Indian Pacing Electrophysiol. J.
2003;3(1):10
Heart Rate Turbulence: a Review
Mari A. Watanabe, MD, PhD
Institute of Biomedical and Life Sciences, West Medical Building,
Glasgow University, Glasgow G12 8QQ, UK and Section of Cardiology,
Division of Cardiovascular and Medical Sciences, Royal Infirmary,
Glasgow University, Glasgow G31 2ER, UK
Address for correspondence: Dr. Mari A. Watanabe, MD, PhD, Institute of
Biomedical and Life Sciences, West Medical Building, Glasgow
University, Glasgow G12 8QQ, UK.
Email: mwata001@udcf.gla.ac.uk
Heart rate turbulence (HRT) is a recently coined phrase that describes
the short term fluctuation in sinus cycle length that follows a
ventricular premature complex (VPC). Its proven clinical significance
lies in
its ability to predict mortality and sudden cardiac death following
myocardial infarction, although small studies suggest that it is also
applicable to many other cardiac diseases. This review will attempt
to summarize the literature to date, and to speculate on possible
mechanisms.
Because HRT is a new field, there are only a handful of full length
papers
on it. In order to present the full breadth of the research being
carried out, the information provided here is based on conference
abstracts as
well as peer reviewed articles, and readers should keep this in mind.
Most of the literature cited here, and downloadable HRT calculation
programs (in C++) are available on the website www.h-r-t.org.
How to compute HRT parameters
After
a VPC, heart rate increases for 1 or 2 beats, then decreases. This
phenomenon was discovered by Georg Schmidt's research group in Munich,
when they averaged the RR interval sequences flanking VPCs (Figure 1).
A rough idea of the amount of RR interval increase that can
be seen is given in a study of 15 patients 1.
In that study, RR interval started to increase at beat 3 after the
paced VPC, and reached a peak bradycardia of 77 ± 111 ms (m
±
sd) over the baseline RR at beat 8 . HRT quantifies these heart rate
changes by 2 parameters, turbulence onset (TO) and turbulence slope
(TS). Roughly speaking, TO is the amount of sinus acceleration
following a VPC, TS is the rate of sinus deceleration that
follows the sinus
acceleration. Figure 2 shows pictorially how HRT is measured.
RR intervals are plotted vs beat number, with 2 beats preceding
and 20 beats succeeding the VPC beat and compensatory pause. TO (%)=
100
x {(RR[1] + RR[2]) - (RR[-3] + RR[-2])} / (RR[-3] + RR[-2]), where the
numbers in brackets denote beat number, with the compensatory pause
being
beat 0. To obtain TS (ms/beat), the slopes of RR change are calculated
by fitting each 5 beat RR sequence following the compensatory pause
(RR[1]~RR[5],
RR[2]~RR[6], ... , RR[16]~RR[20]) with a straight line. The maximum of
the 16 slopes is taken to be TS. TO<0 and TS>2.5 are considered
normal,
TO > 0 and TS < 2.5 are considered
abnormal.
In other words, strong sinus acceleration followed by rapid
deceleration marks a healthy response. In the seminal HRT publication
by Schmidt et al 2, the 24 RR intervals
encompassing each VPC (2 before the VPC, 20 after the compensatory
pause) were averaged over a 24 hour Holter record. HRT was calculated
for this averaged response, such
that each patient was represented by one value each for TS and TO.
Measurement of HRT has not been standardized yet. Some of the recent
studies from the Schmidt laboratory exclude RR sequences that don't
have at least 3 or 5 sinus intervals before the VPC, but have relaxed
the criteria for the minimum number of post-compensatory pause sinus RR
from 20 to 15 3,4. With
regard
to averaging of RR, HRT can also be calculated for each VPC, then
averaged,
to give a mean and standard deviation of HRT parameters for a given
individual 5. For reasons not yet clear,
perhaps due to improvement in signal/noise ratio by the process of
averaging as suggested by Figure 1, the original method of
averaging the RR values before HRT calculation provides better
prediction of mortality, and is to be
recommended whenever circumstances permit. HRT can also be averaged for
groups of VPCs satisfying selected criteria, such as normalized
coupling interval 3.
Figure 1: Example of RR
interval sequences in one patient (thin lines), all aligned at the VPC.
The thick line shows the average of the 60 sequences. Figure supplied
courtesy of Dr. Georg Schmidt.
Figure 2 Schematic
figure showing measurement of TO and TS. TO is the difference in the
average of
the 2 RR intervals preceding and succeeding the VPC/compensatory pause
sequence expressed as a percentage. In the example shown, TO= - 4%
from 100 x (960-1000)/1000. TS is the maximum of regression slopes
computed for 5 consecutive RR sequences. In the example, the regression
lines for beats 3~7 (slope 3) and beats 6~10 (slope 6) are shown, and
TS was 36.4 because slope 3 had the largest slope of 36.4 ms/beat
number
among slopes 1 through 16.
