Download Analysis of vagal effects on ventricular rhythm in patients with atrial

Clinical Science (1994) 86,
531-535
(Printed in Great Britain)
53 I
Analysis of vagal effects on ventricular rhythm in patients
with atrial fibrillation
Maarten P. VAN DEN BERG, Harry J. G. M. CRIJNS, Jaap HAAKSMA, Jan BROUWER
and Kong I. LIE
Department of Cardiology, Thoraxcentre, University Hospital Groningen, Groningen,
The Netherlands
(Received
20 September/6 December 1993; accepted 22 December 1993)
1. Animal studies suggest that the heart-rate-lowering
effect of vagal stimulation during atrial fibrillation is
due to: (1) a direct depressant effect on atrioventricular node conductivity, (2) enhancement of
concealed atrioventricular nodal conduction of atrial
impulses through augmenting fibrillatory activity,
thereby indirectly prolonging atrioventricular nodal
refractoriness. The purpose of the present study was
to analyse these effects in man.
2. Sixteen patients with chronic atrial fibrillation
were studied. After administration of propranolol
(0.2 mg/kg intravenously) baseline ventricular rhythm
was recorded (500 R-R intervals). Recordings were
repeated after methylatropine (0.02mg/kg intravenously). The shortest R-R interval was taken to
represent atrioventricular nodal refractoriness. The
ratio of the longest to the shortest R-R interval and
the coefficient of variation of R-R intervals were
used as parameters of concealed conduction.
3. Methylatropine foremost shortened long R-R
intervals: values for the mean, shortest and longest
R-R intervals decreased from 834 to 685 ms ( 18%)
(P<O.OOI), 573 to 498ms (-13%) (P<O.OOl) and
1228 to 924ms ( - 25%) (P<O.OOl), respectively.
Accordingly, the ratio of the longest to the shortest
R-R interval decreased 2.12 to 1.89 (-11%)
(P<0.05). Also, the coefficient of variation decreased
0.24 to 0.20 ( - 17%) (P< 0.05).
4. This study supports the contention that vagal
stimulation lowers ventricular rate during atrial fibrillation both by exerting a direct effect on the atrioventricular node and by augmenting concealed
conduction.
-
INTRODUCTION
Clinical experience provides abundant evidence
for substantial vagal influences on ventricular
rhythm in patients with atrial fibrillation (AF).
Vagal manoeuvres, for example carotid sinus massage, lower ventricular rate and may even cause
transient asystole. Conversely, after the admini-
stration of vagolytic drugs (atropine) marked
increases in heart rate generally ensue.
The heart-rate-lowering effect of vagal stirnulation
during AF is attributed to a direct depressant effect
on atrioventricular (AV) nodal conductivity. In
addition, it is assumed that vagotonia lowers the
heart rate by indirectly increasing AV nodal refractoriness due to an enhancing effect on atrial fibrillatory activity, thereby augmenting concealed AV
nodal conduction of atrial impulses [l, 21. However,
the evidence to support this assumption is largely
circumstantial [3-91. We are aware of only a single
animal study that has examined the effect of vagal
stimulation during A F on concealed AV nodal
conduction [lo]. In the present study we specifically
addressed this issue by carefully analysing the effect
of methylatropine on ventricular intervals in a
group of patients with AF.
METH0DS
Patients
The study group comprised 16 consecutive
patients hospitalized for elective electrical cardioversion of chronic AF. Their clinical characteristics
are summarized in Table 1. Thirteen patients used
digoxin, verapamil or a p-adrenoceptor blocker, or
a combination, for control of ventricular rate. Three
patients used no such drugs. Patients with suspected
or documented sinus node or AV nodal conduction
disturbances were excluded, as well as patients with
contra-indications for administration of propranolol
and atropine. The study was approved by the Ethics
Committee of our Institution. Informed consent was
obtained from all patients.
Experimental protocol
Patients were in the post-absorptive and u.nsedated state. Ventricular rhythm was recorded
while patients were supine, using a Marquette
Holter recorder (series 8500). Three electrocardiographic leads were used: modified leads V1, V5 and
Key words: atrial fibrillation, atrioventricular node, atropine, parasympathetic nervous system.
Abbreviations: AF, atrial fibrillation; AV, atrioventricular.
Correspondence: Dr M. P. van den Berg, Department of Cardiology, Thoraxcentre, University Hospital Groningen, 9700 RB, PO Box 30.001, Groningen, The Netherlands,
M.
