Download The normal range and determinants of the intrinsic heart rate in man

Cardiovascular Research 45 (2000) 177–184
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Update review
The normal range and determinants of the intrinsic heart rate in man q
Tobias Opthof*
Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 9, P.O. Box 22700, 1105 AZ Amsterdam,
The Netherlands
Abstract
Jose and Collison published a study on the normal range and the determinants of intrinsic heart rate in man in Cardiovascular Research
in 1970 [Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 1970; 4: 160–167)].
The intrinsic heart rate is the heart rate under complete pharmacological blockade. They showed that (i) the resting heart rate is lower than
the intrinsic heart rate and that (ii) the intrinsic heart rate declines with age. They also established that the variability in intrinsic heart rate
between individuals of the same age is of the same order as the effect of ageing at the population level. This update discusses the
relevance of these data with emphasis on sinus node function and autonomic balance. The paper of Jose and Collison was cited more than
200 times. The frequency of citation started to increase more than 10 years after publication.  2000 Elsevier Science B.V. All rights
reserved.
Keywords: Aging; Autonomic nervous system; Gender; Heart rate (variability); Sinus node
1. Introduction
In 1970 Jose and Collison published a study on the
normal range and the determinants of the intrinsic heart
rate in man in Cardiovascular Research. [1]. They did not
only study ‘intrinsic heart rate’, which they defined as the
heart rate under the simultaneous presence of the nonselective b-adrenoceptor antagonist propranolol (0.2 mg /
kg) and the muscarinic receptor blocker atropine (0.04
mg / kg), they also established the inverse relation between
age and intrinsic heart rate. Furthermore they made
separate analyses in females and males. Therefore the
paper included – apart from the measurement of the
intrinsic heart rate itself – additional important pieces of
information for later studies on areas varying from sinus
node dysfunction, autonomic balance, heart rate variability,
gender and aging (see preceding historical note [2]). The
authors could have made their paper even more attractive
by choosing another title. Fig. 1 taken from the original
paper [1] shows the relation between age and intrinsic
heart rate in normal males and females. Both in males and
females the intrinsic heart rate decreases, on the average,
from 107 beats / min at 20 years to 90 beats / min at 50
q
An update of the original paper by Jose AD and Collison D:
(Cardiovasc Res 1970;4:160–167)
*Tel.: 131-20-566-3265; fax: 131-20-697-5458.
E-mail address: [email protected] (T. Opthof)
years. At the same time Fig. 1 shows that the intrinsic
heart rate has 95% confidence limits of 615%. This
implies that the variability between individuals of the same
age is of the same order as the decrease of the mean
intrinsic heart rate of the whole population over about 55
years. In other words, the intrinsic heart rate of an
individual of 20 years may actually be lower than that of
another individual of 50 years. Obviously, this sets limits
to the significance of the aging induced decrease in heart
rate.
The interest of the authors in the pharmacological
concept of intrinsic heart rate had been raised by previous
work of Jose published in 1966 [3] and of Jose and Taylor
published in 1969 [4]. In those studies it had already been
established that heart rate becomes fixed under the combined presence of atropine and propranolol, which is
considered to cause complete autonomic blockade. However, propranolol only partially interferes with the activity
of the sympathetic limb of the autonomic nervous system,
because it blocks b-adrenoceptors but not a-adrenoceptors.
Furthermore, there is a classic, small, but convincing
literature which claims that vagal chronotropic effects
include – apart from the well known negative components
mediated by acetylcholine – also positive, i.e. acceleratory,
components (see section on autonomic balance). The
previous studies [3,4] were directed to normal individuals
as well as to patients with heart failure. Thus, Jose and
Taylor [4] showed that the intrinsic heart rate is different
0008-6363 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved.