Analysis of HRT is not limited to Holter records. HRT analysis has been
conducted on event records from implanted cardiac defibrillators 5. HRT can also be induced by intracardiac pacing
in the electrophysiology lab 1,6,7,8 or in patients with implanted
cardiac defibrillators 9. Such HRT has
been called induced HRT 6 to
distinguish it from that measured from Holter recordings. Figure 3A
shows an example of normal induced HRT. The stimulation protocol
suggested for measuring induced HRT is to compute TS and TO from the
average of RR sequences following 10 extrastimuli given with a spacing
minimum of 20 sinus beats, and a coupling interval that is 60 ~ 70% of
sinus cycle length 6.
Figure 3 Induced HRT. Panel
A. RR intervals from a patient undergoing clinical
electrophysiology study for supraventricular tachycardia. A stimulus
was delivered at the RV apex after 20 sinus beats at various coupling
intervals shorter than the baseline RR interval. Only the RR for the 2
beats before and 10 beats after the extrastimulus and compensatory
pause are shown for each extrastimulus. Panel B. The RR
data from panel A and pulse pressure (systolic - diastolic blood
pressure) for the same beats are shown together. The pulse pressure was
multiplied by 10 and shifted down by 800 mmHg so as not to overlap with
the RR data.
HRT as a predictor of mortality
The
first full length publication introducing HRT and the 2 parameters
quantifying it was Schmidt et al's 1999 Lancet article (hereafter
referred to as the Lancet study) 2. It
was preceded by an abstract, in which HRT was called by its original
name of heart rate chronotropy 10. In the
Lancet study, Holter recordings from one hundred survivors of acute
myocardial
infarction with frequent VPCs were used to determine the discriminating
threshold between normal and abnormal HRT values (TS=2.5, TO=0%). The
recordings were made at least 3 months after the acute myocardial
infarction. These thresholds were blindy (and therefore prospectively
in that sense) applied to Holter records from a total of 1191 patients
from 2 large post-myocardial infarction clinical trial groups, the
placebo arm of the European Myocardial Infarction Amiodarone Trial
(EMIAT n=614), and
the Multicentre Post Infarction Program (MPIP n=577). The Holter
recordings
were made in the 2nd or 3rd week after the index infarction. There were
162 deaths (13.6%) during the median follow-up period of 21 (EMIAT) and
22 (MPIP) months. With total mortality as the endpoint, univariate
analysis showed that TS was the strongest risk stratifier in EMIAT
(relative risk 2.7), while TS was the second strongest risk stratifier
in MPIP (relative risk 3.5) after poor EF (EF<30%). A relative risk
of 3 means that patients with abnormal TS are 3 times more likely to
die than those with normal
TS. Multivariate analysis showed that in EMIAT, each of TO,
TS,
previous infarction history, EF, and mean HR (>75) were independent
predictors, and in MPIP, EF and TS were independent predictors. If one
predictor is independent of another, it means that the criteria
identifies a different group of patients, and that for example, the
patients with high HR do not necessarily coincide with the patients
with low EF. Multivariate analysis also showed that combined TS and TO
was the most powerful risk stratifier in both the EMIAT (relative risk
3.2, 95% confidence interval 1.8-5.6) and MPIP (relative risk 3.2, 95%
confidence interval 1.7-6.0) populations.
(The combined parameter is considered abnormal if both TS and
TO are abnormal.) Indeed, in contrast to TS and EF, none of advanced
age (>65 years), previous myocardial infarction, high mean HR, heart
rate variability triangular index < 20, and presence of
arrhythmia on Holter (>9
VPC/hour or non-sustained ventricular tachycardia of >2 beats), were
independent mortality predictors in the multivariate analysis in the
MPIP
population.
HRT as a predictor of cardiac arrest
Data
from the Autonomic Tone and Reflexes after Myocardial Infarction
(ATRAMI) has been used to study HRT as a predictor of cardiac arrest 11. The study involved 1212 survivors of acute
myocardial infarction, with a mean follow-up period of 20.3 months.
Patients in this study were at lower risk compared to EMIAT in which
only
patients with EF<40% were enrolled, and compared to MPIP in which no
patients had had thrombolytic treatment. The endpoint was cardiac
arrest, both fatal and non-fatal, which was reached in 49 patients
(4.0%). Univariate analysis showed that TS and combined TS and TO both
produced moderately high relative risk values (4.1 and 6.9
respectively, p<0.0001 for both).
A composite index of cardiac autonomic function was made from TO, TS,
the SDNN parameter of heart rate variability, and baroreflex
sensitivity.
Patients in whom all of the factors making up the composite index were
abnormal were found to be 16.8 times more likely to have a cardiac
arrest
than those in whom all 4 factors were normal. Unfortunately, of the 49
patients who had eventual cardiac arrest, only 5 satisfied this
criterion.
At the same time, there were 10 other patients in whom all 4 factors
were abnormal and who did not have cardiac arrest. This brings us to
the
next topic.
The issue of sensitivity
The
sensitivity and positive predictive accuracy of HRT is better than
other available non-invasive tests, but not much better. When TS and TO
were combined, the Lancet study 2 reported
a sensitivity, specificity, and positive predictive accuracy of
approximately 30, 90, and 32% respectively, for both the EMIAT and MPIP
data. In simpler terms, by setting TS and TO thresholds at 2.5 and 0,
we catch 30% of
the patients who will have events, but we also catch so many false
positives that if there are 100 patients with abnormal HRT, only a
third of them will be true positives. The Lancet study reported a
positive predictive accuracy of 18 ~ 24% (EMIAT), and 16~30% (MPIP) for
the other 6 variables of advanced age, previous myocardial infarction,
high HR, low heart rate variability triangular index, presence of
arrhythmia on Holter, and low EF. The positive predictive accuracy
which came closest to matching combined TS and TO as a parameter was EF
in the MPIP data at 30%. However, EF
had better sensitivity (43%) and specificity (85%) than the combined
HRT parameter.