532
P. van den
Table I. Clinical characteristics of the patients. Abbreviations: LA, left
atrium; LVEDD, left ventricular enddiastolic diameter; LVESD, left ventricular endsystolic diameter; RA, right atrium
Characteristic
Value
n
16
Mean age (years)
56 (23-81)
M/F
I0/6
Median duration of arrhythmia (months)
15 (2-144)
Underlying heart disease (no. of patients)
Rheumatic heart disease
Coronary heart disease
Hypertensive heart disease
‘Lone’ arrhythmia
Miscellaneous
Echocardiographic parameters (mm)
LVEDD
LVESD
LA parasternal view
LA apical view
RA apical view
Medication (no. of patients)
Digoxin
Calcium antagonists
PAdrenoceptor blockers
52 *7
35 &6
45 +6
70 +9
61 +8
a
6
3
aVF. A bolus of propranolol (0.2 mg/kg intravenously) was administered to achieve complete
/?-adrenoceptor blockade [ll], both to obviate possible confounding effects of sympathetic nervous
system activity and to limit potentially hazardous
tachycardia. Baseline recordings (e.g. after propranolol) were performed thereafter, lasting 10min.
Methylatropine (0.02mg/kg intravenously) was then
given and recording was continued for 10min more.
The administration of propranolol and methylatropine was unblinded. After the experimental protocol patients underwent electrical cardioversion, as
described previously [12].
Berg et al
tion two parameters were calculated: the ratio of the
longest to the shortest R-R interval and the coefficient of variation of R-R intervals [3-71.
To account for the possibility that after full
/I-adrenoceptor blockade unopposed vagal activity
might cause high-degree AV conduction disturbances, we tested the randomness of the temporal
distribution of R-R intervals, as such an AV block
would be associated with a non-random ventricular
rhythm that might be difficult to detect on a Holter
recording. Randomness was assessed using the technique of autocorrelation [13, 141. Correlation coefficients between successive R-R intervals were calculated up to the 50th interval. Autocorrelograms
were constructed for graphical display.
Statistical analysis
As values were normally distributed between
patients, data are presented as means+SD. Skewness of R-R interval distributions in individual
patients was accounted for by also calculating the
mean longest and shortest R-R intervals, and the
mean ratio of the two. For comparison of baseline
measurements and measurements after methylatropine, paired t-tests were used. Correlation coefficients were calculated using Pearson’s test. We
performed the analyses using the Lotus 123 spreadsheet and the statistical package for the social
sciences (SPSS). P values <0.05 were considered to
be significant.
RESULTS
Besides transient mild blurring of vision and
dryness of mouth in some patients, administration
of propranolol and methylatropine was uneventful.
Cardioversion of A F to sinus rhythm was achieved
in 13 patients. All these patients had a P-R interval
~ 0 . 2 2 In
~ . two of the three other patients normal
P-R intervals were noted on prior electrocardiograms during sinus rhythm. All recordings
were technically adequate.
Data analysis
Quantitative data
The recordings were processed by an experienced
analyst using a Marquette Holter System
(Marquette Laser Holter Systems, series SOOOXP).
Thereafter, episodes of A F containing 500 ventricular intervals (R-R intervals) were transferred to a
P D P 11/73 (DEC) post-processor for further analysis. For each episode of AF, the mean, the shortest
(5th percentile) and longest (95th percentile) R-R
interval were determined. For graphical display of
the effect of methylatropine, interval plots and frequency distribution histograms of the R-R intervals
(class width 50 ms) were also generated. The shortest
R-R interval was taken to represent AV nodal
functional refractoriness [S]. To examine the effect
of methylatropine on concealed AV nodal conduc-
The effects of methylatropine on R-R intervals
and parameters of concealed conduction are shown
in Table 2. After methylatropine all intervals were
shortened. However, after methylatropine the ratio
of the longest to the shortest interval was significantly lower, implying that the effect on long intervals exceeded the effect on short intervals. Methylatropine also lowered the coefficient of variation of
R-R intervals.
Histograms and interval plots
All histograms showed a unimodal distribution of
R-R intervals. At baseline a skewed right-hand tail
was readily apparent in the majority of histograms.
Vagal effects in atrial fibrillation
533
Table 2. Effect of methylatropine on the mean, shortest and longest
R-R interval and parameters of concealed conduction. Values are
means kSD.
Baseline
Atropine
Change P value
(%)
Mean R-R interval (ms)
Shortest R-R interval (ms)
Longest R-R interval (ms)
Longest/shortest
R-R interval (ms)
Coefficients of variation
of R-R intervals
834+192
573k118
1228*356
685*164
498k116
924k275
-18
2. I2 kO.28
I .89 k0.23
-I I
<0.05
0.24 k0.05'
0.20 k0.05
- I7
<0.05
-13
-25
<0.001
<0.001
<0.001
~I
250
No. of R-R intervals
I00
-
I25
75
"
l
E
Y
._
4
OC
50
c
0
z
25
0
0
1
R-R
I25
interval class (ms)
250
No. of R-R intervals
Fig. 2. Example of a plot of R-R intervals at baseline ( a ) and after
methylatropine ( b ) , corresponding with the histograms in Fig. I.