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178
Determinants of the intrinsic heart rate in man
Fig. 1. The intrinsic heart rate in males and females as observed in the combined presence of propranolol (0.2 mg / kg body weight) and atropine sulphate
(0.04 mg / kg body weight). Reprinted from Jose AD, Collison D, The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res
1970;4:160–167, with permission from Elsevier Science.
in normal individuals and in NYHA class I, class II and
class III / IV patients. In normal patients (mean age 25
years) the intrinsic heart rate was 107 beats / min (comparable to the data in Fig. 1 taken from the paper published by
Cardiovascular Research in 1970 [1]). In class III / IV
patients the intrinsic heart rate was 79 beats / min in a
subgroup of patients with nonvalvular heart disease and 75
beats / min in a subgroup of patients with aortic stenosis.
The mean age of those patients was 50 years. The
significance of the paper of Jose and Collison [1] is that
the difference in intrinsic heart rate between normal
individuals and patients with heart failure can partially be
explained by the difference in age. The lower intrinsic
heart rate in patients with heart failure thus may in part
result from the underlying pathology. A lower intrinsic
heart rate has also been demonstrated in dogs with heart
failure (127 beats / min) compared with normal dogs (175
beats / min) [5]. A lower intrinsic heart rate in patients with
heart failure may point to impaired sinus node function. A
prolongation of cycle length in the isolated right atrium of
rabbits with heart failure has indeed been demonstrated [6].
Moreover, the effect of the combined administration of
propranolol and atropine, i.e. the difference between heart
rate at rest and intrinsic heart rate, is different in normal
individuals and in heart failure both in patients [4] and in
dogs [5].
The data of Jose and Collison [1] have been confirmed
by Alboni and colleagues [7] and extended to younger age
by Marcus and colleagues [8].
Intrinsic heart rate can be assessed by three ways: (i) in
vivo by pharmacological tools, (ii) in vivo by surgical
interventions, (iii) in vitro after isolation of the whole heart
(Langendorff perfusion) or the right atrium. Finally, cardiac transplantation is of interest, because those patients
Key publication: A.D. Jose and D. Collison / Cardiovascular Research 1970
179
have two sinus nodes, one innervated (in a rim of
remaining tissue of the explanted heart) and one denervated (the implanted-donor-heart).
2. Intrinsic heart rate and sinus node
The human heart beats about 100 000 times a day
resulting in 2 billion heartbeats during a lifetime. Normally
each cardiac activation originates from the sinus node
which was discovered by Martin Flack and Arthur Keith in
1906 in the mole’s heart [9–11]. The relevance of this new
anatomic structure was appreciated with little debate,
because electrophysiological techniques, needed to verify
the pacemaker hypothesis, were available at about the
same time as the anatomical discovery of the sinus node
[12–14]. The myogenic-neurogenic controversy with respect to cardiac automaticity started to be definitely settled
in 1921 by Eyster and Meek [15].
2.1. Differences in heart rate between species
Specific metabolic rate, that is metabolic rate relative to
body size, decreases in larger mammals [16,17]. Therefore
cardiac output relative to body size also decreases in larger
animals. Thus, it is a little surprising that all mammals
have the same relative heart mass: about 0.6% of body
mass [18]. Stroke volume, one of the two components of
cardiac output, increases also linearly with body weight
[16,17]. The decrease in relative cardiac output is solely
brought about by the other component of cardiac output:
heart rate. Fig. 2 (upper panel) shows the relation between
body weight and cycle length according to the formula
[17,19]:
BCL 5 0.249 ? BW 0.25
(1)
with basic cycle length (BCL) in seconds and body weight
(BW) in kilograms. Cycle length is thus longer (or heart
rate lower) in larger species. Fig. 2 (upper panel) further
shows that longevity (life span) also relates to body weight
according to the formula [20]:
Life span 5 11.8 ? BW
0.20
(2)
as far as mammals in captivity without the effects of
predation or critical food supply are concerned. Interestingly, by dividing formula (2) by formula (1) we obtain
the formula for the total number of heartbeats:
Total heartbeats ¯ 1.5 billion ? BW exp 20.05
(3)
Fig. 2 (lower panel) shows that the total number of
heartbeats during the whole life is more or less similar in
smaller and larger mammalian species, i.e. between 1 and
2 billion. Readers applying this formula to themselves,
may be surprised to be still alive. The formula is not
Fig. 2. Upper panel: Relation between body weight (BW; in kg) and
cycle length (BCL; in ms) according to the formula (1) BCL50.249?
