Ionic Basis of Repolarization and ECG Waveforms

Yoram Rudy

Cardiac Bioelectricity Research and Training Center, Case Western Reserve University,
Cleveland, Ohio, USA

Correspondence: Y Rudy, Cardiac Bioelectricity Center, 509 Wickenden Building, Cleveland, OH 44106-7207, USA.
E-mail: yxr@po.cwru.edu, phone 216-368-4051 fax 216-368-8672

1.  Introduction

Repolarization abnormalities underlie many potentially fatal arrhythmias and sudden cardiac death. The last decade has generated extensive information on the molecular basis of the repolarization process and its alteration by disease. In particular, genetic mutations that affect the structure and function of cardiac ion channels have been identified and linked to cardiac arrhythmias. A major challenge remains the integration of this information into the physiological environment of the functioning cell and tissue, so that arrhythmia mechanisms can be determined. At the clinical end, the challenge is to relate electrocardiographic (ECG) waveforms to cellular-level processes. In my presentation I will illustrate the use of computational biology (mathematical modeling) in studying the ionic basis of repolarization abnormalities and their reflection in ECG waveforms. Examples will be described from the following publications: [Clancy and Rudy, 1999; 2001; 2002]; [Viswanathan and Rudy, 2000]; [Gima and Rudy, 2002].

2.  Materials and Methods

The cardiac ventricular action potential is simulated using the Luo-Rudy model of the guinea-pig ventricular myocyte. Ion channels that are affected by mutations are formulated using Markov models that represent discrete channel states and their interactions [Clancy and Rudy, 1999]. The traditional Hodgkin-Huxley approach is insufficient for representing mutation-induced state-specific channel defects, as required in the simulations. ECG waveforms are computed 2.0 cm away from the epicardium using a 1-dimensional fiber model containing endocardial, midmyocardial, and epicardial sections. The model simulates transmural plane-wave propagation from endocardium to epicardium.

3.  Results

3.1. The Long-QT (LQT) Syndrome

We have simulated mutations in the sodium channel, I_Na [Clancy and Rudy, 1999] and in the rapid delayed rectifier potassium channel, I_Kr [Clancy and Rudy, 2000] that delay action potential repolarization and lead to prolongation of the QT interval on the ECG. ΔKPQ is a mutation in SCN5A (the I_Na encoding gene) that gives rise to the most severe form of the congenital LQT. The ΔKPQ structural defect in the I_Na protein results in two modifications of channel function: (1) Channel reopenings may occur following the first opening in response to depolarization. (2) A transient failure of inactivation may occur, causing channels to bounce back and forth between closed and open states and display frequent opening events. The simulations show that these altered channel behaviors generate an inward current during the action potential plateau that prolongs the action potential and causes the development of arrhythmic early after-depolarizations (EAD) at slow pacing rate [Clancy and Rudy, 1999]. The simulated behavior is consistent with the clinical observation that arrhythmogenic episodes in patients carrying this mutation are bradycardia-related and occur during sleep or relaxation.

More than 50 mutations in HERG, the gene that encodes I_Kr, have been linked to congenital LQT. We have simulated selected mutations that alter the channel function in a well-characterized fashion [Clancy and Rudy, 2001]. An important finding of the study is that the severity of the phenotype (i.e., degree of action potential prolongation, EAD development) depends on the specific kinetic changes caused by the mutation and how they affect I_Kr during the time course of the action potential. An interesting mutation (N6290) leads to loss of pore selectivity to K⁺, allowing passage of Na⁺ ions into the cell. An inward current is generated during the late plateau phase, leading to action-potential prolongation and LQT.

3.2. The Brugada Syndrome

A single mutation in the C-terminus of I_Na, 1795insD (insertion of aspartic acid) was shown recently to cause two distinct clinical syndromes, LQT (prolonged QT interval on the ECG at slow heart rate) and Brugada (ST segment elevation on the right precordial ECG leads). Coexistence of these syndromes is seemingly paradoxical; LQT is associated with enhanced I_Na function (frequent opening), while Brugada with reduced function (enhanced inactivation and reduced channel availability). Simulations of the 1795insD mutation [Clancy and Rudy, 2002] show that it affects epicardial cells and midmyocardial cells differently. The effect on midmyocardial cells results in action potential prolongation (LQT), while the effect on epicardial cells results in their early repolarization and ST segment elevation. Thus, a single gene defect, through its interaction with a heterogeneous physiological substrate, can give rise to multiple distinct phenotypes with different clinical manifestations.

3.3. ECG Waveforms

These simulations were aimed at providing principles and a mechanistic cellular basis for interpretation of electrocardiographic waveforms [Gima and Rudy, 2002]. The following principles were established: (1) Voltage gradients created by heterogeneities of the slow delayed rectifier (I_Ks) and transient outward current (I_to) inscribe the T wave and J wave, respectively. (2) Alterations of I_Ks, I_Kr, I_Na in LQT are reflected in characteristic QT interval and T wave changes. (3) Accelerated inactivation results in ST segment elevation (Brugada syndrome) that reflects the degree of severity. (4) The ATP-sensitive potassium current, I_K(ATP), is sufficient to cause ST segment elevation associated with acute ischemia.

4.  Conclusion

We have used mathematical modeling to link molecular processes to the electrophysiology of cardiac cells and to the morphology of ECG waveforms. In particular, we have provided examples of genetic mutations that result in abnormal repolarization and associated ST segment and T wave changes on ECG waveforms. It is our hope that this approach will aid in making mechanism-specific diagnoses, so that mechanism-based therapy can be administered for the prevention and cure of cardiac arrhythmias.

Acknowledgements

Supported by grants RO1 HL49054 and R37 HL33343 from the NIH – National Heart, Lung, and Blood Institute.

References

Clancy, CE and Rudy R, Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia, Nature, 400:566-569, 1999.

Clancy, CE and Rudy R, Cellular consequences of HERG mutations in the Long QT syndrome: precursors to sudden cardiac death, Cardiovascular Research, 50:301-313, 2001.

Viswanathan, PC and Rudy Y, Cellular arrhythmogenic effects of the congenital and acquired Long QT syndrome in the heterogeneous myocardium, Circulation, 101:1192-1198, 2000.

Clancy CE and Rudy Y, A Na⁺ channel mutation that causes both Brugada and Long QT syndrome phenotypes: a simulation study of mechanism, Circulation, 105:1208-1213, 2002.

Gima K and Rudy Y, Ionic current basis of electrocardiographic waveforms: a model study, Circulation Research, 90:889-896, 2002.