The
excellent commentary by Macfarlane accompanying the Lancet article
specifically compares HRT to commonly used electrocardiographic
predictors, namely, heart rate variability, late potentials, ST-T
changes, QT dispersion, and prolonged QT 12.
In the commentary, sensitivity, specificity and positive predictive
accuracy of low heart rate variability (SDNN< 50 ms) are given as
34, 89 and 34%, neatly matching values for combined TS and TO. The
positive predictive accuracy of HRT and heart rate variability is at
least 2 times greater than that of the other predictors, but the
sensitivity of late potentials, for example, is much higher at 93%. How
does HRT compare to baroreflex sensitivity? According to a study based
on the ATRAMI data, TS had a positive predictive accuracy of 12.5% at
40% sensitivity, and thus came out ahead of low baroreflex sensitivity
with its positive predictive accuracy of 7.8% 13.
Certainly, predictive accuracy can be improved by combination with
other risk predictors. At 40% sensitivity, abnormal TS combined with
poor heart rate variability gave a positive predictive accuracy of
20.3%, and TS combined with low EF, a positive predictive accuracy of
17.3% 13, although as mentioned 2
paragraphs before, combining tests also results in fewer patients
who satisfy the criteria.
In
summary, the key number to remember out of the forest of statistics
concerning HRT is the number 30. TS and TO combined (when both are
abnormal) give a sensitivity of 30%, and a positive predictive accuracy
of approximately 30%. This is consistent with another"30" from the
Lancet
study 2. When comparing patients who had
0,
1 or 2 abnormal HRT measures, the 2 year mortality rate was 9, 15,
and 32% in the MPIP population, and 9, 18 and 34% in the EMIAT
populations.
In other words, 1 in 3 post-myocardial infarction patients whose TS and
TO are both abnormal 2 weeks after their infarction, are likely to be
dead in 2 years.
HRT is not always measurable
HRT
has the opposite problem from heart rate variability. Ectopic beats are
always excluded from analyses of heart rate variability, and criteria
exist for how much of a Holter record can be deleted before portions of
it are considered invalid. In contrast, HRT obviously cannot be
measured in subjects who do not have VPCs. This makes the study of HRT
in healthy subjects difficult, and researchers have to resort to
studying induced HRT. In the Lancet study, 138 of 715 patients (19%) in
the MPIP population, and 129 of 743 (17%) in the EMIAT population had
to be excluded because of absence of VPCs, atrial fibrillation,
insufficient or missing Holter recordings, and missing EF data (MPIP) 2.
According to Raphael Schneider (personal communication), if one
excludes
patients with atrial fibrillation, approximately 10% of patients with
Holter records cannot have HRT measured because of absence of VPCs.
In a study in which our research group looked at 1000 beat RR data from
patients with implanted defibrillators, we found that too many VPCs
also resulted in exclusion of some records from study, the reason being
that the 20 beat sinus RR following the compensatory pause were
interrupted
by VPCs, precluding measurement of TS 5.
In
this high risk group, 14 of 84 (17%) control records and 9 of 84 (11%)
arrhythmia records had no VPCs. A further 21 (25%) control and 19 (23%)
arrhythmia records had no stretches of > 10 sinus RR following the
compensatory pause. However, one should note that these are results for
1000 beat records, i.e., short 10~15 minute records, and that
furthermore,
a full 10 beats is frequently unnecessary to determine whether TS is
normal
or not, because the average record has an RR change slope that reaches
a maximum for the 5 beat RR sequence RR[3]~RR[7] or RR[4]~RR[8] [5].
Applicability of HRT to patients on beta-blockers
Most
predictors for post-acute myocardial infarction mortality perform
poorly in patients on beta-blockers. In a study of 591 patients in
EMIAT's placebo arm, 271 patients were on beta-blockers, 320 were not 14. In the patients on beta-blockers, combined TO
and TS was found to be the only independent predictor of mortality with
a relative risk of 3.8 (p=0.004). Mean HR, previous myocardial
infarction and low EF which were independent predictors for patients
not taking beta-blockers, all failed when applied to the patients on
beta-blockers. In this regard, HRT is seen to have a distinct advantage
over some of the
other risk predictors.