BW 0.25 for mammals. See also Refs. [17,19]. Relation between body
weight (BW; in kg) and life span (in years) according to the formula (2)
Life span511.8?BW 0.20 for mammals. See also Refs. [17,20]. Lower
panel: Relation between body weight (BW; in kg) and total heart beats
(?billion) for mammals. This relation has been obtained by dividing
formula (2) by formula (1).
pertinent to humans, because we live much longer than
expected from body weight.
How is it possible that the heart of a small animal beats
so much faster than the heart of a larger animal? For
instance, at one side of the mammalian spectrum of
pacemaking we find the bat. During flight its heart rate
may increase to more than 1000 beats / min [21]. More
recently, by the interest in transgenic mice, data have
become available on heart rate in freely moving mice. It is
about 500 beats / min in rest [22,23] and it can easily
increase to 800 beats / min ([22]; but see also Rappaport in
Ref. [24]). Heart rate in big animals as elephants is about
25 beats / min [25] and in whales it can be well below 20
beats / min [24]. Are the intrinsic properties of the pace-
180
Determinants of the intrinsic heart rate in man
maker fibres in these species so very different, or does a
longer cycle length, also result from the coupling of
increasing numbers of more or less similar cells? Coupling
of sinus node cells is a prerequisite for regularity, because
isolated pacemaker cells have a variable beat-to-beat
interval [26,27]. Also the sinus node beats faster if
detached from the right atrium [28] and subdivision of a
whole rabbit sinus node (73230.3 mm) into small
specimens (0.830.830.3 mm) renders numerous pieces
with a substantially higher rate than the whole sinus node
[27]. Coupling of more and more automatic elements thus
results in lower heart rate. The decrease in intrinsic heart
rate with age (Fig. 1) may result from changes in density
of specific membrane currents (beyond the scope of this
paper, but see [29–32]), intercellular coupling by specific
connexins forming gap junctions (beyond the scope of this
paper, but see [33,34]) and / or fibrosis (see next section).
2.2. Differences in nodal dimensions between species
In the previous section we have shown that larger hearts
have lower heart rates. Also, we have seen that coupling of
more pacemaker cells yields regularity, but also a lower
rate. Thus, the question arises whether larger hearts have
larger sinus nodes.
There is surprisingly little information on sinus node
dimensions. As with the atrioventricular node node [35],
there is a tendency towards larger sinus nodal dimensions
in larger animals (for review [36]). Thus, in rodents the
nodal length is in the mm range [36], whereas reports on
the length of the human sinus node vary from 7 mm [37]
to 20 mm [14]. In cow and horse the length is 30 mm
[38,39]. It is not clear, whether a larger sinus node is a
prerequisite for pacemaking in a larger heart per se, or
that, alternatively, a larger sinus node is a prerequisite to
obtain a slower heart rate, which is necessary to maintain
adequate pump function in a larger heart. It is emphasised
that the boundaries of the SAN cannot be determined
accurately.
2.3. Differences in heart rate with aging: collagen and
myocyte content or intrinsic electrophysiological
changes?
Electrical coupling is important for the automaticity of
the sinus node, but also for driving the whole heart. Too
much electrical coupling may lead to quiescence of the
sinus node caused by the hyperpolarizing atrium, whereas
too little electrical coupling may lead to a ‘pace, but not
drive’ condition [40]. There are no data on the effects of
aging on intercellular coupling to explain a change in
intrinsic heart rate as observed by Jose and Collison [1].
Fibrosis may, however, present another parameter that may
substantially affect intercellular coupling.
