Integrative modeling of the cardiac ventricular myocyte

Abstract

Cardiac electrophysiology is a discipline with a rich 50-year history of experimental research coupled with integrative modeling which has enabled us to achieve a quantitative understanding of the relationships between molecular function and the integrated behavior of the cardiac myocyte in health and disease. In this paper, we review the development of integrative computational models of the cardiac myocyte. We begin with a historical overview of key cardiac cell models that helped shape the field. We then narrow our focus to models of the cardiac ventricular myocyte and describe these models in the context of their subcellular functional systems including dynamic models of voltage-gated ion channels, mitochondrial energy production, ATP-dependent and electrogenic membrane transporters, intracellular Ca dynamics, mechanical contraction, and regulatory signal transduction pathways. We describe key advances and limitations of the models as well as point to new directions for future modeling research. WIREs Syst Biol Med 2011 3 392-413 DOI: 10.1002/wsbm.122

FIGURE 1

(a) Reconstruction of the three-dimensional t-tubular system in a rat ventricular myocyte (Reprinted with permission from Ref . Copyright 1999 American Heart Association). (b) Ca transport in ventricular myocytes (Reprinted with permission from Ref . Copyright 2002 Macmillan Magazines Ltd.). Inset shows time course of action potential, Ca transient, and contraction.

FIGURE 2

Schematic representation of the cardiac sarcomere. The sarcomere is made up of thick (myosin) filaments (A-band) and thin (actin) filaments (I-band), which are interconnected by titin (with segments shown by colored bars on the top). The Z-line is the boundary between sarcomeres and the M-line is central portion of the A-band (Reprinted with permission from Ref . Copyright 2008 The Company of Biologists).

FIGURE 3

Schematic of the membrane currents that underlie a ventricular action potential (AP) shown with a control (solid line) and failing (dotted line) AP with phases labeled. (Reprinted with permission from Ref . Copyright 1999 Elsevier).

FIGURE 4

State diagram of the HERG and HERG+hKCNE2 Markov model. C_l, C₂, and C₃ are closed states, O is the open state, and I is the inactivated state (Reprinted with permission from Ref . Copyright 2001 American Heart Association).

FIGURE 5

General scheme of the excitation–contraction coupling-mitochondrial energetics guinea pig model including membrane currents, sarcolemmal ion transport, Ca compartmentalization, and mitochondrial function.

FIGURE 6

Protein kinase A signaling pathways in cardiac myocytes (Reprinted with permission from Ref . Copyright 2008 Springer Science+Business Media). See text and Figure 2 of Ref for further details.