HRT as a risk predictor in other diseases affecting the heart
HRT
has been assessed in patients with diabetes mellitus 15,16, congestive heart failure 17,18, idiopathic dilated cardiomyopathy 19,20,21, and
Chagas disease 22. In the earlier study
of diabetes, one hundred patients with coronary artery disease were
divided into 2 groups, those with and without diabetes 15. TO was found to be a significant predictor of
cardiac mortality (p<0.05), although TS was not. In a second study
of diabetes using 586 patients from the placebo arm of the EMIAT, HRT
parameters failed as independent predictors of mortality in the 95
patients with diabetes 16. In a study of
199 patients with congestive heart failure (mean duration of follow-up
971 ± 378 days, median EF of 22% and 47 cardiac deaths),
abnormality of both TO and TS produced the highest risk ratio of 4.1
for cardiac deaths, compared to 3.3 for presence of non-sustained
ventricular tachycardia, 2.6 for abnormal baroreflex sensitivity, and
2.0 for the triangular index of heart rate variability 17. With regard to idiopathic dilated
cardiomyopathy, a small study of 12 patients showed that TS and TO were
significantly worse (both p<0.01) compared to 13 healthy subjects 20. A larger study was reported recently,
involving 178 patients also with idiopathic dilated cardiomyopathy 21. The endpoint was heart transplantation;
follow-up duration was 28 ± 17 months.
21 patients required a heart transplant. Statistical analysis showed
that TS, TO, and combined TS and TO were significantly worse in
patients
requiring transplant (p<0.05). The relative risk, however, was found
to be very low, and the setting of a different threshold of HRT
parameters
for patients with dilated cardiomyopathy was suggested. In a comparison
of 11 healthy subjects and 126 patients with Chagas disease, TS and TO
values were found to be significantly different (p<0.001) 22. These preliminary studies show that HRT is
diminished not only in post-myocardial infarction patients, but those
with a variety of diseases affecting the heart, and in the case of
congestive heart
failure and possibly diabetes, may provide clinically useful risk
stratification information
Mechanism of HRT
The
gross mechanism of HRT is easy to understand. BP of a VPC beat is
normally small because of several factors. Diastolic filling is
incomplete leading to low ejection volume. Various membrane ion
channels have not recovered fully, leading to a short action potential
(electrical restitution). The low volume/stretch leads to reduced
contractility (Frank Starling mechanism). Finally, the abnormal
sequence of activation of the ventricles leads to a less synchronized
contraction. The sudden drop in blood pressure due to all of these
factors activates the aortic and carotid baroreceptors, which increase
HR through the baroreflex arc. A VPC is normally followed by a
compensatory pause. The BP of the compensatory pause beat is higher
than BP of a sinus beat, a phenomenon called post-extrasystolic
potentiation. Some of the long time constant ion channels have
recovered more fully leading to a longer action potential, and
intracellular calcium is greater due to mechanisms still debated. The
sudden increase of BP reduces HR,
again via the baroreflex arc. If HR simply tracks BP changes, the
sequence
of events just described explains tidily, the sinus acceleration and
deceleration that is HRT. In summary, VPC -> low BP -> HR
increase -> compensatory pause -> high BP -> HR decrease.
A
figure in a recent publication illustrates this beautifully. Voss et al
show a simultaneous ECG and BP trace from a healthy subject 20. In the ECG trace, use of a caliper shows that
RR interval shortens following the VPC, then lengthens. In contrast,
changes in the BP trace caused by the VPC demonstrate a striking
resemblance to the HRT pattern of RR intervals (as shown in figure 1).
After the compensatory pause, both systolic and diastolic BP are low
for 2 beats, then gradually increase, peaking at about the 7th beat
before gradually returning
to normal. If this BP trace is typical of a normal response, HRT
mirrors BP turbulence closely. Figure 3B shows the
similarity
of pulse pressure values to RR values during induced HRT.
In
contrast to this gross mechanistic picture, the fine details of HRT's
mechanism have not been established. The main unanswered question
concerns sympathovagal balance. During the sinus acceleration
quantified by TO, does vagus withdrawal predominate or sympathetic
recruitment? What about during the sinus deceleration quantified by TS?
It is important to ask this question, because answering it will give us
clues as
to why HRT is a cardiac arrest predictor, and how cardiac arrest might
be prevented. Several lines of evidence point to a predominant vagal
mechanism. The strongest of these is the fact that atropine abolishes
HRT completely 7,23.
Based
on an induced HRT study of 16 patients without structural heart
disease, it has also been shown that intravenous esmolol doesn't alter
TS or
TO 24. Thirdly, as mentioned earlier, HRT
is effective as a risk predictor even in patients on beta blockers 14. The case for a predominant sympathetic
role is weaker. A mathematical model has shown beta-blockade to reduce
TS, although not TO 25. However, before
drawing any conclusions, the phenomenon of accentuated antagonism must
be taken into account. Sympathetic and para-sympathetic effects are
not additive; taking away one limb does not leave one with the other
limb, it reduces the other limb as well. For example, vagal effects are
stronger in the presence than in the absence of sympathetic tone.
Therefore,
the importance of the sympathetic nervous system in producing a healthy
HRT pattern cannot be ruled out solely on the basis of studies using
atropine
and beta blockers. The fact that TS and TO are independent risk
predictors
also suggests that HRT is not a purely vagal phenomenon. If that were
the case, patients with abnormal TS and TO should overlap
significantly.
Separating the sympathovagal influences on HRT is complicated by the
bidirectional change in BP seen with the VPC and subsequent
compensatory pause. What if no compensatory pause were present? What
happens to HRT? One might expect atrial premature contractions and
interpolated VPCs to form a good testing ground, because they lack a
compensatory pause. The HRT characteristics of the latter have not been
studied yet, but atrial premature contractions have been studied, and
it appears that they evoke HRT 26,27.
