Ventricular repolarization duration and dispersion adaptation after atropine induced rapid heart rate increase in healthy adults

doi:10.1016/j.jelectrocard.2017.03.014

Journal of Electrocardiology

Volume 50, Issue 4, July–August 2017, Pages 424-432

https://doi.org/10.1016/j.jelectrocard.2017.03.014 Get rights and content

Highlights

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Ventricular repolarization (VR) adaption to rapid heart rate increase was assessed.
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A rapid heart rate increase was induced by an atropine bolus in healthy subjects.
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Continuous vectorcardiography provided VR duration & dispersion measures.
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The RR & QTend/QTpeak responses were single-exponential; QT/QTp ~5× slower than RR.
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VR dispersion responses were double-exponential and much faster than QT/QTp.

Abstract

Background

Proper adaptation of ventricular repolarization (VR) to rapid heart rate (HR) increase is crucial for cardiac electro-mechanical function. The pattern and temporal aspects of this adaptation and its components (duration and dispersion) during normal conduction are, however, incompletely known in humans and were the topic of this study.

Methods & results

The VR duration (QT & QTpeak) and dispersion (Tamplitude, Tarea & ventricular gradient; VG) responses were studied by continuous vectorcardiogram after a bolus injection of atropine 0.04 mg/kg b.w. in 31 healthy young adults (16 men). The primary measure (T90 End) was the time to reach 90% change from baseline to end value 300 s later.

Mean (SD) of T90 End was 23 (9) s for a 41% RR decrease, 130 (35) s for a 16% QTend decrease and 110 (36) s for a 19% QTpeak decrease; the response was single-exponential for these measures. For 35–43% decreases of Tamplitude, Tarea & VG, mean (SD) of T90 End were 21 (10), 38 (20) and 40 (23) s and the response pattern was double-exponential with varying overshoot.

Conclusions

VR duration and dispersion responses to a very rapid HR increase during normal conduction differed substantially. In contrast to the well-known single-exponential delay in VR duration adaptation the responses of VR dispersion measures were double-exponential and much more rapid. We describe a new and completely non-invasive phenotypic characterization of different components of VR adaptation.

Introduction

The duration of ventricular repolarization (VR) depends on the preceding diastolic interval, a phenomenon known as electrical restitution. Electrical restitution characteristically shows hysteresis, a delay which builds not only on one but on hundreds of preceding diastolic intervals, a phenomenon also referred to as ultra-rapid cardiac memory [1]. The physiologic advantage of hysteresis is a gradual change of the relation between systolic ejection and ventricular filling time and optimization of the time for coronary perfusion. Hysteresis also dampens fluctuations in VR duration and thereby reduces the risk for oscillations (alternans) that may predispose for life-threatening arrhythmias [2].

Knowledge about the physiology and pathophysiology of electrical restitution and its hysteresis therefore has both theoretical and clinical interest, and can create a foundation for how to assess and reduce the risk for life-threatening arrhythmias. Present knowledge of these phenomena is based on pacing studies, a method suitable for research but with limited applicability in clinical routine for practical and ethical reasons and with protocol dependent results [3].

Furthermore, although prolongation of VR duration is mechanistically linked to triggering of ventricular arrhythmia by a premature beat (due to early or late after depolarizations), the sustenance of such arrhythmias is presumably dependent on VR dispersion [4]. Adaptation of VR dispersion has been studied during ventricular pacing [5], [6], but neither its response during increasing HR and normal ventricular conduction, nor its relation to VR duration. Global VR dispersion can be evaluated non-invasively by vectorcardiography (VCG) measuring e.g. Tarea, the ventricular gradient (VG), and Tamplitude. The aim of this study was therefore to define the pattern and temporal aspects of the adaptation of VR duration and global VR dispersion during normal ventricular conduction in response to a rapid HR increase induced by a bolus injection of atropine in adult healthy subjects. Although a delay of the VR duration response would be expected from previous research, the VR dispersion response and its relation to that of duration would be important whatever the result.

Section snippets

Methods

This study is based on a de novo beat-to-beat analysis of the atropine part of the protocol of a prior study of the signal-averaged repolarization response to pharmacologically induced autonomic nervous system (ANS) modulation [7]. Restitution curves are created by plotting VR duration measures against the preceding diastolic interval. We focused, however, on defining the response pattern and within what time-frame measures of VR duration and dispersion adapt to a rapid decrease in RR intervals

Results

Thirty-one participants 20 to 36 years old received on average (SD) 2.85 (0.47) mg of atropine. There were no interfering extra-systoles.

Discussion

We defined in young healthy adults the time and response pattern for the adaptation of VR duration and dispersion measures during normal ventricular conduction following a rapid HR increase induced by atropine by applying beat-to-beat analysis of continuous VCG recordings. The main findings were: 1) Atropine induced a very rapid single-exponential RR decrease of 41% with T90 End on average 23 s without any sex difference and without any relation between the time and magnitude of change between

Conclusion

The adaptation of VR duration and dispersion measures to a very rapid HR increase induced by an atropine bolus injection differed both with regard to the response pattern and temporal aspects. The delay of the single-exponential VR duration adaptation was expected from many previous studies. In contrast to this response and as novel observations, there was no or only a small delay of VR dispersion adaptation which followed a double-exponential pattern with overshoot. The atropine test during

Sources of funding

This study was supported by the Sahlgrenska University Hospital and the Swedish Heart-Lung Foundation.

