BASIC SCIENCE

Europace (2014) 16, 1092–1098 doi:10.1093/europace/eut357

Induced and spontaneous heart rate turbulence in mice: influence of coupling interval Florian Sto¨ckigt*, Sonja Po¨hlmann, Georg Nickenig, Jo¨rg Otto Schwab†, and Jan Wilko Schrickel† Department of Medicine—Cardiology, University Hospital Bonn, Sigmund Freud Str. 25, 53127Bonn, Germany Received 31 July 2013; accepted after revision 21 October 2013; online publish-ahead-of-print 26 March 2014

Aims

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Heart rate turbulence † Mice † Baroreflex † Electrophysiological investigation † Long-term ECG recording

Introduction Baroreflex-mediated short-term fluctuations in sinus cycle length (CL) occur physiologically after ventricular premature complexes (VPCs) and are termed heart rate turbulence (HRT). Schmidt et al. 1 established two relevant parameters to define HRT: turbulence onset (TO, the early acceleration in heart rate immediately following the VPC) and turbulence slope (TS, amount of late deceleration in heart rate). Pathological values for HRT, i.e. a TO . 0% and a TS , 2.5 ms/RR-interval, have been demonstrated to be a strong independent prognostic parameter in cardiac risk stratification in patients suffering from coronary artery disease in several retrospective as well as prospective studies.2 By default, HRT is measured during long-term electrocardiogram (ECG) recordings after spontaneous VPCs. As the HRT pattern is frequently masked by heart rate variability, signal averaging is applied to the responses to several VPCs.3 Additionally, HRT can also be

determined in the setting of electrophysiological (EP) investigations, using ventricular extrastimulus (VES) pacing.4,5 Increasing basic heart rate as well as increasing age have negative influences on HRT in the human heart.6 Divergent data exist concerning the influence of the coupling interval of an extrastimulus on TO. In an EP investigation with 25 patients, a significant positive correlation was found between the prematurity of the delivered extrastimulus and TO5 whereas in another study with 28 patients a relationship was observed only individually but not in the pooled population.7 The aim of this study was to establish HRT as a new non-invasive indirect measurement for baroreflex sensitivity in mice, both spontaneous and induced, as it has been validated only in humans before. Mouse models play an important role in the investigation of EP disorders associated with pathological structural or molecular alterations of the heart. Murine models provide various advantages: ease of breeding, ease of genetic manipulation, and ability to study sufficient individuals in a reasonable time frame.

* Corresponding author. Tel: +49 228 28715507; fax: +49 228 28712329, E-mail: [email protected]

Both senior authors equally contributed to this work.

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].

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Heart rate turbulence (HRT) is a prognostic parameter for risk stratification in patients suffering from coronary artery disease. The aims of this study were to demonstrate the feasibility of quantifying HRT in mice, both in long-term electrocardiograms (ECGs) as well as after extrastimulus pacing, and to analyse its characteristics. ..................................................................................................................................................................................... Methods We performed long-term ECG recordings using implanted telemetric chips and electrophysiological (EP) investigations, and results using transvenously inserted EP catheters, in healthy mice. Heart rate turbulence was calculated using the established turbulence onset (TO) and slope (TS) algorithm. After spontaneous ventricular premature complexes (VPCs), we found a negative TO (22.2 + 7.5%) and positive TS (15.5 + 18.3 ms/RR interval). Electrophysiological investigations revealed positive values for TO (0.6 + 1.1%) and TS (6.5 + 2.9 ms/RR interval) after extrastimulus pacing maneuvers. The shortening of the extrastimuli coupling intervals delivered during EP investigations significantly influenced TO (r ¼ 0.57; P ¼ 0.01): shorter coupling intervals provoked more positive TO values. ..................................................................................................................................................................................... Conclusion Mice display both spontaneous and induced HRT. In terms of TO, VPCs generated by extrastimulus pacing are significantly dependent on the coupling interval. Determining HRT in mice is feasible and provides insight into basic mechanisms of blood pressure regulation, which is realized by the baroreflex.

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What’s new? † Determining heart rate turbulence in mouse models is feasible both in telemetry recordings and after extrastimulus pacing. † The parameter of turbulence onset generated by extrastimulus pacing is dependent on the coupling interval of the induced extrasystole. † The evaluation of heart rate turbulence in murine models facilitates the measurement of baroreflex sensitivity in genetically or structurally altered animals non-invasively.

