| Summary: | <p><b>Background:</b>
Arrhythmogenic Cardiomyopathy (ACM) is a potentially
lethal form of cardiomyopathy, with a high incidence of mortality.
It is prominently characterised by abnormal ventricular anatomy, Fbrofatty
replacement of the myocardium and the His-Purkinje system, as well as
electrophysiological remodelling. It remains unknown how the broad spectrum of ACM-related co-morbidities alter the 12 lead electrogram (ECG).
Ventricular activation abnormalities result in QRS complex and terminal
activation duration prologation, as well as abnormal R-wave progression
and low amplitude signals are diagnosis criteria of ACM on the 12-lead
ECG. The pathological remodelling leading to the above electrocardiographic findings can be of electrical, geometrical or structural nature or
a combination of substrates. Diagnosis of this clinical entity is challenging and relies on a combination of ECG, non-invasive imaging approaches
to access myocardial muscle structrure and geometry as well as genetic
testing.
Despite the multi-modality diagnosis approach, misdiagnosis is
common and some patients are not diagnosed until post-mortem examination is performed. Improvements in diagnosis are much needed and one
challenge is understanding the link between ECG manifestations and underlying disease burden. Furthermore, no ACM specific treatments exist
to date and life quality of sufferers is greatly reduced as cardiac defibrillators and guidelines to avoid physical activity are the treament norm.
Obtaining an accurate diagnosis non-invasively can contribute to better
risk stratification and patient management, ultimately improving the life
quality and safety of patients.</p>
<p>
<b>Aims:</b>
It is known that several mechanisms can lead to slow electrical conduction in the ventricles of ACM patients.
Plausible single cell
electrophysiological mechanisms, such as co-modulation of
I<sub>Na</sub> - I <sub>K1</sub>
ionic
channels, leading to tissue level electrical conduction velocity modulation
in ACM are explored. This thesis aims to uncover which mechanisms of conduction slowing prevail in patients with ACM by integrating information from imaging data and performing personalised activation sequence
simulations of patients diagnosed with ACM. The scope is to also relate
the different conduction abnormalities to signature traits on the ECG, so
as to help refine diagnosis and disease burden non-invasively.</p>
<p><b>Methods:</b>
The effect of ACM specific ionic channel joint reduction of
conduction is explored via a study relating co-modulation in key ionic
channels ( I<sub>Na</sub> - I<sub>K1</sub> ), known to be remodelled in ACM variants and
the tissue level electrical conduction velocity in 2D tissue simulations.
Personalised models of electrical conduction are created from Magnetic
Resonance Imaging (MRI) data of a cohort of ACM patients with 15
definite, 3 borderline and 2 plausible patients according to the 2010 international diagnosis guidelines. Patient ventricular and torso anatomies
are extracted from the MRI images and regional fibrotic scar information is extracted from contrast agent enhanced MRI imaging. Different
types of remodelling were introduced into graph-based models of sinus
rhythm activation, namely localised fibrosis-mediated conduction slowing
in the myocardial muscle or in the Purkinje-myocardial fast conduction
system, myocardial tissue uncoupling leading to global ventricular tissue
conduction slowing, right ventricular (RV) muscle disappearance leading
to slowed conduction localised in the RV, RV muscle volume dilation and
RV wall thinning. Insights from slab tissue simulations were used to estimate the order of magnitude of conduction velocity modulation due to
ionic remodelling, clinical data (contrast enhanced MRI) for scar based
conduction anomalies and from other computational studies quantifying
conduction velocity modulation in the ACM myocardium were used to
find physiological parameter intervals for the computational study. The
effects of the above types of remodelling on features of the ECG relating
to activation dynamics were quantified.</p>
<p><b>Results:</b>
Slab tissue simulations revealed that ACM-specific ionic remodelling of the
I<sub>Na</sub> - I<sub>K1</sub>
macromolecular complex can result in up to
45% bulk myocardial tissue CV modulation.
A computational pipeline
was adapted to access the effect of ACM ventricular substrates on conduction properties of the ventricles. The personalised data-driven models
of two ACM patients with varying disease burden were used to successfully explain how the underlying whole ventricular remodelling impacted
6the clinical patients' ECG recordings. Computer simulations demonstrate
that, in ACM, mild QRS prolongation (>100 ms), in absence of other QRS
abnormalities, is explained by regional myocardial conduction slowing in
the areas of MRI-identified fibrosis.
However, MRI-segmented myocardial fibrosis and RV dilation alone proved insufficient to recapitulate more
severe QRS abnormalities, such as severely prolonged mean QRS duration (>120 ms) across precordial leads, mean terminal activation dura-
tion across V1-V4 (>55 ms), and low QRS mean R-wave amplitude (<2
mV) in precordial leads, as well as poor R-wave progression across precordial leads. A 70% decrease in Purkinje-endocardial conduction and 30%
RV wall thinning were additionally required to explain these more severe
abnormalities.</p>
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