The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of cardiologists, cardiac electro-physiologists, 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 fits well within the NHLBI Strategic Plan by seeking to integrate understanding of the molecular and physiological bases of health and disease and to develop more effective approaches to cardiac disease diagnosis, treatment, and prevention.
“Systems approach” can be defined as an integrative approach that, in contrast to the reductionist approach of science, assembles the system (in this case, the heart) from its molecular, cellular, and tissue components. The past decade has generated a wealth of information at the genetic, molecular, and cellular scales of the cardiac system. It is timely and important to begin integrating this information within and between scales to the level of the whole heart because electromechanical cardiac function and its alteration by disease (eg, heart failure and arrhythmias) occur at the organ level.
Until the recent advances in genomics, proteomics, metabolomics, and genetic engineering, our ability to understand how the most basic building blocks of life, DNA and the gene, affect the behavior of the living organism was limited to a handful of rare genetic diseases. Identifying the full complement of mRNA transcripts produced in the heart (the transcriptome), the proteins that they encode (the proteome), and the small metabolites that define the fluid state of the cells (the metabolome) provides a roadmap to eventually link genotype to phenotype.1,2
With the ability to alter genes through genetic engineering, moreover, it has become possible to directly explore at will the relationship between genotype and phenotype in animal models.3
This has become a powerful tool for cataloging how individual genes affect phenotype and has illuminated the molecular basis of a number of (mostly rare) monogenic diseases in humans.
However, even in monogenic diseases (such as congenital long-QT syndromes), interactions with modifier genes and environment are critically important in establishing the phenotypic severity (such as arrhythmia risk) among affected family members. Moreover, it has become increasingly clear that most common human diseases, including myocardial ischemia, heart failure, and arrhythmias, are not due to the strong effect of a single defective gene but rather to modest effects of multiple genes combined with modest effects of multiple environmental factors. Therefore, merely cataloging the effects of all possible genetic mutations, even if it were technically feasible, would be unlikely to provide the mechanistic insight required to develop cures for most human diseases. Given this limitation, it is essential to develop new integrative systems approaches to human disease that begin with but go well beyond genotype–phenotype associations to the quantitative prediction of phenotypes from genotypes and their in vivo context in health and disease.
In addition to characterizing and analyzing networks of functional interactions between genes and proteins, these approaches should aim to integrate understanding across physical scales of increasing complexity, from molecule to cell, tissue, the whole heart, and ultimately the whole patient (). Adequate experimental and computational tools currently exist to allow such an integration; the challenge is to have these approaches accepted and used to achieve mechanistic understanding of human cardiac disease at each of the intermediate scales of biological organization between the genome and the living organism. Such an understanding also will provide a formal and quantitative means of extrapolating mechanisms from animal models of cardiac disease to individual patients.
Role of multiscale modeling in the systems approach to understanding electromechanical activity in the human heart.
The workshop convened by the NHLBI recognized limitations in the use of data from nonhuman animal species for elucidation of human electromechanical function/activity and identified 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. Workshop members specifically reviewed and discussed (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.