A literature search yielded only few studies that have evaluated HRT parameters in mice8,9—but no data on general standard values for TO or TS in healthy wild-type mice exist until now. It remains unclear whether the pre-existing cut-off values validated in humans can be transferred in a 1 : 1 manner into the mouse model. Although it has been shown that mice exhibit typical baroreflex reactions,10 it has not been evaluated systematically whether these animals, which present with spontaneous heart rates of up to 700 b.p.m., respond to VPCs with relevant compensatory pauses to initiate the specific pattern of HRT at all.

Laboratory animals The studies were performed in 31 adult wild-type C57/bl6 mice. The investigations were approved by the National Office for Nature, Environment and Consumer Protection in Recklinghausen, NordrheinWestfalen, Germany (Permit Number: 50.203.2-BN 22, 22-4 and 8.87-50.10.37.09.272) and the handling of all animals was conducted in conformity with the animal protection law stated in the German civil code and the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985). The mice had free access to water and standard laboratory chow diet and were kept at a natural light/ dark cycle at 20 –228C.

Long-term electrocardiogram recording Heart rate turbulence was measured from ECGs recorded by telemetry devices (model EA-F20; DataSciences International) that were implanted subcutaneously in 10 mice. Surgery was performed under inhalation anaesthesia (induction period 2.5 vol.%, maintenance 1.2 vol.% isoflurane in 70% N2O/30% O2) and intraperitoneally applied anaesthesia with ketamine hydrochloride (0.033 mg/g). The implantable 3.5 g wireless radiofrequency transmitter was inserted into a subcutaneous tissue pocket after performing a midline incision on the back along the spine. The leads were subcutaneously directed ventrally and fixed to the pectoral muscles in an Einthoven II position. Afterwards, skin incisions were sutured. Ten days after recovery from surgical instrumentation, recordings were made in the conscious state between 8:00 AM and 4:00 PM for 8 h in a constant environment. Electrocardiogram signals were recorded with the use of a telemetry receiver (PhysioTel Receiver RPC-1; DataSciences International) and digitized with 12 bits precision at a sampling rate of 1 kHz (AD Instruments, Powerlab 8/30).

Electrophysiological investigation The in vivo transvenous EP investigations were performed in 21 mice, using a single catheter technique as described before.11,12 A surface 6 lead ECG was monitored continuously and analysed under stable conditions. All data were amplified, filtered, sampled at 2 kHz, and digitally stored (LabSystem, C.R. Bard Inc.). All EP procedures were performed under inhalation anaesthesia (induction period 2.5 vol.%, maintenance 1.2 vol.% isoflurane in 70% N2O/30% O2). The jugular vein was dissected and a 2-French octapolar mouse EP catheter [eight 0.5 mm circular electrodes; electrode-pair spacing 0.5 mm (Ciber Mouse, NuMed Inc.)] was positioned in the right cardiac cavities on atrial and ventricular level. Intracardiac electrograms and transvenous ventricular stimulation manoeuvres were registered and recorded as previously described.11,12 Right ventricular premature pacing was performed using a modified multi-programmable stimulator (Model 5328; Medtronic). Single extrastimuli were given 10 times with a delay of 6000 ms between each stimulus. The Schmidt et al. 1 criteria were used to determine whether or not the extrastimulus was included in the analysis.

Analysis of heart rate turbulence parameters In the long-term ECG recordings, 3 R-R intervals before and up to 21 intervals after each PVC were analysed to calculate the sinus CL (mean of R23R22 and R22R21), the coupling interval of the PVC, the compensatory pause (first R-R after the PVC) and TO as well as TS as previously described.3 In summary, TO was defined as the quotient of [(RR1 + RR2) 2 (RR22 + RR21)] and (RR22 + RR21) multiplied by 100 (%). Turbulence slope was defined as the maximum positive regression slope assessed over any 5 consecutive sinus rhythm R-R intervals within the first 15 sinus rhythm R-R intervals after the VPC. Because normal values for TO (,0%) and TS (.2.5 ms/R-R interval) have been defined for humans whose normal heart rate is approximately 75 b.p.m., the CLs in this study were additionally normalized to 800 ms (75 b.p.m.) for the comparison of values of a heart rate corrected TS (TSC). The normalization was performed by multiplying each CL by the quotient of 800 and the mean sinus CL. Since TO values are uninfluenced of this calculation, it was only applied to TS. A supplementary parameter that was calculated was TS(3)—the maximum positive regression slope assessed over any three consecutive sinus rhythm R-R intervals. This was done to rule out a potentially faster proceeding late deceleration in mice that might have been missed with a calculated slope over 5 beats. Moreover, we calculated TO with consideration of the first three R-R intervals after the compensatory pause rather than just two, in order to detect a possible later onset of heart rate acceleration in mice according to the formula TO3 ¼ [((RR1 + RR2 + RR3) 2 (RR23 + RR22 + RR21))/ (RR23 + RR22 + RR21)] × 100 (%). The evaluation of HRT parameters after stimulated extrasystoles in the EP investigations was performed analogously to the measurement described in the long-term ECG recordings.