A study of 227 atrial premature contractions from 10 normal subject
Holter records found TS of 17 ± 1 (mean ± sem), which was
significantly smaller (p<0.001) than the TS for VPCs found in the
same group of subjects (26 ± 2)27.
This suggests that the compensatory pause is irrelevant for producing
HRT, with the smaller TS in the case of atrial premature contractions
being due to the less dramatic fall in BP, because the sequence of
ventricular contraction is preserved in atrial premature contractions.
In a study that could be interpreted as leading to the opposite
conclusion, Voss et al showed that HRT was much reduced and the BP of
the compensatory pause beat much higher in patients with idiopathic
cardiomyopathy than in healthy subjects 20.
Based on this observation, they reasoned that the high BP of the
compensatory
pause in the myopathy patients swamped any effects of the low BP of the
VPC and therefore reduced HRT. In other words, the compensatory pause
affected
(reduced) HRT greatly. A possible flaw of this hypothesis is that RR
variability
is already low in DCM 28. To attribute
reduced
HRT to high BP from the compensatory pause raises the question, what
causes the reduced RR variability in the stretches of record that lack
VPCs? However, the truth is, post-extrasystolic potentiation occurs
even
in the absence of a fully compensatory pause, and neither interpolated
VPCs nor atrial premature contractions prevent the post-extrasystolic
pressure
increase that is probably responsible for the sinus deceleration phase
of HRT.
Effect of HR on HRT
Practically all of the studies that have looked at the relationship
between HRT and HR agree that HRT is reduced by high HR 29,6,30. One
of the
larger studies involved 591 patients with suitable Holter records from
the placebo arm of the EMIAT population 29.
During follow-up, 82 patients died. The 38,374 and 40,409 VPCs,
respectively from the survivors and non-survivors were pooled and
sorted according to the HR (calculated from the pre-VPC RR) before
calculation of TS and TO. Linear regression showed correlations between
HRT parameters and HR (all p<0.0001, r value range 0.65~0.93), both
for survivors and non-survivors. In survivors, regression of TO on HR
gave a slope of 0.044, regression of TS on HR gave a slope of -0.061.
The linear regression of
TO on HR in non-survivors was poor (r=0.65), because at HR above 80, TO
became approximately 0 (was abolished).
A
small study of induced HRT in a mix of 28 patients with
supraventricular and ventricular tachycardia, similarly found a
significant correlation between TS and HR when each patient was
represented by one mean TS value and HR preceding the VPC (p<0.02 ),
but not for TO [6]. Another study found TO to be diminished (close to
0) at high HR, leading to warnings about false positive TO at high HR
30. Such an influence of HR on HRT raises the
question of whether threshold values for normal and abnormal HRT values
have to be tied to HR, similar to
Bazett's formula for QTc. Schmidt's group have already reported that a
parameter which they call turbulence dynamics, defined as steepness of
the regression line of TS on HR, has strong predictive value for
mortality 31.
Effect of VPC coupling interval on HRT
Several studies have looked into the relationship between HRT and VPC
coupling interval 3, 27,8,6. Three of these studies, (two
based on Holter recordings, one based on induced HRT), found
correlations of varying degrees between VPC coupling interval and HRT
parameters, with shorter coupling intervals generally producing greater
absolute values of TS and TO 3,27,8. The largest of these
studies involved the same 591 patients from the placebo arm of the
EMIAT population as in the HR/HRT discussion above3.
The VPCs from the survivors and non-survivors were pooled and sorted
according to normalized VPC coupling interval before calculation of TS
and TO. Linear regression showed correlations between HRT parameters
and VPC coupling interval (all p<0.0001, r value range 0.67 ~ 0.89),
both for survivors and non-survivors. In survivors, regression of TO on
coupling interval gave a slope of 0.028, regression of TS on coupling
interval gave a slope of -0.066, whereas the absolute value of these
slopes were smaller for the non-survivors at 0.017 and -0.049
respectively. A second study focused on 171 VPCs from 10 normal
subjects and found a significant correlation between TS and normalized
VPC coupling interval (r=-0.4, p<0.001) 27.
In it, TS was also found to correlate significantly with atrial
premature beat coupling interval. A third study measured induced HRT in
37 patients undergoing evaluation for ventricular tachycardia 8. This study only found correlations between TS
and TO and normalized coupling interval in patients with EF>40%
(r=-0.61, 0.68 respectively, p<0.0001), and found no correlations
between atrial premature beat coupling interval and HRT parameters.
A
fourth study, also measuring induced HRT in 28 patients undergoing
evaluation for supraventricular or ventricular tachycardia, found no
correlations at all between VPC coupling interval and HRT parameters,
regardless of whether patient data were pooled as in the 3 studies that
did
find correlations, or whether correlations were sought in individual
patients6. How is it possible for one study
to find no correlation at all, when 2 studies found correlations with
p<0.0001? The most probable mechanistic reason is the effect of
baseline heart rate. As discussed
in the previous paragraph, HRT is blunted at high HR. If HR is high,
then
regardless of normalized coupling interval, HRT will be low and
unlikely
to be correlated with coupling interval. This is especially true of TO,
because at HR above 80~90, TO is nearly 0, and may be the reason it is
easier to show a coupling interval/TS correlation than a coupling
interval/TO
correlation. In the study that found no correlation, 12 of the 28
patients
in the 4th study had mean HR>75 bpm. It must also be noted that in
one
study reporting a high correlation, VPCs with normalized coupling
intervals
of 100% and greater were included8. Because
a coupling interval of 100% should diminish blood pressure very little,
and therefore produce no HRT, inclusion of this obligate zero
skews the results towards better statistical significance, because TS
is generally positive and TO is generally negative.
