The State of Biophysics - Biophysical Journal

1020

Zylla and Thomas

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.

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 ( 10 ). 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. Driven by observations from clinical practice ( 11 ), 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 ( 12–14 ). 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 Stress as trigger for TdP tachycardia

current ( 7 ). 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 ( 8,9 ). 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 ( 10 ). 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 ( 10 ). Furthermore, alterations in potassium channel function lead to a spatial dispersion of repolariza-

Biophysical Journal 110(5) 1017–1022