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Materials and methods

LabChart 7pro (v7.3.3, AD Instruments) was used for a manually performed beat to beat interpretation to detect spontaneous VPCs.

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Statistical analysis Data are shown as mean + standard deviation and calculated using Prism 5.03 (GraphPad Software Inc.). Differences between the two groups were assessed using a two-tailed Student’s t-test. Linear regression models were performed to assess the relationships of HRT parameters. A P value of ,0.05 was regarded as statistically significant.

Results Heart rate turbulence after spontaneous ventricular premature complexes Healthy mice have a generally low incidence in spontaneous VPCs. Two mice had no VPCs in their recordings. Figure 1A demonstrates

(A)

the tachograms of all eight animals with spontaneous VPCs (n ¼ 2.0 + 1.4 VPCs per animal). The baseline characteristics of these eight animals are listed in Table 1. At a mean sinus CL of 99.9 + 13.9 ms, the mice exhibited VPCs with a coupling interval ranging from 61 to 90 ms corresponding to a prematurity of 63.3 –76.8%. These were followed by significant compensatory pauses with post VPC intervals of at least 20% longer than the preceding intervals. The mean TO was 22.9 + 4.8% (range of 211.7 to 2.7%) indicating an early acceleration in heart rate (Figure 2A). Similarly, an acceleration in heart rate could be demonstrated, when considering the first three R-R intervals after the extrasystole to calculate TO(3). A late deceleration could be detected in all mice with a maximum CL between the 8th and the 15th R-R interval following the VPC. After correction for heart rate, six of eight mice showed TS(C) values .2.5 ms/R-R interval (Figure 2B). When shortening the

Tachograms by telemetry ECG 140 Mouse no. 1 Mouse no. 2 Early acceleration

Mouse no. 4 Mouse no. 5 Mouse no. 6

100

Mouse no. 7 Mouse no. 8 Mean

80

Late deceleration 0

5

10 15 # of RR interval

20

25

Tachograms by extrastimulus pacing

(B)

SCL 120ms Early acceleration

150

SCL 90ms

Cycle length (ms)

SCL 120ms SCL 100ms 140

SCL 90ms Mean

130

Late deceleration

120 0

5

10 15 # of RR interval

20

25

Figure 1 Tachograms of heart rate turbulence. (A) Tachograms recorded by telemetry ECG. Displayed are the tachograms of the eight mice whose heart rate turbulence following spontaneous VPCs were evaluated. Marked in black is the mean value of all animals. The first dip in CL indicates the VPC, the first rise in CL the compensatory pause. (B) Tachogram induced by extrastimulus pacing. Shown are five tachograms (thin lines) and the averaged tachogram (thick line) of one mouse that demonstrated early acceleration (TO ¼ 21.5%) of heart rate following extrastimuli with a mean coupling interval of 104 ms (79.9% of baseline sinus CL 136 ms). The first dip in CL indicates the extrastimulus, the first prolongation the compensatory pause. Clearly visible is the early acceleration that is followed by a late deceleration (TS(C) ¼ 12.7 ms/R-R interval). SCL, stimulus cycle length.

