Priebe, Beuckelmann, 1998

Model Status

This model has been curated and is known to replicate the published output in PCEnv and COR.

Model Structure

Patients with severe heart failure are at a high risk of sudden cardiac death. In most of these patients, sudden cardiac death is thought to be caused by ventricular tachyarrhythmias. The mechanisms underlying these fatal arrhythmias are not fully understood. However, it is thought that alterations of the electric properties of single myocytes during heart failure may favour the occurrence of ventricular arrhythmias by inducing early or delayed afterdepolarisations (EADs or DADs). In human studies, it has been observed that the ventricular myocytes of heart failure patients display prolonged action potentials relative to those of control, healthy patients. In addition to changes in several ionic currents, during heart failure [Ca²⁺]_i handling is also often altered, and activity of the Na⁺-Ca²⁺ exchanger is enhanced.

It is hoped that mathematical models of the cellular action potential and its associated ionic currents may enhance our understanding of the mechanisms underlying cardiac arrhythmias. In turn, this better understanding may lead to the testing of potential therapies on the electrical excitability of the human ventricular myocardium. With this aim, in 1998 Priebe and Beuckelmann developed an electrophysiological model of a single human ventricular cell (see the figure below). This model was mainly based on the Luo-Rudy II model of a guinea-pig ventricular myocyte, (see the CellML version of the Luo-Rudy Ventricular Model II (dynamic), 1994 for the original model). However, five currents (I_Kr , I_Ks , I_Ca , I_to and I_K1 ) were based on experimental data obtained from human myocytes. The remaining currents taken from the LR II model were also scaled to fit human cell data. Priebe and Beuckelmann used their model of the human ventricular action potential to compare the electrophysiological properties of healthy and failing ventricular myocytes. The results from model simulations suggest that:

The action potential of in ventricular myocytes from failing hearts is longer than than in non-failing hearts;
The mechanisms underlying this prolongation in failing myocytes are enhanced activity of the Na⁺-Ca²⁺ exchanger, reduced inward rectifying K⁺ current, and reduced activity of the Na⁺-K⁺ pump;
The fast and slow components of the delayed rectifier K⁺ current (I_Kr and I_Ks ) play essential roles in determining the repolarisation of the action potential. Inhibition of I_Kr induces early afterdepolarisations in failing myocytes; and
Spontaneous Ca²⁺ release from the sarcoplasmic reticulum induces a premature action potential in failing myocytes.

The complete original paper reference is cited below:

Simulation Study of Cellular Electric Properties in Heart Failure, Leo Priebe and Dirk J. Beuckelmann, 1998, Circulation Research , 82, 1206-1223. (PDF and full text versions of the article are available to subscribers on the journal website.) PubMed ID: 9633920

A schematic diagram describing the transmembrane ionic currents through channels, pumps and exchangers, that are captured in the Priebe and Beuckelmann 1998 model of a human ventricular myocyte. The intracellular compartment in the diagram represents the sarcoplasmic reticulum (SR). This is divided into the two subcompartments, the network SR (NSR) and the junctional SR (JSR). Ca²⁺ buffers are present in both the cytoplasm and the JSR - troponin (TRPN), Calmodulin (CMDN), and calsequestrin (CSQN).