For the sake of clarity only the first 250 intervals are depicted. Besides the
loss of long intervals after methylatropine, clearly the 'dispersion' of the
intervals is also less.
Autocorrelation
0
750
R-R interval class (ms)
1.500
Fig. 1. Example of a histogram of R-R intervals at baseline ( a ) and
after methylatropine (b). After methylatropine the histogram is shifted
to the left. In addition, the shape of the histogram is altered with
diminution of the right-hand tail, indicating that methylatropine foremort
affected long intervals.
Methylatropine particularly affected this right-hand
tail. Fig. 1 shows a representative example of the
effect of methylatropine on histogram morphology.
In Fig. 2 the corresponding interval plots are
shown.
Autocorrelation analysis indicated the presence of
random R-R interval distributions in all recordings,
including those obtained at baseline. With the
exception of the first correlation coefficients, which
by definition equal + 1, in none of the recordings
did subsequent coefficients differ significantly from
zero. A representative example of an autocorrelogram is shown in Fig. 3.
DISCUSSION
To our knowledge, this study is the first attempt
systematically to analyse vagal effects on ventricular
rhythm in patients with AF. Our findings strengthen
the contention that the mechanism underlying the
heart-rate-lowering effect is twofold; (1) vagal stimulation exerts a direct depressant effect on AV node
conductivity, (2) vagal stimulation also indirectly
prolongs AV nodal refractoriness by enhancing concealed conduction.
M. P. van den Berg et al.
534
Methodological considerations
I
25
50
Coefficient no.
Fig. 3. Example of an autocorrelogram. With the exception of the first
correlation coefficient none of the coefficients differ significantly from zero,
indicating that the distribution of R-R intervals is random.
AV node conduction during AF
According to the prevailing concept [3-7, lo],
during A F the AV node is randomly bombarded by
atrial impulses, penetrating it to varying depths,
thereby rendering the node refractory for the conduction of subsequent impulses (‘concealed conduction’). Accordingly, an inverse relation exists
between atrial and ventricular rate. The shortest
R-R interval represents the functional refractory
period of the AV node, containing no concealed
atrial impulses. The longest R-R interval reflects
maximal concealment. In the present study, after
methylatropine the shortest R-R interval was significantly decreased, suggesting that vagal stimulation
increases AV nodal functional refractoriness during
AF. Furthermore, after methylatropine the parameters of concealed AV nodal conduction decreased, suggesting that vagal stimulation also augments concealed conduction. This study therefore
supports the presumed dual mechanism underlying
vagal effects on ventricular rhythm during A F [1,2].
Our findings in patients fully comply with experimental observations by Moe and Abildskov [lo],
who have shown that vagal stimulation during A F
in the dog heart both prolongs short and long
intervals, the effect on long intervals being more
pronounced.
An enhancing effect of vagal stimulation on concealed conduction during A F is readily conceivable,
considering the effect of vagal stimulation on atrial
fibrillatory activity. Vagal activity markedly shortens atrial refractoriness, thereby reducing the wavelength of atrial impulses during AF [S, 91. As a
result, fibrillatory activity, e.g. the number of circulating wavelets, increases. This in turn will lead to
enhanced concealed AV nodal conduction, as the
number of atrial impulses impinging on the node
thus increases [3-7, lo].
The majority of patients had associated cardiac
disorders. Although the presence of a P-R interval
I
0.22 s excludes gross AV conduction disturbances,
in patients with rheumatic and coronary heart
disease in particular the AV node may have been
diseased. In addition, most patients used drugs for
the control of ventricular rate, that affect atrial and
AV nodal electrophysiological properties. These
included digoxin, which exerts both direct and
indirect (vagomimetic) effects [lS]. These factors
hamper the interpretation of our findings.
Ventricular rhythm was random in all recordings,
including recordings after full-dose propranolol
(baseline). This implies that basal vagal tone (unopposed by sympathetic activity) was not associated
with high-degree AV block. Likewise, digoxinintoxication was unlikely, as associated rhythm and
conduction disturbances that may otherwise be hard
to detect, such as accelerated junctional rhythm and
high-degree AV block, would also cause nonrandomness. Finally, the fact that all histograms
showed a unimodal distribution (no separate peak
of R-R intervals) favours the absence of drug
toxicity.
At present, ‘in-site’ measurement of concealed AV
nodal conduction during A F is not feasible. Instead,
we used two indirect parameters of concealed conduction: the ratio of the longest to the shortest R-R
interval and the coefficient of variation of R-R
intervals. These parameters, however, possibly do
not ‘truly’ reflect the degree of concealed conduction. Therefore, no definite conclusions regarding
the effect of vagal stimulation on concealed conduction can be drawn from this study.
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