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Cycle length (ms)

Mouse no. 3 120

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Table 1 Baseline ECG parametes, TO and TS Telemetry ECG (n 5 8)a

EPI (n 5 21)b

................................................................................ Sinus cycle length (ms)

99.9 + 13.9

129.6 + 13.6*

P (ms)

12.2 + 3.0

13.1 + 3.3

PQ (ms) QRS (ms)

36.2 + 2.0 10.5 + 0.6

39.4 + 4.6 11.7 + 1.8

QTc (ms)

22.3 + 2.0

26.7 + 7.4

Coupling interval (CI) (ms) Prematurity of CI (%)

70.4 + 9.8 70.6 + 5.1

77.5 + 14.9 60.2 + 12.1*

Compensatory pause (ms)

129.3 + 22.9

181.9 + 28.3*

Turbulence onset TO (%) TO3 (%)c Turbulence slope (TS) TS (ms/RR)d

22.9 + 4.8

0.4 + 0.9*

23.6 + 5.3

0.3 + 0.8*

1.4 + 1.3

1.0 + 0.4

TS(C) (ms/RR)e

8.9 + 9.9

2.9 + 1.4*

TS(3) (ms/RR)f

13.5 + 11.4

6.2 + 3.3*

a

registration interval for the slope to TS(3), seven of eight mice exhibited values .2.5 ms/R-R interval.

Heart rate turbulence after extrastimulus pacing The mean sinus CL of the 21 mice who underwent in vivo EP studies was significantly longer (by 29 ms, P , 0.05) compared with the 8 mice that received telemetry devices as a result of the anaesthetic. The mean coupling interval of the extrastimuli was 8.8 ms longer than the coupling interval of spontaneous VPCs to preceding sinus beats in the telemetry mice, but without significance (P . 0.05). The overall TO was calculated to 0.4 + 0.9% (range 21.5 to 2.3%), which implied a slight deceleration in heart rate after induced VPCs. In detail, six mice showed a clear early acceleration with TO , 0% (Figure 1B), four mice exhibited a deceleration of .1%, and the remaining 11 presented TO values between 0 and 1% (Figure 2A). When calculating TO over the first three post-stimuli R-R intervals (TO3), values were similar to TO. Turbulence slope (TS) presented a late deceleration after all extrastimuli but with a weaker expression as compared with the values after spontaneous VPCs (Table 1). The maximum of the late deceleration was between the 5th and the 14th R-R interval following the extrastimulus. After adjusting for heart rate, a significant increase in TS(C) relative to TS was observed (2.9 + 1.4 vs. 1.0 + 0.4 ms/R-R interval; P , 0.001) (Figure 2B). The calculation for TS(3) revealed a further significant increase compared with TS(C) (11.2 + 6.4 ms/ R-R interval; P , 0.001).

When compared with the standard values of humans in previous studies,1 most data gained by EP investigations regarding TO in mice were found to be in the ‘pathological’ range (Figure 2C). Yet, a significant positive correlation was found between the prematurity of the extrastimulus and TO after VES pacing, indicating more negative values for TO with longer coupling intervals (Figure 3A). The range of the applied coupling interval accounted for 56 –105 ms, representing 40.8–80.0% prematurity, respectively. Regression analysis revealed negative values for TO with an early acceleration up to a mean prematurity of 68.9%; a further increase of prematurity (or shortening of the coupling interval) resulted in positive values. The prematurity of spontaneous occurring VPCs during the long-term ECG recordings were significantly longer than the mean coupling intervals of induced VPCs during the EP study (70.6 + 5.1% vs. 60.2 + 12.1%; P ¼ 0.026), and did not influence TO characteristics (Figure 3B). Owing to the different sinus CLs in both groups, we calculated the influence of the preceding sinus CL on the coupling interval of the extrasystoles (spontaneous and induced) as well as on TO. We found a positive correlation between the sinus CL and the coupling interval (r ¼ 0.37; P ¼ 0.046), even though very weak, but not between sinus CL and TO (Figure 3C and D). The linear regressions of sinus CL, coupling interval, compensatory pause, and TO on TS showed consistently low correlation coefficients without statistically significant differences.

Discussion Our study demonstrated the feasibility of HRT measurement in mice. We found that the HRT parameter TO inversely correlated with the prematurity of the extrasystole. Heart rate turbulence is triggered by a transient loss of vagal efferent activity in response to the missed baroreflex afferent input caused by VPC-induced hemodynamically inefficient ventricular contractions.13 Several methods have been described to assess baroreceptor function in humans including neck suction,14 Valsalva’s maneuver15 and vasoactive drugs.16,17 In rodent models the most common procedures are vasoactive drug infusion,18,19 or the sequence technique,20 which was initially described by Bertinieri et al. 21 However, both methods are dependent on invasive blood pressure measurement by cannulating the carotid or femoral artery and have to be considered as terminal investigations due to their invasiveness. Determining barorecepor sensitivity with HRT measurement allows non-invasive measurements by long-term ECG recordings, with the animal surviving and allowing further in vivo investigations. Moreover, this method comprises the unambiguous advantages of independency from vasoactive drugs, the non-invasiveness, and the possibility to perform the investigations without narcotics compared with the established invasive procedures. When determining HRT during an EP study, advantages rest in the immediate comparability to standard EP parameters, i.e. refractory periods or inducibility of arrhythmias. Elevated heart rates are associated with a reduced HRT.22 However, the very high heart rates in mice are per se no reason for a possible reduced HRT, as heart rate and HRT both share the