A substantial amount of collagen is present in the sinus
node [41]. In normal human hearts the amount of collagen
increases until 20 years [41–46]. According to some
authors this gradual increase stabilizes at 20 years [46] or
at 40 years [43], whereas a more gradual increase until 80
years [45] and a relatively late increase (above 70 years)
have also been described [44]. This confusion is presumably explained by the fact that at any age the differences
between individuals are more striking than the effect of
aging itself [42,46]. Unfortunately, it is unknown whether
the amount of collagen is of any value at all in assessing
pacemaker function. There are both clinical [47] and
experimental examples [48] of extreme structural abnormalities with apparently normal function. An increase in
collagen content is not synonymous with a decrease in
myocyte content, because collagen fibres may also substitute for fibroblasts or amorphous matrix. A decrease in
myocyte content with age has been determined in normal
hearts [41,43,49,50], but such a decrease would in itself
not necessarily lead to a decrease in heart rate. Despite the
availability of a relatively large amount of studies on
collagen content, we cannot be sure that an increased
amount of collagen explains the constant decrease in
intrinsic heart rate with age as shown by Jose and Collison
in Fig. 1 [1]. Even the large interindividual variability in
intrinsic heart rate at any age (615%, see Fig. 1) may be
associated, but not necessarily causally related with the
large interindividual variability in collagen content of
human sinus nodes of the same age (see Fig. 4 in Ref.
[46]). An experimental study in cat and rabbit sinus node
has demonstrated that the rate of diastolic depolarisation
decreases with aging [51]. Therefore decreased diastolic
depolarisation of the sinus node with aging constitutes the
only parameter with a causal relation with the decrease in
intrinsic heart rate.
2.4. Differences between individuals within the same
species of the same age
So far we have dealt with interspecies differences in
heart rate and with differences caused by age. There are,
however, also striking differences between individuals of
the same species and age. In a selection of studies on
isolated rabbit right atrium preparations sinus rate varied
from 77 to 218 beats / min (Fig. 3 in Ref. [52]). A
subselection of studies with identical temperature and
extracellular K 1 concentration still showed sinus rates
from 114 to 185 beats / min [52]. These were averaged
sinus rates in different studies in the rabbit. Fig. 3 (from
Ref. [53]) shows that sinus rate of individual isolated
rabbit right atria varies from 120 to 200 beats / min (cycle
length 300–500 ms) within the same study. Lower and
higher sinus rates probably result from different sets of
membrane currents. Fig. 3 shows that this interindividual
variability disappears when both the Na 1 and Ca 21
concentrations are lowered by 50% resulting in a constant
sinus rate of 143 beats / min (cycle length 418 ms).
Apparently the intrinsic differences between individual
Key publication: A.D. Jose and D. Collison / Cardiovascular Research 1970
Fig. 3. Cycle length of rabbit sinus node at normal Na 1 concentration
(100%) and normal Ca 21 concentration (2.2 mMol / l), at normal Na 1
concentration (100%) and low Ca 21 concentration (1.1 mMol / l), at low
Na 1 concentration (50%) and normal Ca 21 concentration (2.2 mMol / l)
and at low Na 1 concentration (50%) and low Ca 21 concentration (1.1
mMol / l). Under all circumstances there is a large variability between
individual sinus nodes despite identical experimental circumstances.
However, if both the Ca 21 and the Na 1 concentrations are low, this
interindividual variability disappears and cycle length is about 420 ms in
sinus nodes from all animals (n510). Reproduced with permission of the
American Society for Pharmacology and Experimental Therapeutics from
Ref. [53].
sinus nodes disappear under those circumstances by impaired driving force for currents responsible for diastolic
depolarisation. Unfortunately, voltage- or patch-clamp
studies on single cells isolated from intact sinus nodes
cannot easily explain these differences in intrinsic rate,
because single cells are irregular [27].