In
summary, HRT as a mortality predictor should probably be assessed at HR
<80 bpm whenever possible. The effect of coupling interval as
separate from HR seems debatable, and awaits further study. Plotting
HRT vs both HR and non-normalized coupling interval as shown in an
early abstract, may be one effective approach to answering this question32.
Correlation of HRT to other autonomic indicators
As
might be expected, there is a strong correlation between HRT parameters
and other autonomic indicators. In one study, TS and TO were found to
correlate significantly with almost all heart rate variability time
domain parameters, including SDNN, heart rate variability index, TINN,
and RMSSD (p<0.0001 for most) [33]. TO (but not TS) also correlated
with pNN50. In another study looking at HRT parameters and baroreflex
sensitivity, both TS and TO correlated moderately (r=0.44, r=-0.34
respectively) but significantly (p<0.001) with baroreflex
sensitivity measured invasively (iv phenylephrine) 11.
TS has also been reported as correlating strongly (r=0.70, p<0.0001)
with baroreflex sensitivity alpha-index, a non-invasive baroreflex
sensitivity measure 34. Finally, in
line with what is known about the effects of age and gender on other
autonomic indicators 35, HRT diminishes
with age 36, and is greater in women 30.
AV nodal turbulence
If a
VPC affects sinus rate through baroreflexes, it is probable that AV
conduction is affected as well. Two studies have looked at this. The
first measured the 20 AA and VV intervals following right ventricular
extrastimuli and plotted one against the other. All points lay cleanly
on a line of slope 1 (r2= 0.999), indicating no effect of
VPCs on AV nodal conduction time 23. A
very recent study did find an effect 37.
In that study, patients with normal induced HRT patterns (14/26) in
their RR intervals also exhibited AV conduction delay turbulence.
Compared to RR interval turbulence, AV delay turbulence onset was
barely existent (-0.6 ± 3.4%), and AV delay turbulence slope was
0.9 ± 1.3 ms/beat, clearly smaller than TS of RR interval (14.7
± 16.5). The pooled RR and AV delay vs beat number profiles
showed a 6% difference between maximum and minimum RR, and a difference
< 2% for AV delay. It is probable that just as ventriculophasic
modulation of AV nodal conduction is masked by opposing effects of
ventriculophasic modulation of the sinus rate 38,
increases in PP interval prevent AV nodal conduction delay from
becoming manifest in the case of HRT.
Novel HRT measures
In
addition to TS and TO, there are various HRT parameters that have been
proposed and studied. Turbulence dynamicity was already defined
in the HRT/HR section 31. Turbulence
frequency decrease is a parameter that measures HRT in the
frequency domain 39. This parameter is
obtained by
fitting a sine wave equation to the post-compensatory pause RR values
with a frequency term that decreases over time. It appears to contain
mortality information independent of the time domain parameters TS and
TO 39. Turbulence timing is a
parameter that notes the first beat number of the 5 RR interval
sequence
where TS is found (where the slope of RR change is maximum) 5,6. Turbulence timing is
dependent on HR, and the relationship indicates that the sinus
deceleration phase of HRT is earlier at slow heart rates 6. Turbulence jump is a parameter which
quantifies the maximum
difference between adjacent RR intervals 9.
It was found to predict recurrence of ventricular tachycardia and
fibrillation in patients with dilated cardiomyopathy. Correlation
coefficient
of TS is the correlation coefficient of the regression line fitted
to the 5 RR intervals giving the maximum slope (i.e., where TS is
defined)40. It is an independent predictor
of mortality in post-infarction patients, but its risk ratio is lower
than that for TS
or TO. Further studies are needed to see if any of these parameters
provide significantly superior risk stratification to TS and TO, given
that
TS and TO are simpler to measure than some of these parameters, and can
be measured in short records.
Summary
Despite its limitation, namely, the fact that one cannot measure HRT in
patients with atrial fibrillation and patients lacking VPCs, HRT is a
simple and elegant way of measuring cardiac autonomic function in
patients at risk. It is nature's own autonomic perturbation experiment,
and is non-invasive. Compared to other non-invasive risk predictors,
the
relative risk and positive predictive accuracy of HRT are only modestly
better, but the ease with which it can be measured, and its
applicability as a predictor in patients on beta-blockers make HRT
significantly more attractive.
One might even instruct general practitioners to see if RR interval
after
a random VPC on an electrocardiogram increases by at least 12 ms from
the shortest to longest RR within 10 beats, as a lazy man's HRT. Such
conjecturing aside, if ways can be found of increasing HRT's positive
predictive accuracy, we may be one step closer to deciding who needs to
get an automatic implantable defibrillator in a cost effective way.
With
such obvious promises in store, HRT is being considered for inclusion
in a large scale ICD implantation trial. This author, for one, has high
expectations for HRT's future.
