dc.description.abstracteng | The regular, coordinated contraction of the heart muscle is orchestrated by periodic
waves generated by the heart’s natural pacemaker and transmitted through the heart’s
electrical conduction system. Abnormalities occurring anywhere within the cardiac
electrical conduction system can disrupt the propagation of these waves. Such dis-
ruptions often lead to the development of high frequency spiral waves that override
normal pacemaker activity and compromise cardiac function. The occurrence of high
frequency spiral waves in the heart is associated with cardiac rhythm disorders such as
tachycardia and fibrillation. While tachycardia may be terminated by rapid periodic
stimulation known as anti-tachycardia pacing (ATP), life-threatening ventricular fibril-
lation requires a single high-voltage electric shock that resets all the activity and restore
the normal heart function. However, despite the high success rate of defibrillation, it
is associated with significant side effects including tissue damage, intense pain and
trauma. Thus, extensive research is conducted for developing low-energy alternatives
to conventional defibrillation. An example of such an alternative is the low-energy
anti-fibrillation pacing (LEAP). However, the clinical application of this technique,
and other evolving techniques requires a detailed understanding of the dynamics of
spiral waves that occur during arrhythmias. Optogenetics is a tool, that has recently gained popularity in the cardiac research,
which serves as a probe to study biological processes. It involves genetically modifying
cardiac muscle cells such that they become light sensitive, and then using light of
specific wavelengths to control the electrical activity of these cells. Cardiac optogenetics
opens up new ways of investigating the mechanisms underlying the onset, maintenance
and control of cardiac arrhythmias. In this thesis, I employ optogenetics as a tool to
control the dynamics of a spiral wave, in both computer simulations and in experiments.In the first study, I use optogenetics to investigate the mechanisms underlying de-
fibrillation. Analogous to the conventional single electric-shock, I apply a single
globally-illuminating light pulse to a two-dimensional cardiac tissue to study how wave
termination occurs during defibrillation. My studies show a characteristic transient
dynamics leading to the termination of the spiral wave at low light intensities, while at
high intensities, the spiral waves terminate immediately. Next, I move on to explore the use of optogenetics to study spiral wave termina-
tion via drift, theoretically well-known mechanism of arrhythmia termination in the context of electrical stimulation (e.g. ATP). I show that spiral wave drift can be
induced by structured illumination patterns using lights of low intensity, that result in
a spatial modulation of cardiac excitability. I observe that drift occurs in the positive
direction of light intensity gradient, where the spiral also rotates with a longer period.
I further show how modulation of the excitability in space can be used to control the
dynamics of a spiral wave, resulting in the termination of the wave by collision with
the domain boundary. Based on these observations, I propose a possible mechanism of
optogenetic defibrillation. In the next chapter, I use optogenetics to demonstrate control over the dynamics
of the spiral waves by periodic stimulation with light of different intensities and pacing
frequencies resulting in a temporal modulation of cardiac excitability. I demonstrate
how the temporal modulation of excitability leads to efficient termination of arrhythmia.
In addition, I use computer simulations to identify mechanisms responsible for arrhyth-
mia termination for sub- and supra-threshold light intensities. My numerical results are
supported by experimental studies on intact hearts, extracted from transgenic mice. Finally, I demonstrate that cardiac optogenetics not only allows control of excita-
tion waves, but also by generating new waves through the induction of wave breaks.
We demonstrate the effects of high sub-threshold illumination on the morphology of
the propagating wave, leading to the creation of new excitation windows in space that
can serve as potential sites for re-entry initiation. In summary, this thesis investigates several approaches to control arrhythmia dy-
namics using optogenetics. The experimental and numerical results demonstrate the
potential of feedback-induced resonant pacing as a low-energy method to control
arrhythmia. | de |