The State of Biophysics - Biophysical Journal

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.

LQTS: how delay causes acceleration

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

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

FIGURE 3 Conduction system of the heart. An

electrical impulse is generated by the sinoatrial

(SA) node or sinus node (

). Electrical activity

then spreads across the atria, which causes contrac-

tion of atrial myocardium (

and

). After passing

the AV node, electrical activation is propagated to

excite the ventricular myocardium via bundle

branches and Purkinje fibers (

and

). To see

this figure in color, go online.

Biophysical Journal 110(5) 1017–1022

Biophysics and Inherited Arrhythmias

1019