Glossary of abbreviations
BP
blood pressure
EF
left ventricular ejection fraction
HR
heart rate
HRT
heart rate turbulence
TO
turbulence onset
TS
turbulence slope
VPC ventricular
premature contraction
ATRAMI autonomic tone and reflexes after myocardial
infarction
EMIAT european myocardial infarction amiodarone
trial
MPIP multicentre
post-infarction program
NN normal
QRS to normal QRS interval
pNN50 proportion, NN50/NNtotal
RMSSD root of mean squared differences of NN
SDNN standard deviation of NN
TINN triangular
interpolation of NN histogram
References
1. Roach D, Koshman ML, Sheldon R.
Turbulence: a focal, inducible, source of heart period variability
associated with induced, transient hypertension. PACE 2000; 23: Part II
709.
2.
Schmidt G, Malik M, Barthel P, Schneider
R, Ulm K, Rolnitzky L, Camm AJ, Bigger Jr. JT, Schömig A.
Heart-rate turbulence after ventricular premature beats as a predictor
of mortality after acute myocardial infarction. Lancet 1999; 353:
1390-96.
3.
Bauer
A, Barthel P, Schneider R, Malik M, Schmidt G. Impact of coupling
interval
on heart rate turbulence. Eur Heart J 2001; 22: Suppl. p. 438, P2324.
4.
Bauer A, Barthel
P, Schneider R, Schmidt G. Dynamics of heart rate turbulence.
Circulation 2001; 104: Supplement II-339, 1622.
5.
Watanabe
MA, Josephson ME. Heart rate turbulence in the spontaneous ventricular
tachy-arrhythmia
database. PACE 2000; 23: Part II 686.
6.
Watanabe MA, Marine JE, Sheldon M, Josephson
ME.
Effects of ventricular premature stimulus coupling interval on blood
pressure
and heart rate turbulence.
Circulation 2002; 106: 325-330.
7.
Guettler
N, Vukajlovic D, Berkowitsch A, Schulte B, Erdogan A, Carlsson J,
Neuzner J, Pitschner HF. Effect of vagus blockade with atropine on
heart rate turbulence. PACE 2001; 24: Part II
625.
8.
Savelieva I, Wichterle D, Harries M, Meara M,
Camm J, Malik M. Different effects of atrial and ventricular
prematurity on heart rate turbulence: relation to left ventricular
function. PACE 2002; 25: Part II 608.
9.
Berkowitsch A, Guettler N, Neumann T,
Vukajlovic
D, Schulte B, Neuzner J, Pitschner HF. Turbulence jump - a new
descriptor
of heart-rate turbulence after paced premature ventricular beats. A
study
in dilated cardiomyopathy patients. Eur Heart J 2001; 22: Suppl. p.
547,
P2941.
10.
Schmidt G, Malik M, Barthel P, Schneider R,
Ulm,
K, Rolnitzky L, Bigger Jr. JT, Schömig A. Heart rate chronotropy
following ventricular premature beats predicts mortality after acute
myocardial infarction. Circulation 1998; 98: I-1 to I-1016; Suppl. 3713.
11.
Ghuran A, Reid F, La Rovere MT, Schmidt G,
Bigger JT, Camm AJ, Schwartz PJ, Malik M. Heart rate turbulence-based
predictors of fatal and nonfatal cardiac arrest (The Autonomic Tone and
Reflexes After Myocardial Infarction substudy). Am J Cardiol 2002; 89:
184-90.
12.
Macfarlane PW. Renaissance in
electrocardiography. Lancet 1999; 353:1377-1379.
13.
Malik M, Schmidt G, Barthel P, Schneider R, La
Rovere MT, Bigger Jr. JT, Schwartz PJ. Heart rate turbulence is a
post-infarction mortality predictor which is independent of and
additive to other
recognised risk factors. PACE 1999; 22: Part II 741.
14.
Schmidt G, Malik M, Barthel P, Schneider R,
Camm AJ, Schömig A. Heart rate turbulence in post-MI patients on
and off ß-blockers. PACE 2000; 23: Part II 619.
15.
Barthel P, Schmidt G, Schneider R, Ulm K, Malik
M, Schömig A. Heart rate turbulence in patients with and without
autonomic dysfunction. J Am Coll Cardiol 1999; 33: Suppl. A 136A.
16.
Barthel P, Schmidt G, Malik M, Schneider R,
Hierl A, Camm AJ, Schömig A. Heart rate turbulence in post-mi
patients with and without diabetes. J Am Coll Cardiol 2000; 35: Suppl.
A 144A.
17.
Morley-Davies A, Dargie HJ, Cobbe SM,
Schneider
R, Schmidt G. Heart rate turbulence: a novel holter derived measure and
mortality in chronic heart failure. Eur Heart J 2000; 21:Abstr. Suppl.
408.
18.
Koyama J, Toda S, Kon-No Y, Yamada A, Koseki Y,
Watanabe J, Shirato K. Evaluation of heart-rate turbulence as a new
prognostic marker in patients with chronic heart failure. PACE 2002;
25: Part
II 608.
19.