Disclosures

None.

Acknowledgements

The Scientific Reader platform used in the customized software development is the property of Ortivus AB, Danderyd, Sweden.

Glossary

ANS: Autonomic nervous system
APD: Action potential duration
Baseline: Time 0 = start of the heart rate reaction after atropine
Baseline value: The average value of the measured parameter during 90 s before time 0.
∆End: The change from the baseline value to the End value 300 s later
∆Max: Maximum change from the baseline value in the 0–300 s interval
End: Time point 300 s after time 0.
End value: The value of the measured parameter 300 s after time 0
HR: Heart rate
Overshoot: Difference between ∆Max and ∆End expressed in % of

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Adaptation of ventricular repolarization dispersion during heart rate increase in humans: A roller coaster process
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Citation Excerpt :
A similar response pattern in the interventricular gradient over 2 min was later shown in the human heart by Bueno-Orovio et al. using VP and comparing invasively recorded unipolar electrograms from one area each in the left and right ventricles [4,19]. In addition, two studies by our group using Frank VCG for data collection during normal conduction showed a double-exponential response pattern of global dispersion measures over 2.5–3 min [13,14]. In the study by Rosenbaum et al., the adaptation was accomplished after 5–10s (16 heart beats) while it took 1–2 min in humans [4,6,19].
Regional differences in ventricular activation sequence and action potential duration and morphology result in dispersion in ventricular repolarization (VR). VR dispersion is a key factor in arrhythmogenesis. We studied the adaptation of global VR dispersion in humans during normal and abnormal ventricular activation, and the relation to the QT adaptation (hysteresis).
We measured global VR dispersion as T amplitude, T area, and ventricular gradient (VG), using continuous Frank vectorcardiography, in response to abrupt and sustained atrial (AP) or ventricular pacing (VP) aiming at 120 bpm, in 21 subjects with permanent pacemakers.
Following pacing start, VR adaptation showed an initially rapid and complex tri-phasic pattern, most pronounced for T amplitude. There were major differences in the patterns of VR dispersion adaptation following abrupt AP vs VP, confirming that the adaptation pattern is activation dependent. In response to AP, an instantaneous decrease in VR dispersion occurred, followed by an increase and then a slow decrease, all at a lower level than baseline. In contrast, following VP there was an immediate increase to ~4× baseline in T amplitude and T area (but not in VG), with a subsequent biphasic adaptation lasting longer during VP than AP. The initial rapid changes occurred within the time for QT adaptation to reach steady-state.
Our results corroborate and expand data from animal and invasive human studies, showing similarities of the adaptation pattern on different scales. The initial rapidly changing VR adaptation phase presumably reflects a window of increased vulnerability to arrhythmias.
Spatial peak and mean QRS-T angles: A comparison of similar but different emerging risk factors for cardiac death
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These values were, however, not an exclusion criterion for being assigned as healthy and a new diagnosis of HT by repeated blood pressure measurement was not pursued as part of the SCAPIS protocol. A Frank VCG was recorded using the CoroNet II system (Ortivus AB, Danderyd, Sweden) and analyzed as described previously [13,34]. Fig. 1a shows the 8 electrode positions.
The spatial peak and mean QRS-T angles are scientifically but not clinically established risk factors for cardiovascular events including cardiac death. The study aims were to compare these angles, assess their association with hypertension (HT) and diabetes mellitus (DM), and explore the relation between the mean QRS-T angle and the ventricular gradient (VG; reflecting electrical heterogeneity), which both are derived from the QRSarea and Tarea vectors.
Altogether 1094 participants (aged 50–65 years, 550 women) from the pilot of the population-based Swedish CArdioPulmonary bioImage Study with Frank vectorcardiographic recordings were included and divided into 5 subgroups: apparently healthy n = 320; HT n = 311; DM n = 33; DM + HT n = 53; miscellaneous conditions n = 377. Abnormal peak and mean QRS-T angles were defined as >95th percentile.
Peak QRS-T angles were generally narrower than the mean QRS-T angles; both were narrower in women than in men. Abnormal peak (>124°) and/or mean (>119°) QRS-T angles were found in 73 participants (6.7%). The concordance regarding abnormal versus normal-borderline QRS-T angles was good (Cohen's kappa 0.61). The prevalence of abnormal angles varied from 2.5% in healthy to 21.2% in DM. There was an inverse logarithmical relation between the mean QRS-T angle and the VG.
The peak and mean QRS-T angles are not interchangeable but complementary. DM, HT, sex and absence of disease are important determinants of both QRS-T angles. The mean QRS-T angle and the VG relationship is complex. All three VCG derived measures reflect related but differing electrophysiological properties and have potential prognostic value vis-à-vis cardiovascular events.
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View full text

Ventricular repolarization duration and dispersion adaptation after atropine induced rapid heart rate increase in healthy adults

Highlights

Abstract

Background

Methods & results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Conclusion

Sources of funding

Disclosures

Acknowledgements

Glossary

Trends Cardiovasc Med

Biophys J

Prog Biophys Mol Biol

Heart Rhythm

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Heart Rhythm

Restitution of action potential duration during sequential changes in diastolic intervals shows multimodal behavior

Circ Res

In vivo human left-to-right ventricular differences in rate adaptation transiently increase pro-arrhythmic risk following rate acceleration

PLoS One

Slow adaptation of ventricular repolarization as a cause of arrhythmia?

Methods Inf Med