The State of Biophysics - Biophysical Journal

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current ). The effect on a cellular level is a delay in
repolarization.
However, the cell lines and the experimental setup that
were used do not represent the native environment of cardi-
omyocytes. To confirm this finding in circumstances more
analogous to the human myocardium, insights from stem
cell biology and studies on cell differentiation were em-
ployed. Various differentiated cells, such as human skin
cells from a patient’s small skin biopsy, can be reprog-
rammed into pluripotent stem cells. These have the ability
to differentiate into various kinds of tissue and are called
‘‘induced pluripotent stem cells’’ (iPSC). To investigate un-
derlying mechanisms in LQTS, iPSCs generated from
affected patients’ tissue were differentiated into beating car-
diomyocytes that were genetically homologous to the cardi-
omyocytes of the patients. Thus, these cells also expressed
the respective dysfunctional ion channels. Similarly, in the
iPSC model, investigations regarding the biophysical prop-
erties of the affected potassium channels confirmed the
reduced potassium current and the resulting loss of function
of these ion channels .
Different mutations have been found in genetic screening
of affected families since the LQTS was first described in
the 1960s by Romano and Ward. Experimental data have
elucidated different molecular mechanisms that lead to a
dysfunction of potassium channels. In general, these can
affect either the quantitative expression of channels on the
cell membrane or the speed and extent of channel closing
and opening ). The resulting effect in both cases is a
delay in repolarization.
A prolonged repolarization period influences recovery of
calcium channels, which operate during the active contrac-
tion period of the cardiomyocyte and the plateau phase of
the action potential. After the plateau phase and during
repolarization, calcium channels should remain inactivated
until the subsequent activation cycle. Premature reactiva-
tion results in so-called afterdepolarizations, resulting in
a prematurely triggered action potential and reactivation
of the cell ). Furthermore, alterations in potassium
channel function lead to a spatial dispersion of repolariza-
tion within different parts and layers of the ventricular
muscle. Instead of proceeding in only one direction due
to well-distinguished areas of excitable and inert myocar-
dium, the electrical activity can spread in multiple direc-
tions, initiate reentry mechanisms or degenerate into a
chaotic pattern ). These aspects are thought to form
the basis for potentially life-threatening TdP tachycardias
in these patients.
The girl in our case example additionally suffered from
inner ear hearing loss. Although affecting two entirely
different organs her cardiac arrhythmias and her hearing
problem have a common cause: KCNQ1-channels are ex-
pressed both in cardiomyocytes and in cells responsible
for sensory transduction in the inner ear. Thus, a dysfunction
of these channels affects not only cardiac but also inner ear
function in a subtype of LQTS, called Jervell-Lange-Niel-
sen syndrome. This is one example in which biophysical
studies on ion channels deliver important findings to
different medical fields.
Stress as trigger for TdP tachycardia
Driven by observations from clinical practice ), bio-
physical studies also helped to elucidate the mechanisms
by which certain triggers, like physical activity, drive the
development of the arrhythmia. Stress hormones are able
to influence biophysical properties and trafficking of potas-
sium channels . Well-known examples of stress
hormones are catecholamines such as adrenaline and
noradrenaline that are produced in the adrenal gland.
They bind to specific receptors on different cell types of
the heart to adapt heart rate and contractility in response
to increased demand for peripheral oxygen supply. This
is required during physical activity and in situations of
mental or emotional stress, such as being startled due to
sudden noises or from nervousness before an exam or a
performance on stage. However, as long-QT patients often
display arrhythmias during physical exercise or emotional
stress, catecholamines have been suspected to exceed this
typical physiological effect and may contribute to the
FIGURE 4 Example of self-terminating TdP
tachycardia. Normal sinus rhythm (marked by
blue line) is disrupted by a short period of TdP
tachycardia’’ (red line), which is self-terminating
and followed, again, by normal sinus rhythm
(blue line). To see this figure in color, go online.
Biophysical Journal 110(5) 1017–1022
1020 Zylla and Thomas