The State of Biophysics - Biophysical Journal

Biophysics and Inherited Arrhythmias

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FIGURE 3 Conduction system of the heart. An electrical impulse is generated by the sinoatrial (SA) node or sinus node ( 1 ). Electrical activity then spreads across the atria, which causes contrac- tion of atrial myocardium ( 2 and 3 ). After passing the AV node, electrical activation is propagated to excite the ventricular myocardium via bundle branches and Purkinje fibers ( 4 and 5 ). To see this figure in color, go online.

arrhythmia, the heart fails to supply the central nervous system with sufficient amounts of oxygenated blood. If these arrhythmias are self-terminating, the patient experi- ences dizziness or loss of consciousness for a short period of time. However, TdP tachycardia may degenerate into ventricular fibrillation, which is often the cause of SCD in these patients. Genetic analyses of patients with LQTS have, in the ma- jority of cases, revealed mutations in genes encoding for cardiac potassium channels. Prominent subtypes of potas- sium channels that may be affected are KCNQ1-channels or hERG-channels ( 4–6 ). These potassium channels are both involved in the repolarization phase of cardiomyo- cytes (phase 3, Fig. 2 ). Biophysics enters at this stage. Bio- physical studies were designed to assess mechanistic consequences of these identified gene mutations for the function of the respective ion channel. For this purpose, genetic information from long-QT patients was transferred to nonexcitable cells, which are easy to examine and do not express other endogenous ion channels, or other noncardiac cell lines. These cells consecutively expressed the defective potassium channels, encoded by the trans- ferred genetic information, on their cell membrane. Thus, they constituted an experimental model in which cellular electrical activity could be measured and biophysical prop- erties of defined ion channels could be analyzed. These ex- periments revealed that the changes in protein structure lead to altered biophysical properties of these potassium channels and, as a result, a reduction of the potassium

electrical activity can proceed to the neighboring myocar- dium in only one direction. Of importance, this intricate coordination depends on the length of the action potential, which ensures a balance between heart rate and excitation properties of the cardiomyocytes. The length of the action potential, however, is dependent on the coordinated inter- play of ion channels. Therefore, if one type of ion channel is dysfunctional, the electrical activation of the single cell is altered, which, in turn, results in a disturbance of the elec- trical properties and the contraction process of the whole ventricular muscle. One example for impaired ventricular function due to a dysfunction of ion channels is the LQTS, which was diag- nosed in the girl from our clinical case example. Most patients with LQTS present at a young age with recurrent loss of consciousness. Depending on the subtype of LQTS, sudden loss of consciousness often occurs dur- ing physical activity (particularly during swimming), in response to startling sudden noises or to emotional stress. The reason for loss of consciousness in these patients is the development of a fast ventricular arrhythmia. Due to its characteristic morphology of twisting spikes around an isoelectric baseline, this arrhythmia is called ‘‘torsa- des-de-pointes’’(TdP) tachycardia ( Fig. 4 ). As a result of severely elevated heart rates and a disturbed spread of electrical activity through the ventricles during the LQTS: how delay causes acceleration

Biophysical Journal 110(5) 1017–1022