NHLBI: Systems Approach to Understanding Electromechanical Activity in the Human Heart

Executive Summary

The National Heart, Lung, and Blood Institute (NHLBI) convened a Workshop of expert cardiac electrophysiologists, cell biophysicists, and computational modelers on August 20-21, 2007, in Washington, D.C., to advise the NHLBI on new research directions needed to develop integrative approaches to elucidate human cardiac function. The Workshop fits well within the NHLBI Strategic Plan by seeking to integrate understanding of the molecular and physiological basis of health and disease and develop more effective approaches to cardiac disease diagnosis, treatment, and prevention.

Discussion:

The workshop aimed to identify limitations in using data from non-human animal species for elucidation of human electromechanical function/activity and to identify what specific information regarding ion channel kinetics, calcium handling and dynamic changes in the intra-/extracellular milieu is needed from human cardiac tissues to develop more robust computational models of human electromechanical activity. Workshop members specifically reviewed and discussed (1) the limitations of animal models and how they differ 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 kinds of human data are presently needed and how to obtain it.

Recommendations:

The specific recommendations are that the NHLBI should:

Improve the quality and reliability of human cardiac electromechanical data by:

Supporting research that identifies optimal conditions and methodologies for human cardiac tissue procurement, handling and storage.
Developing new tools and protocols for the perfusion and preservation of explanted human hearts that are unsuitable for transplantation but which may be useful for physiologic studies.
Improving protocols for the isolation and short-term culture of human myocytes.
Making all of these protocols broadly available to the scientific community.
Supporting studies of electrophysiology, calcium handling, and sarcomeric properties (and regulation) of the human myocardium at more institutions, while promoting data sharing between investigators and institutions.

Improve the understanding of mechanisms underlying the normal and abnormal activity of the human heart through supporting:

Basic research to establish interrelationships among kinetics and the structure of human cardiac ion channels, transporters, and sarcomeric proteins using compendiums of disease producing mutations and presumed "normal" genetic variations to link structure to function.
Comparative studies of human versus animal cardiac gene expression, electrophysiology and excitation-contraction coupling, and supporting model-based strategies for extrapolating information from animal to human models.
The development of large animal models modified by genetic manipulation (viral infection, siRNA, etc.) to identify the mechanisms underlying atrial and ventricular arrhythmogenesis and the development of heart failure in longitudinal studies of aging, remodeling, and disease progression.
The study of electromechanical activity in normal human hearts and in specific disease states (i.e., heart failure, ischemia/infarction, hypertrophy, specific genetic disorder that adversely affect cardiac activity) across life stages (i.e., fetal, pubertal, adult, senescence). Such studies should involve the (1) development of novel cell systems for the recapitulation of human cardiac molecular complexes and regulatory function, (2) identification and characterization of cardiac channel macromolecular complexes and their electrophysiology, participation in calcium handling and sarcomere function, (3) determination of the effects of age, disease states, and remodeling on regulatory control (e.g., by phosphorylation, oxidation etc.) of human ion channels, calcium handling proteins and sarcomeric proteins, and (4) examination of the intracardiac heterogeneities, at each life stage and disease state, to determine regional myocyte properties (right ventricle versus left ventricle, base to apex, epicardial to endocardial, and atria versus ventricles).
The development of novel non-invasive technologies for assessing detailed structural and functional properties of the human heart.

Support the development and experimental validation of integrative multiscale computational models of the normal human heart and of specific cardiac diseases (arrhythmias, heart failure, and myocardial ischemia/infarction) and their progression, that:

Integrate multiple subsystems specific to the pathogenesis of the disease state, and characterize the dynamics of their interactions at each scale. This will also require support to develop and maintain advanced computational tools and technologies needed to ensure computational tractability as well as robust and efficient models of human electromechanical activity.
Incorporate the structural alterations associated with specific diseases at each scale.
Characterize the adaptive and maladaptive responses that underlie the progression of disease.
Integrate across scales to predict the electromechanical outcomes of genetically-based and acquired perturbations.
Inform clinical diagnosis and guide the selection of appropriate therapies in a patient-specific manner. Molecular/cellular investigations of explanted tissues, including histological and/or immunohistochemical characterization should be combined with clinical data and high resolution, non-invasive structural (CT, MRI), functional (echocardiography) and electrophysiologic imaging obtained before surgery.

Convene a series of workshops to build consensus and improve communication among investigators working at (1) the same horizontal level (e.g., those measuring and modeling individual ion channels, transporters or myofilament properties in myocytes), and (2) different vertical levels (genomic/proteomic to cellular, and cellular to more integrative levels). This is part of a broader aim to support collaboration and cooperation among molecular and cellular experimental, computational modeling, bioengineering, and clinical investigators in a true systems approach to understanding electromechanical activity in the normal and diseased human heart.

Publication Plans:

NHLBI Contact:

David A. Lathrop, Ph.D., NHLBI, NIH
lathropd@nhlbi.nih.gov; 301-435-0507

Dennis Przywara, Ph.D., NHLBI, NIH
przywarad@nhlbi.nih.gov; 301-435-0506

Working Group Members:

Chair: Yoram Rudy, Ph.D., Washington University in St. Louis

Members:

Michael J. Ackerman, M.D., Ph.D., Mayo Clinic Rochester

Donald M. Bers, PhD, Loyola University Chicago

Colleen E. Clancy, Ph.D., Weill Medical College of Cornell University

Steven R. Houser, Ph.D., Temple University School of Medicine

Barry London, M.D., Ph.D., University Of Pittsburgh

Andrew McCulloch, Ph.D., University of California, San Diego

Randall Rasmusson, Ph.D., SUNY Buffalo

R. John Solaro, Ph.D., University of Illinois at Chicago

Natalia A. Trayanova, Ph.D., Johns Hopkins University

David R. Van Wagoner, Ph.D., Cleveland Clinic Lerner College of Medicine-CWRU

András Varró, M.D., Ph.D., D.Sc., University of Szeged, Albert Szent-Györgyi Medical and Pharmaceutical Centre

James N . Weiss, M.D., University of California, Los Angeles

Last updated: October 3, 2007

NHLBI Workshop Systems Approach to Understanding Electromechanical Activity in the Human Heart

Executive Summary

NHLBI Workshop
Systems Approach to Understanding Electromechanical Activity in the Human Heart