Mechanisms of Ventricular Rate Adaptation

8/9/2019 Mechanisms of Ventricular Rate Adaptation

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Pueyo E, Husti Z, HornyikT, Baczko I, Laguna P, Varro Aand Rodriguez B.

Am J Physiol Heart Circ Physiol

March 5, 2010

Mechanisms of ventricular rate

adaptation as a predictor of arrhythmic

risk


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Introduction

y Abrupt change in heart rate results in progressive adaptation

of the QT interval (QTI) because of short term cardiac

memory effects

y

Prolonged QTI adaptation to abrupt heart rate (HR) changesis a clinical arrhythmic risk maker

y The study investigated the ionic mechanisms of QTI and APD

rate adaptation

yUtilized computer simulations and experimental recordingsin human and canine ventricular tissue


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Methods

y 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


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Methods

y 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

- fast and slow characterize these phases

- QTI or APD adaptation is defined as protracted when slow

is abnormally long


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Methods

y Evaluation of Proarrhythmic risk

Risk markers considered:

1. AP triangulation: = APD/ APD50 considered to be an

indicator of an early afterdepolarization (EAD) occurrence2. APD restitution curve slope

3. Calcium current reactivation, as the product of the

inactivation gates of L-type calcium current


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Methods

y Experimental Methods

- Conducted in human ventricular tissue (n=2) and canine

(n=21)

- APD HR adaptation was evaluated using the same protocolas in simulations


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Results

y QTI Adaptation

QTI adaptation begins with a fast QTI accomodation (fast =17/34s), followed by a second slow accomodation (slow =

122/122s)


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Results

y APD AdaptationExperimental

APD HR adaptation dynamics are

comparable with QTI HRadaptation dynamics.

- Suggest that QTI adaptation is a

manifestation of cellular APD

adaptation


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Results Ionic mechanisms

The numbers

indicate the number

of beats following

the CL change


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Results Ionic mechanisms


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Results Fast phase of adaptation

- ICaL and IKs experience greatest percentage of total

change and are key mechanisms driving the fast phase


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Results Slow phase of adaptation

- [Na+], [Ca+], INaK , INaCa and several potassium currents

experience important changes


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-This suggests that sodium dynamics determine the slow

phase of adaptation

- Changes to potassium currents are secondary to APDalterations caused by sodium regulation


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Results HR Adaptation and Arrhythmic Risk


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Results HR Adaptation and Arrhythmic Risk

-Despite the enhancement of AP triangulation with large fast values,

no afterdepolarizations were observed for 60% change in f, xs,

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)


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Conclusions

y 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

y

Protracted QTI rate adaptation could be a reflection ofadverse ionic changes that may facilitate arrhythmia initiation

via an increased likelihood of EAD generation

y INaK inhibition, as it occurs in ischemia and heart failure

patients, results in slower [Na+] dynamics and delayed APD

accommodation


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Conclusions

y Delayed APD adaptation could be caused by an increase in

fast or in slowy Conditions associated with flat restitution slopes allow wave

break and could favor reentrant wave stability.y Large slow due to INaK inhibition increases AP triangulation

and the likelihood of ICaL reactivation, increasing the risk of

EAD formation

y

Large slow values are also associated with flat APDR slopes,which could favor the stability of reentrant circuits


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Limitations

y Limited set of experiments in humans was performed

y Differences exist in IK1 and Iks in canine vs human ventricular

tissue, which would lead to differences in ventricular rate

adaptationy The human model does not include a description of the late

sodium current

y The IKs conductance was defined based on APD

measurements, which could explain a larger contribution ofIKs in simulations compared with experiments

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Mechanisms of Ventricular Rate Adaptation