3. Innervation and the autonomic balance
3.1. Innervation and receptor density
Papers on innervation of the sinus node report that
‘nerve supply is rich’ [54–56], but there is little detailed
information available. The location of ganglion cells in or
near the sinus node is species dependent [57]. There is
inhomogeneity in innervation because vagal stimulation
[58–62] and sympathetic stimulation [63,64] both cause
shifts in the site of pacemaker dominance and activation
pattern. There is also dispersion in receptor density,
because addition of acetylcholine and adrenaline also
changes pacemaker hierarchy [65–67]. Small nerves in the
sinus node in general contain 5–15 axons. When the nerves
become smaller and smaller they gradually lose the
Schwann sheet and they end as naked axons in clefts
between the nodal cells. Gaps between varicosities and
nodal cells are 20–100 mm depending on the species [68].
Adrenergic and non-adrenergic varicosities are found in
181
close vicinity of each other. In one study, electrophysiological measurements preceded the analysis of nerve
supply in the rabbit sinus node [69]. There is a large
ganglionic complex inferior to the sinus node. Nerves
impinge on the sinus node from the direction of the
superior and inferior venae cavae and from the interatrial
septum. Two or more major intrinsic nerves traverse the
sinus node parallel to the crista terminalis. Moreover, small
neurons (10–12 mm) seem to be clustered, forming baskets
around nodal cells [69] rather than being homogeneously
distributed over the nodal area. This may explain why
pacemaker shifts due to changes in temperature or ionic
composition of the extracellular fluid are more or less
gradual, whereas adrenaline or acetylcholine produce more
abrupt changes in activation pattern, because the dominant
pacemaker area ‘jumps’ from one area with a certain ratio
of adrenoceptors and muscarinic receptors towards another
with another ratio [36]. With respect to muscarinic receptors it should be kept in mind that areas with the lowest
density are more prone to establish pacemaker dominance
than areas with a high density. Probably, also afferent
nerve endings are present in the sinus node [68,70,71].
Quantitative data on receptor density are scarce. Given
the more dense nerve supply to the sinus node compared to
normal atrium, it is not surprising that the density of
muscarinic and b 1 -adrenoceptors are five and three times
larger respectively in the canine sinus node than in atrial
myocardium [72].
3.2. Autonomic balance
The interrelations of vagal and sympathetic effects on
cardiac rate were for the first time quantitatively assessed
by Rosenblueth and Simeone in 1934 [73] by the formula:
HR 5 m ? n ? HR 0
in which HR is heart rate (beats / min), m is sympathetic
influence (m$1), n is vagal influence (0,n#1) and HR 0
is intrinsic heart rate (beats / min). The sympathovagal
balance can be approached by HR / HR 0 . Fig. 4 (adapted
from the original Figs. 1 and 2 in Ref. [52]) shows that the
rate of an isolated rabbit right atrium is much lower than
the in vivo heart rate. Also, there is much more beat to
beat variability in the in vivo heart rate. Thus, there is a
prevailing sympathicotonus in the rabbit (as in rodents).
This does not imply that there is no vagal influence:
deafferentiation of the aortic and carotid baroreceptors
increases heart rate. Table 1 (compiled from Refs. [74,75])
shows vagal predominance in the dog: the spontaneous
heart rate in the instrumented conscious dog is lower (112
beats / min) than under combined muscarinic plus b-adrenoceptor blockade (160 beats / min) [74]. Also, in man
vagal predominance results in a much lower resting heart
rate than in the intrinsic heart rate shown by Jose and
Collison [1].
182
Determinants of the intrinsic heart rate in man
Fig. 4. Heart rate in normal conscious rabbits (‘in vivo’) and in rabbits
with deafferentiated baroreceptors in the carotic and aortic sinuses
(‘deafferentiated’). The isolated right atrium has a lower rate and displays
hardly beat to beat variability (‘right atrium’). The in vivo heart rate is
faster indicating a prevailing sympathetic tone. A vagal tone is nevertheless present, because deafferentiation causes a further increase in heart
rate. Compiled from Ref. [52].