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Data derived from long-time ECG recordings. Data derived from electrophysiological investigations by extrastimulus pacing. c TO assessed with consideration of the first three post-extrasystole RR-intervals. d TS over five consecutive R-R intervals without correction for heart rate. e TS over five consecutive R-R intervals after heart rate correction to 800 ms. f TS over three consecutive R-R intervals after heart rate correction to 800 ms. Values are mean + standard deviation. *P , 0.05 between groups. b

Correlations of individual heart rate turbulence parameters

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P = 0.005

(A) 10

(C) 30

TS(c) (ms/RR)

5

TO (%)

0 –5

20

10

–10 2.5 0

–15 Telemetry ECG

EPI

–10

–5 TO (%)

0

P = 0.008

(B) 30

TS(c) (ms/RR)

Telemetry ECG EPI 20

Normal TO and TS Pathological TO Pathological TS

10

2.5 0 Telemetry ECG

EPI

Figure 2 Turbulence onset and slope. (A) Turbulence onset after spontaneous ventricular premature contractions (n ¼ 8) showed a mean acceleration (negative TO) with large standard deviation. The heart rate turbulence induced with programmed stimulation (n ¼ 21) produced slightly positive TO values. The horizontal line indicates the mean. (B) Mean TS values after correction for the heart rate for both groups were positive. After induced extrastimuli during electrophysiological investigations a lesser extend in TS could be registered but with minor differences in variation. (C) Turbulence onset and slope values of spontaneous and induced premature beats after correction for the heart rate. The hatched areas indicate general standard values in humans (TO , 0%, TS . 2.5 ms/RR-interval). Based on human criteria, 17 of 29 animals would be considered ‘pathological’ with regard to TO and 13 ‘pathological’ with regard to TS.

same sympathovagal modulation.23 Furthermore, since HRT may reflect intrinsic sinus nodal properties24 a correction of HRT parameters for heart rate seems to be possible.25 The baroreceptor sensibility in healthy wild-type mice, i.e. the increase in R-R interval divided by the increase in blood pressure, can be calculated to 2.1 ms/ mmHg,26 whereas studies in humans showed values of 15 ms/ mmHg.27 When normalizing these values to equal sinus rhythm heart rates, a comparatively weaker response of change in CLs can be found in mice. This is in analogy to our findings, showing that TO and TS parameters in mice are weaker in expression than compared with the situation found in humans. In our investigation, we presented that VPCs in mice led to compensatory pauses that were followed by a specific HRT pattern. The data of our animals showed that the given general standard values for TO and TS in humans most likely are applicable to mice. Relating to the original CLs parameters in mice, this would conform to cut-off values for TO of ,0% and for TS of .0.38 ms/ R-R interval. However, prior to defining definite cut-off values, examinations of a mouse model with marked structural cardiac disease as

control group should be performed in further studies. With regard to the higher heart rates in mice, a faster or earlier time course of the TS might have been expected. This, however, could be ruled out since the maximum of late deceleration could be found up to the 15th sinus rhythm beat with non-pathological values determined even with five consecutive beats, analogously to human data. Despite scarce occurrence of VPCs in healthy wild type mice, the technique of recording spontaneous VPCs must be considered the gold standard as it represents the most physiological status in which HRT can be measured. At least five VPCs should be averaged in humans for reliable construction of the tachograms.3 This number could not be reached in healthy mice and therefore the results have to be treated cautiously. Yet, due to the low incidence of spontaneous premature beats, we examined the feasibility of the more practicable way with induction of extrasystoles by pacing manoeuvres during an EP investigation. By this, an adequate number of coupled extrastimuli can be applied to register reproducible results and to achieve sufficient data for analysis. Moreover, this technique can be applied additionally while performing an EP study, without further need for

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Pathological TO and TS

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HRT determined by EPI r = 0.58; P = 0.006

(A)

