2006, Annals of the New York Academy of Sciences.

[40]  Yoram Rudy,et al.  Regulation of Ca2+ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents. , 2007, American journal of physiology. Heart and circulatory physiology.

[41]  Y. Rudy,et al.  Noninvasive electrocardiographic imaging for cardiac electrophysiology and arrhythmia , 2004, Nature Medicine.

[42]  Stefan Kääb,et al.  Susceptibility genes and modifiers for cardiac arrhythmias. , 2005, Cardiovascular research.

[43]  M. Kirk,et al.  Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome. , 2008, The Journal of clinical investigation.

[44]  Hideki Hayashi,et al.  The dynamics of cardiac fibrillation. , 2005, Circulation.

[45]  Yoram Rudy,et al.  Computational biology in the study of cardiac ion channels and cell electrophysiology , 2006, Quarterly Reviews of Biophysics.

[46]  D. Tester,et al.  Genetic testing for cardiac channelopathies: ten questions regarding clinical considerations for heart rhythm allied professionals. , 2005, Heart rhythm.

[47]  Michael R Rosen,et al.  I(f) and the biological pacemaker. , 2006, Pharmacological research.

[48]  S. Lai,et al.  Targeted high-efficiency, homogeneous myocardial gene transfer. , 2007, Journal of molecular and cellular cardiology.

[49]  M. S. Jafri,et al.  Mitochondrial Calcium Signaling and Energy Metabolism , 2005, Annals of the New York Academy of Sciences.

[50]  R. Kass,et al.  Regulatory actions of the A-kinase anchoring protein Yotiao on a heart potassium channel downstream of PKA phosphorylation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[51]  R. Blaustein,et al.  Constraints on Voltage Sensor Movement in the Shaker K+ Channel , 2006, The Journal of general physiology.

[52]  László Virág,et al.  Restricting Excessive Cardiac Action Potential and QT Prolongation: A Vital Role for IKs in Human Ventricular Muscle , 2005, Circulation.

[53]  R. Solaro,et al.  Calcium, thin filaments, and the integrative biology of cardiac contractility. , 2005, Annual review of physiology.

[54]  Donald M Bers,et al.  Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes , 2003, Circulation research.

[55]  Donald M Bers,et al.  A mathematical treatment of integrated Ca dynamics within the ventricular myocyte. , 2004, Biophysical journal.

[56]  Thomas J. Wang,et al.  The search for new cardiovascular biomarkers , 2008, Nature.

[57]  Yoram Rudy,et al.  Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model , 2004, Circulation.

[58]  B. London,et al.  Knockin Animal Models of Inherited Arrhythmogenic Diseases: What Have We Learned From Them? , 2007, Journal of cardiovascular electrophysiology.

[59]  Y. Rudy,et al.  Ionic Current Basis of Electrocardiographic Waveforms: A Model Study , 2002, Circulation research.