The effect of pharmacological autonomic blockade is
complicated. The Table 1 shows differences between the
effects of combined muscarinic blockade and b-adrenoceptor blockade and vagotomy and b-adrenoceptor blockade. Obviously, in the conscious dog [74] the intrinsic
heart rate is much higher during (complete?) pharmacological blockade (160 beats / min) than during the combination of vagotomy and b-adrenoceptor blockade (95 beats /
min). This discrepancy may be due to the presence of
Table 1
Heart rate in conscious dogs (1) without pharmacological blockade and
(2) with pharmacological autonomic blockade by timolol (0.2 mg / kg and
0.2 mg / kg / h i.v.) and methylatropine (0.5 mg / kg and 0.5 mg / kg / h i.v.)
and (3) with vagotomy during b-adrenoceptor blockade (timolol; 0.2
mg / kg and 0.2 mg / kg / h i.v.) and (4) in isolated right atria from dogs a
Condition
Spontaneous
Vagotomy
b-adrenoceptor blockade
b-adrenoceptor1
muscarinic blockade
b-adrenoceptor blockade1
vagotomy
Isolated right atrium
a
Heart rate
(beats / min)
Reference
112
128
77
[74]
[74]
[74]
160
[74]
95
127
[74]
[75]
Compiled from Ref. [74] (‘spontaneous and autonomic blockade’)
and Ref. [75] (‘isolated sinus node’). The isolated sinus node data were
from pups [75].
cardio-accelerator fibres in the vagal nerves [76–81]. The
mediators of this ‘non-muscarinic’ effect is probably a
peptide factor [80,81].
Pacemaker shifts are relevant for the chronotropic
response to changes in sympathetic (autonomic) tone [36].
The same amount of (nor)epinephrine produces little
acceleration, when the acetylcholine concentration or vagal
tone is higher [66,82,83]. In contrast, in the presence of a
high noradrenaline concentration or a high sympathetic
tone, the effect of acetylcholine is large. This phenomenon
has been named ‘accentuated antagonism’ and has been
explained by interaction between the two limbs of the
autonomic nervous system at the pre- and postjunctional
sites [82,84]. Although this explanation seems valid, it
should be noted that at least the rabbit sinus node
comprises areas with low, intermediate and high responsiveness to both transmitters of the autonomic nervous
system [67]. A high vagal tone shifts pacemaker dominance to areas with low responsiveness to both transmitters, whereas a high sympathetic tone shifts pacemaker
dominance to areas with high responsiveness to both
transmitters. It has been observed in dogs that bilateral
vagal stimulation results in lower heart rate in combination
with stellate ganglion stimulation than in combination with
norepinephrine infusion [85]. Although a prejunctional
interaction may explain this observation, there certainly is
an alternative explanation. High vagal tone will shift the
pacemaker to an area with lowest innervation. Such an area
may still accelerate in response to circulating catecholamines, but not or much less to sympathetic stimulation,
simply because there is little innervation of that particular
area. Thus, in addition to pre- or post-junctional interaction, pacemaker shifts certainly in part explain the
‘accentuated antagonism’. We emphasise the intricate
mechanism by which the sinus node responds to catecholamines, because heart rate often is taken as an index for
general sympathetic or autonomic input to the whole heart.
However, even if heart rate is kept constant, although
exerted by different combinations of vagal and sympathetic
input, it has been demonstrated that refractoriness in atria
and ventricles may change substantially [86] (see also
[87–89]).
4. Concluding remarks
Jose and Collison have demonstrated that the intrinsic
heart rate decreases with age in man [1]. Unfortunately, it
is not completely certain that the intrinsic heart rate as
determined by Jose and Collison [1] really reflects an
intrinsic characteristic of the heart. Two issues remain to
be settled: (i) The observed decrease in heart rate with age
in the combined presence of propranolol and atropine may
also be caused by a change in a-adrenoceptor density in
the sinus node area. (ii) The non-muscarinic effects of
vagal stimulation may change during aging. As long as
Key publication: A.D. Jose and D. Collison / Cardiovascular Research 1970
these two issues have not been settled, changes in ‘intrinsic
heart rate’ between control groups of patients and groups
of patients with heart disease cannot unequivocally be
ascribed to an intrinsic property of the heart (the sinus
node), even if there is no age difference between the
groups.
