Mechanisms of ventricular rate adaptation as

a predictor of arrhythmic risk

Pueyo E, Husti Z, Hornyik T, Baczko I, Laguna P,

Varro A and Rodriguez B.
Am J Physiol Heart Circ Physiol
March 5, 2010
Introduction
Abrupt change in heart rate results in progressive
adaptation of the QT interval (QTI) because of short
term cardiac memory effects
Prolonged QTI adaptation to abrupt heart rate (HR)
changes is a clinical arrhythmic risk maker
The study investigated the ionic mechanisms of QTI
and APD rate adaptation
Utilized computer simulations and experimental
recordings in human and canine ventricular tissue
Methods
Computer modelling & simulation:
- Human and canine ventricular cell models
- QTI from pseudo-ECG was measured as the time
interval between the QRS complex onset and the T-
wave end
Methods
Characterization of HR adaptation dynamics
- Pacing at a cycle length (CL) of 1000ms until steady
state, CL changed to 600ms for 10 minutes and back to
a CL of 1000 ms for another 10 minutes
- Identified fast and slow phases of adaptation
- τfast and τslow characterize these phases
- QTI or APD adaptation is defined as protracted when
τslow is abnormally long
Methods
Evaluation of Proarrhythmic risk
Risk markers considered:
1. AP triangulation: δ = APD/ APD50 considered to be
an indicator of an early afterdepolarization (EAD)
occurrence
2. APD restitution curve slope
3. Calcium current reactivation, as the product ρ of the
inactivation gates of L-type calcium current
Methods
Experimental Methods
- Conducted in human ventricular tissue (n=2) and
canine (n=21)
- APD HR adaptation was evaluated using the same
protocol as in simulations
Results
QTI Adaptation

QTI adaptation begins with a fast QTI accomodation (τfast

= 17/34s), followed by a second slow accomodation (τslow
= 122/122s)
Results
APD Adaptation
Experimental

APD HR adaptation dynamics

are comparable with QTI HR
adaptation dynamics.
- Suggest that QTI adaptation is
a manifestation of cellular APD
adaptation
Results – Ionic mechanisms

The numbers
indicate the
number of beats
following the CL
change
Results – Ionic mechanisms
Results – Fast phase of adaptation
- ICaL and IKs experience greatest percentage of total
change and are key mechanisms driving the fast
phase
Results – Fast phase of adaptation
Results – Fast phase of adaptation
Results – Slow phase of adaptation
- [Na+], [Ca+], INaK , INaCa and several potassium
currents experience important changes
Results – Slow phase of adaptation

-This suggests that sodium dynamics determine the

slow phase of adaptation
- Changes to potassium currents are secondary to
APD alterations caused by sodium regulation
Results – Slow phase of adaptation
Results – HR Adaptation and Arrhythmic Risk
 Results – HR Adaptation and Arrhythmic Risk
-Despite the enhancement of AP triangulation with large τfast
values, no afterdepolarizations were observed for 60%
change in τf, τxs, ICaL conductance, and Iks conductance
- INaK inhibition results in an increased likelihood of EAD
generation
- INaK inhibition by 60% following HR deceleration results in
EADs (both in models and experiments)
Conclusions
Both QTI and APD HR adaptation follow similar
dynamics, consisting of two phases, driven by ICaL and
IKs kinetics and conductances, and [Na+] dynamics and
INaK
Protracted QTI rate adaptation could be a reflection of
adverse ionic changes that may facilitate arrhythmia
initiation via an increased likelihood of EAD
generation
INaK inhibition, as it occurs in ischemia and heart
failure patients, results in slower [Na+] dynamics and
delayed APD accommodation
Conclusions
Delayed APD adaptation could be caused by an
increase in τfast or in τslow
Conditions associated with flat restitution slopes allow
wave break and could favor reentrant wave stability.
Large τslow due to INaK inhibition increases AP
triangulation and the likelihood of ICaL reactivation,
increasing the risk of EAD formation
Large τslow values are also associated with flat APDR
slopes, which could favor the stability of reentrant
circuits
Limitations
Limited set of experiments in humans was performed
Differences exist in IK1 and Iks in canine vs human
ventricular tissue, which would lead to differences in
ventricular rate adaptation
The human model does not include a description of the
late sodium current
The IKs conductance was defined based on APD
measurements, which could explain a larger
contribution of IKs in simulations compared with
experiments