(B) 90

HRT determined by Telemetry ECG r = 0.68; P = n.s

% Prematurity of Cl

% Prematurity of Cl

80

60

40

80

70

60 –1

0

1 TO (%)

2

3

(C)

–10

(D)

Sinus CL (ms)

Sinus CL (ms)

100

60

80 100 Coupling interval (ms)

120

5

150

100

–10

–5

0

5

10

TO (%)

Figure 3 Correlation analysis of TO, coupling interval, and sinus CL. (A) A significant correlation could be demonstrated between the prematurity of the coupling interval (CI) of the extrastimulus, expressed as percentage of baseline sinus CL and TO during the electrophysiological investigation. (B) This correlation could not be verified for the prematurity of the CI of spontaneous occurring ventricular premature contractions during the long-term ECG recordings. (C) A weak relationship between the sinus CL and the coupling interval of the extrasystoles, both induced and spontaneous, was present. (D) No significant correlation could be calculated between the sinus CL and TO.

instrumentation, to receive information on baroreceptor function in structurally altered mouse models. While performing the EP investigation one has to pay special attention to the significant correlation of the interval of the applied extrastimuls to TO. When excluding shorter coupling intervals in our study, negative values for TO could be demonstrated up to a prematurity of 63.1%. This is in analogy to the shortness of the coupling interval of spontaneously occurring VPCs which showed a mean prematurity of 70.6%. Therefore, we conclude that the shorter VES pacing intervals, which did not lead to the early acceleration in heart rate, resulted from an unphysiological prematurity. The results are also consistent with previous data derived from a human EP study.5 The early acceleration is mainly triggered by the blood pressure drop of the second post-extrasystole beat.3 A shorter coupling interval of an extrastimulus leads to a greater blood pressure amplitude of the first post-extrasystole beat. This in consequence might lead to a more mitigated drop of blood pressure in the second post-extrasystole beat compared with longer coupling intervals resulting in a reduction of heart rate acceleration. The nearly abolished early acceleration in heart rate after the extrastimulus might also have been influenced by the technique of

the examination since baroreceptor effects can be altered by volatile narcotics. Isoflurane, however, attenuates the baroreceptor sensitivity in a dose-related manner28 and a significant depression of the chronotropic component of the reflex has only been demonstrated with minimal alveolar concentrations of ≥2.6%.29 For this reason, we used an isoflurane concentration of 1.2% in our study. Nevertheless, smaller values were also found for TS in the anaesthesia group compared with the telemetry group. Therefore, we cannot exclude that this effect might be attributed to the volatile narcotic despite the use of the low dosage. Beyond that we do not believe that isoflurane influenced the linear correlation between the prematurity of the extrastimulus and TO, because similar correlations had already been described in human studies even without the use of narcotics.5,7 Our experiments provide the basis for further studies to address baroreceptor sensitivity in mice. The evaluation of HRT can contribute to a better analysis of cardiac autonomic function and its resulting impact on the cardio-circulatory system in existing murine models of structural heart diseases, both induced and/or genetically altered, as well as for endocrine and neurodegenerative diseases. Additional studies should address HRT in the setting of concomitant structural heart diseases such as left ventricular infarction and

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40

0

r = 0.27; P = n.s

r = 0.37; P = 0.046 150

–5 TO (%)

1098 hypertrophy to verify the prognostic value of this parameter in the mouse model with regard to inducible ventricular tachycardias and hemodynamic parameters.

Conclusion The measurement of HRT parameters in mice is feasible as mice respond to VPCs derived from telemetry ECG or extrastimulus pacing with a prolonged compensatory pause that is followed by distinctive heart rate alterations. Special attention has to be paid to the coupling intervals of the extrastimuli as these influence TO parameters. Further studies in pathological settings should address the value of HRT measurement in mice as a convenient non-invasive measurement of baroreflex sensitivity to indirectly assess the severity of cardiac disease in the tested animal model. Conflict of interest: none declared.

Funding

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This work was supported by a research grant from the German Cardiac Society awarded to F.S. (DGK Stipendium 2012) and from grants of the German Research Foundation (DFG, SCHR1294/3.-1) awarded to J.W.S.

F. Sto¨ckigt et al.

Induced and spontaneous heart rate turbulence in mice: influence of coupling interval.

Heart rate turbulence (HRT) is a prognostic parameter for risk stratification in patients suffering from coronary artery disease. The aims of this stu...
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