References
[1] Jose AD, Collison D. The normal range and determinants of the
intrinsic heart rate in man. Cardiovasc Res 1970;4:160–167.
[2] Opthof T, Coronel R. The normal range and determinants of the
intrinsic heart rate in man. Historical note on the paper by Jose AD,
Collison D. (Cardiovasc Res 1970; 4: 160–167). Cardiovasc Res
2000;45:175–176.
[3] Jose AD. Effect of combined sympathetic and parasympathetic
blockade on heart rate and cardiac function in man. Am J Cardiol
1966;18:476–478.
[4] Jose AD, Taylor RR. Autonomic blockade by propranolol and
atropine to study intrinsic myocardial function in man. J Clin Invest
1969;48:2019–2031.
[5] Vatner SF, Higgins CB, Braunwald E. Sympathetic and parasympathetic components of reflex tachycardia induced by hypotension in
conscious dogs with and without heart failure. Cardiovasc Res
1974;8:153–161.
[6] Opthof T., Rademaker H., Vermeulen J.T. et al. Intrinsic sinoatrial
cycle length and the responsiveness to acetylcholine increase during
the progression of heart failure in the rabbit. Eur Heart J 1997;18
(Abstr Suppl):358 (abstract).
[7] Alboni P, Malacarne C, Pedroni P, Masoni A, Narula OS. Electrophysiology of normal sinus node with and without autonomic
blockade. Circulation 1982;65:1236–1242.
[8] Marcus B, Gillette PC, Garson A. Intrinsic heart rate in children and
young adults: an index of sinus node function isolated from
autonomic control. Am Heart J 1990;119:911–916.
[9] Keith A, Flack M. The form and nature of the muscular connections
between the primary divisions of the vertebrate heart. J Anat Physiol
1907;41:172–189.
[10] Keith A. The sino-auricular node: a historical note. Br Heart J
1942;4:77–79.
[11] Brooks CMC, Lu HH. The sinoatrial pacemaker of the heart,
Springfield, Illinois: Charles C. Thomas, 1972.
[12] Flack M. An investigation of the sino-auricular node of the
mammalian heart. J Physiol 1910;41:64–77.
[13] Lewis T, Oppenheimer BS, Oppenheimer A. The site of origin of
the mammalian heart-beat; the pacemaker in the dog. Heart
1910;2:147–169.
[14] Lewis T. The mechanism of the heartbeat, London: Shaw, 1911.
[15] Eyster JAE, Meek WJ. The origin and conduction of the heart beat.
Physiol Rev 1921;1:1–43.
[16] Kleiber M. The fire of life. An introduction to animal energetics,
New York: Wiley, 1961.
[17] Schmidt-Nielsen K. Scaling. Why is animal size so important,
Cambridge / New York / Melbourne: Cambridge University Press,
1984.
[18] Prothero J. Heart weight as a function of body weight in mammals.
Growth 1979;43:139–150.
[19] Stahl WR. Scaling of respiratory variables in mammals. J Appl
Physiol 1967;22:453–460.
[20] Sacher GA. Relation of life span to brain weight and body weight in
mammals. In: Wolstenholme GEW, editor, Ciba foundation colloquium on aging, Vol 1, 1959, pp. 115–141.
[21] Studier EH, Howell DJ. Heart rate of female big brown bats in
flight. J Mammal 1969;50:842–845.
183
[22] Kramer K, Van Acker SA, Voss HP et al. Use of telemetry to record
electrocardiogram and heart rate in freely moving mice. J Pharmacol
Toxicol Methods 1993;30:209–215.
[23] Desai K, Sato R, Schauble E et al. Cardiovascular indexes in the
mouse at rest and with exercise: new tools to study models of
cardiac disease. Am J Physiol 1997;272:H1053–H1061.
