Heterogeneity of Activation Recovery Interval and Restitution in Non-Ischemic Cardiomyopathy and its relation to Ventricular Arrhythmias

Ventricular arrhythmias (VA) are a common cause of sudden cardiac death[1].
However, different substrates and mechanisms may operate in the heterogeneous
group of non-ischemic cardiomyopathy (NICM) patients with VA. Previously focus
has been placed on the role of depolarization abnormalities and anisotropic
conduction resulting in conduction delay and unidirectional conduction block.
These are the preconditions for fixed re-entry often observed in patients with
ventricular scar and monomorphic ventricular tachycardia. However, in patients
with NICM, polymorphic, pleomorphic VT and ventricular fibrillation is often
observed, likely due to a different mechanism. There is little data on the
potential role of heterogeneity in repolarization, which may play an important
role in the arrhythmogenesis in NICM VA.

Activation Recovery Intervals (ARI) are considered reliable surrogates for
Action Potential Duration (APD) and as such provide insight into repolarization
duration.[2] [3] Small studies have shown that apico-basal heterogeneity in ARI
exists in patients at higher risk for VA [4] and this heterogeneity may play a
role in sympathetic induced arrhythmias as demonstrated in an animal model [5].
However, the majority of the few included patients had prior myocardial
infarction with compact scars, suggesting that induced VTs are likely due to
slow conduction and scar related re-entry. In addition, for evaluation of
epicardial ARIs the venous system has been used, restricting measurements to
limited epicardial sites such that an evaluation of endocardial/epicardial
3-dimesional heterogeneity could not be performed. Finally, normal values
obtained in patients without structural heart disease are sparse. We propose
that a certain amount of apico-basal heterogeneity is to be expected but that 3
dimensional analysis of the variation in ARI is necessary to determine its role
in the arrhythmogenesis of NICM VA.

Action Potential Duration Restitution (APDR) relates an APD to its proceeding
diastolic interval (DI). Research has suggested that steep APDR curves promote
wave breaks and fibrillation [6, 7]. Cut-off valves of Restitution curves
necessary for VF have been proposed, [8] and these values are supported by
current clinical research[9, 10], but these values have never been validated in
humans with NICM. We hypothesise that it is not the value of APDR but rather
the heterogeneity of this parameter that indicates arrhythmogenicity.

Understanding of ARI and APDR heterogeneity in NICM patients will provide
insights into the substrate and potential mechanisms of VA. Knowledge of the
mechanism is mandatory for treatment and risk stratification. The proposed
method of data acquisition using standard catheter techniques may have
important clinical and practical implications.

References:
1. Bayes de Luna, A., P. Coumel, and J.F. Leclercq, Ambulatory sudden cardiac
death: mechanisms of production of fatal arrhythmia on the basis of data from
157 cases. Am Heart J, 1989. 117(1): p. 151-9.
2. Coronel, R., et al., Monophasic action potentials and activation recovery
intervals as measures of ventricular action potential duration: experimental
evidence to resolve some controversies. Heart Rhythm, 2006. 3(9): p. 1043-50.
3. Haws, C.W. and R.L. Lux, Correlation between in vivo transmembrane action
potential durations and activation-recovery intervals from electrograms.
Effects of interventions that alter repolarization time. Circulation, 1990.
81(1): p. 281-8.
4. Chauhan, V.S., et al., Increased ventricular repolarization heterogeneity in
patients with ventricular arrhythmia vulnerability and cardiomyopathy: a human
in vivo study. Am J Physiol Heart Circ Physiol, 2006. 290(1): p. H79-86.
5. Ajijola, O.A., et al., Functional differences between junctional and
extrajunctional adrenergic receptor activation in mammalian ventricle. Am J
Physiol Heart Circ Physiol, 2013. 304(4): p. H579-88.
6. Taggart, P., et al., Effect of adrenergic stimulation on action potential
duration restitution in humans. Circulation, 2003. 107(2): p. 285-9.
7. Ng, G.A., et al., Sympathetic nerve stimulation produces spatial
heterogeneities of action potential restitution. Heart Rhythm, 2009. 6(5): p.
696-706.
8. Weiss, J.N., et al., Chaos and the transition to ventricular fibrillation: a
new approach to antiarrhythmic drug evaluation. Circulation, 1999. 99(21): p.
2819-26.
9. Garfinkel, A., et al., Preventing ventricular fibrillation by flattening
cardiac restitution. Proc Natl Acad Sci U S A, 2000. 97(11): p. 6061-6.
10. Hayashi, M., et al., Ventricular repolarization restitution properties in
patients exhibiting type 1 Brugada electrocardiogram with and without inducible
ventricular fibrillation. J Am Coll Cardiol, 2008. 51(12): p. 1162-8.

Primary Objectives:
1. To assess the values of ARI and APDR in NICM patients.
2. To assess the three-dimensional heterogeneity of ARI and APDR in NICM
patients.
3. To compare 1. and 2. with the same data collected from non-NICM patients.
4. To correlate inducibility, type and occurrence of spontaneous VA with
findings in 1. and 2.

Secondary Objective:
1. To compare findings from Primary Objectives 1. and 2. with ECG parameter
(depolarisation, repolarisation), electrophysiology parameters obtained during
routine Electrophysiology study (Ventricular Refractory Period) and mapping
(total activation time, local conduction delay, unipolar voltage)

This will be a single-center prospective observational case-control study.

Risk
In all patients, the electrophysiological study and mapping procedure will be
clinically indicated and scheduled before inclusion in the study. The technique
will be performed according to current standards. The only change introduced by
this protocol will be a slightly longer procedure time. During procedures *down
time* regularly exists: time in which mapping data is reviewed, before ablation
is performed. As much as possible the data collection for this protocol will be
conducted in this *down time* and as such will not add additional procedural
time. If it is not possible to collect data during *down time* the procedure
will be lengthened by a maximum of 35 minutes.
Benefit
Patients in the case group may not directly benefit from participating in this
study. However, insights in potential VA mechanism not approachable by catheter
techniques may help to select other treatment strategies like antiarrhythmic
drugs. This study is likely to provide new insights that improve therapy for VA
which may be applied to study participants in the future.
Patients in the control group may benefit from participating in this study if
previously unrecognized arrhythmic pathologies are discovered during the
procedure.

Future patients
Future patients with NICM will probably benefit most from this study. This
study may
improve our understanding of the substrate and mechanism of VA in NICM
patients, so that more effective, individualized and substrate-based treatments
of VA can be applied and further developed. Such a treatment may significantly
reduce morbidity and mortality of VA in NICM patients. Furthermore, this study
may improve risk stratification for VA in NICM. This may allow more efficient
allocation of preventative therapies (e.g. ICD implantation). Although NICM
patients are the group of interest in this proposal/research protocol, the
proposal may be applicable to larger groups of patients suffering from various
diseases leading to cardiac arrhythmias.