De Martino G, Dello Russo A, Sanna T,
Pelargonie G, Antonaci S, Belloni F, Messano L, Zecchi P, Lanza GA,
Bellocci F. Prognostic role of heart rate turbulence in patients with
idiopathic dilated
cardiomyopathy. Eur Heart J 2001; 22: Suppl. p. 436, P2314.
20.
Voss A,
Baier V, Schumann A, Hasart A, Reinsperger F, Schirdewan A, Osterziel
KJ, Leder U. Postextrasystolic regulation patterns of blood pressure
and heart rate in patients with idopathic dilated cardiomyopathy. J
Physiol 2002; 538: 271-8.
21.
Grimm W,
Sharkova J, Maisch B. Prognostic significance of heart rate turbulence
in patients with idiopathic dilated cardiomyopathy. Europace 2002; 3:
A153 146/2.
22.
Sousa MR,
Ribeiro AL, Schmidt G, Lombardi F, Perez AA, Gomes ME, Barros MV,
Machado FS, O Rocha M. Heart rate turbulence in Chagas disease.
Europace 2002; 3: A42 58/5.
23.
Marine JE,
Watanabe MA, Smith TW, Monahan, KM. Effect of atropine on heart rate
turbulence. Am J Cardiol 2002; 89: 767-9.
24.
Lin LY, Lai
LP, Lin JL, Du CC, Shau WY, Chan HL, Tseng YZ, Huang SK. Tight
mechanism correlation between heart rate turbulence and baroreflex
sensitivity: sequential autonomic blockade analysis. J Cardiovasc
Electrophysiol 2002; 13: 427-31.
25.
Mrowka R,
Persson PB, Theres H, Patzak A. Blunted arterial baroreflex causes
"pathological" heart rate turbulence. Am J Physiol Regulatory
Integrative Comp Physiol 2000; 279: R1171-5.
26.
Savelieva
I, Wichterle D, Ghuran A, Meara M, Camm J, Malik M. Heart rate
turbulence can be detected after atrial premature beat. J Am Coll
Cardiol 2002; 39: Suppl. A.
27.
Indik JH,
Ott P, Marcus FI. Heart rate turbulence and fractal scaling coefficient
in response to premature atrial and ventricular complexes and
relationship to the degree of prematurity. J Am Coll Cardiol 2002; 39:
Suppl. A.
28.
Binkley PF,
Nunziata E, Haas GJ, Neslwon SD, Cody RJ. Parasympathetic withdrawal is
an integral componment of autonomic imbalance in congestive heart
failure: Demonstration in human subjects and verification in a paced
canine model of ventricular failure. J Am Coll Cardiol 1991; 18:
464-472.
29. Bauer A, Schneider R, Barthel P, Malik M,
Schmidt G. Heart rate turbulence dynamicity. Eur Heart J 2001; 22:
Suppl,
p. 436, P2316.
30. Schwab JO, Coch M, Veit G, Eichner G,
Waldecker
B. Post-extrasystolic heart rate turbulence in healthy subjects:
influence
of gender and basic heart rate. Circulation 2001; 104: II-490, 2324.
31. Bauer A, Barthel P, Schneider R, Malik M,
Schmidt G. Dynamics of heart rate turbulence as independent risk
predictor after dynamic myocardial infarction. PACE 2002; 25: Part II
608.
32. Schmidt G, Bauer A, Schneider R, Barthel P,
Malik M, Camm AJ, Schömig A. Heart rate turbulence: Impact of
coupling interval and preceding sinus interval. Eur Heart J 2000; 21:
Suppl
552.
33. Yap YG, Camm AJ, Schmidt G, Malik M. Heart
rate
turbulence is influenced by sympathovagal balance in patients after
myocardial
infarction - EMIAT substudy. Eur Heart J 2000; 21: Suppl. 474.
34.. Davies LC, Francis DP, Ponikowski P, Piepoli
MF, Coats AJS. Relation of heart rate and blood pressure turbulence
following premature ventricular complexes to baroreflex sensitivity in
chronic congestive heart failure. Am J Cardiol 2001; 87: 737-42.
35. Tsuji H, Venditti FJ, Manders ES, Evans JC,
Larson MG, Feldman CL, Levy D. Determinants of heart rate variability.
J
Am Coll Cardiol 1996; 28: 1539-1546.
36. Barthel P, Schneider R, Malik M, Schmidt G.
EMIAT substudy: Impact of age on heart rate turbulence indices. Eur
Heart J 2001; 22: Suppl. p. 436, P2315.
37. Wichterle D, Savelieva I, Ghuran A, Meara M,
Camm J, Malik M. The dynamics of atriventricular delay after
ventricular premature beat. Europace 2002; 3: A134 153P/7.
38. Skanes AC, Tang ASL. Ventriculophasic
modulation of atrioventricular nodal conduction in humans. Circulation
1998; 97: 2245-2251.
39. Schneider R, Röck A, Barthel P, Malik M,
Camm AJ, Schmidt G. Heart rate turbulence: rate of frequency decrease
predicts mortality in chronic heart disease patients. PACE 1999; 22:
Part II 879.
40. Schmidt G, Schneider R, Barthel P. Correlation
coefficient of the heart rate turbulence slope: New risk stratifier in
post-infarction patients. Eur Heart J 2001; 22: Suppl p. 72, P484.
