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Inherited Arrhythmias: Of Channels, Currents, and Swimming
Maura M. Zylla1 and Dierk Thomas1
1Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany
Inherited arrhythmia syndromes may predispose individuals
to life-threatening arrhythmias and sudden cardiac death
(SCD). Affected patients are usually young and their
everyday life may be impaired by recurrent loss of conscious-
ness, palpitations, or dizziness. They might have even been
saved from SCD by successful cardiopulmonary resuscita-
tion, which may be the first manifestation of their disease.
Making the diagnosis is often difficult, as signs and symp-
toms may by unspecific, variable in time, and depend on
external influences or situations. Biophysical studies, how-
ever, have contributed significantly to characterizing spe-
cific inherited arrhythmias, analyzing their underlying
cause(s) and mechanism(s), identifying risk factors for the
development of life-threatening arrhythmias, as well as
developing specific treatment strategies.
Many inherited arrhythmias result from dysfunctional ion
channels, which are proteins at the cell surface dedicated to
enable movement of ions across the cell membrane. These
diseases are therefore named ‘‘channelopathies.’’ Biophysi-
cal methodology is particularly suitable for the investigation
of ion channel function to deduce potential therapeutic tar-
gets. Different experimental models can be employed,
ranging from the expression and characterization of muta-
tion-derived ion channels on single cells to observations in
affected patients during diagnostic clinical procedures.
Additionally, therapeutic agents are tested in laboratory ex-
periments to confirm their efficacy in restoring coordinated
electrical activity.
The field of inherited arrhythmias is one example of how
biophysical research contributes to elucidating disease
mechanisms and developing specific therapeutic strategies.
As a consequence, evidence derived from biophysical
studies can be transferred to clinical practice to the benefit
of patients affected by inherited arrhythmia syndromes.
Clinical case: the unexpected end of a
swimming trip
On a summer day, a 7-year-old girl suddenly becomes un-
conscious during swimming in a public pool and is rescued
out of the water by her father. Several months ago, she
already had to spend 1 week in the hospital after a concus-
sion due to loss of consciousness while riding her bike.
When she was 2 years old, she received cochlear implants
due to inner ear hearing loss. Both parents are healthy.
Her 5-year-old brother experienced loss of consciousness
for the first time 2 days ago. She is taken to the outpatient
clinic of the local hospital by her parents.
As a first step, an electrocardiogram (ECG) is obtained
A). The pathological finding becomes apparent
when comparing the ECG signal to the signal of a healthy
person B). The time period marked by the blue
line is strikingly prolonged in this young patient. This
time period reflects the time between the start of electrical
activation of the ventricular muscle (seen as the Q-Wave
in the ECG, A), and the time at which the ventricular
muscle enters the resting state again (marked by the end of
the T-wave, A). The disease that is suspected in this
girl is called long-QT syndrome (LQTS).
Inherited arrhythmias and sudden cardiac death
The LQTS is an inherited arrhythmia that is associated with
loss of consciousness and may be a cause of sudden cardiac
death. SCD refers to death by cardiovascular cause within
1 h of acute onset of symptoms. SCD rates are estimated be-
tween 50 and 100 per 100,000 deaths in the general popula-
tion and 180,000–450,000 cases in the United States
annually ). The prominent underlying reason for SCD is
arrhythmia affecting the lower chambers of the heart, the
ventricles, which are responsible for pumping blood into
the circulatory system of the body and lungs. In most cases,
acquired structural heart disease, e.g., coronary artery dis-
ease or thickening of the heart muscle due to longstanding
untreated hypertension or heart valve dysfunction, predis-
poses for the development of ventricular arrhythmias
). However, ~5% of SCD cases are estimated to result
from inherited arrhythmias ). Additionally, in many cases
of an undiscovered cause of SCD, an inherited arrhythmia
may have been the predisposing factor.
Ion channels and cellular electrical activity
The underlying mechanisms for inherited arrhythmias were
comprehensively investigated in genetic and biophysical
studies. Many inherited arrhythmias have been found to
result from dysfunctional ion channels on the cardiac
Submitted September 17, 2015, and accepted for publication December 7,
2015.
*Correspondence:
Maura M. Zylla and Dierk Thomas contributed equally to this work.
2016 by the Biophysical Society
0006-3495/16/03/1017/6
1017