[24] White PD, King RL, Jenks J. The relation of heart size to the time
intervals of the heart beat, with particular reference to the elephant
and the whale. New Engl J Med 1953;248:69–70.
[25] Kolbe E. Lehrbuch der physiologie der haustiere, 4th ed., Jena:
Gustav Fischer Verlag, 1981.
[26] Jongsma HJ, Tsjernina L, De Bruijne J. The establishment of regular
beating in populations of pacemaker heart cells. A study with tissue
cultured rat heart cells. J Mol Cell Cardiol 1983;15:123–133.
[27] Opthof T, Van Ginneken ACG, Bouman LN, Jongsma HJ. The
intrinsic cycle length of small pieces isolated from the rabbit
sinoatrial node. J Mol Cell Cardiol 1987;19:923–934.
[28] Kirchhof CJHJ, Bonke FIM, Allessie MA, Lammers WJEP. The
influence of the atrial myocardium on impulse formation in the
¨
rabbit sinus node. Pflugers
Arch 1987;410:198–203.
[29] Brown HF. Electrophysiology of the sinoatrial node. Physiol Rev
1982;62:505–530.
[30] Noble D. The initiation of the heartbeat, Oxford: Clarendon Press,
1979.
[31] Noble D. The surprising heart: a review of recent progress in cardiac
electrophysiology. J Physiol 1984;353:1–50.
[32] Irisawa H, Brown HF, Giles WG. Cardiac pacemaking in the
sinoatrial node. Physiol Rev 1993;73:197–227.
[33] Opthof T. Gap junctions in the sinoatrial node: immunohistochemical localization and correlation with activation pattern. J Cardiovasc
Electrophysiol 1994;5:138–143.
[34] Verheule S. Distribution and physiology of mammalian cardiac gap
junctions. Utrecht: University of Utrecht, 1999 (Thesis).
[35] Meijler F, Janse MJ. Morphology and electrophysiology of the
mammalian atrioventricular node. Physiol Rev 1988;68:608–647.
[36] Opthof T. The mammalian sinoatrial node. Cardiovasc Drugs Ther
1988;1:573–597.
[37] Truex RC, Smythe MQ, Taylor MJ. Reconstruction of the human
sinoatrial node. Anat Rec 1967;159:371–378.
[38] Glomset DJ, Glomset AT. Morphologic study of cardiac conduction
system in ungulates, dog and man. Am Heart J 1940;20:389–397.
[39] Hayashi K. An electron microscopic study on the conduction system
of the cow heart. Jpn Circ J 1962;26:765–842.
[40] Joyner RW, Van Capelle FJL. Propagation through electrically
coupled cells. How a small SA node drives a large atrium. Biophys J
1986;50:1157–1164.
[41] James TN. The sinus node. Am J Cardiol 1977;40:965–986.
[42] James TN. Anatomy of the human sinus node. Anat Rec
1961;141:109–139.
[43] Lev M. Aging changes in the human sinoatrial node. J Gerontol
1954;9:1–9.
[44] Fujino M, Okada R, Arakawa K. The relationship of aging to
histological changes in the conduction system of the normal human
heart. Jpn Heart J 1983;24:13–20.
[45] Buruljanowa I, Wassilew G, Radanov S. Altersbedingte Strukturver¨
anderungen
in dem Reizleitungssystem des menslichen Herzens.
Zentralbl allg Pathol pathol Anat 1987;133:433–438.
[46] Alings AM, Abbas RF, Bouman LN. Age-related changes in
structure and relative collagen content of the human and feline
sinoatrial node. A comparative study. Eur Heart J 1995;16:1655–
1667.
[47] Demoulin JC, Kulbertus HE. Histopathological correlates of
sinoatrial disease. Br Heart J 1978;40:1384–1389.
´
[48] Opthof T, De Jonge B, Masson-Pevet
M, Jongsma HJ, Bouman LN.
Functional and morphological organization of the cat sinoatrial
node. J Mol Cell Cardiol 1986;18:1015–1031.
[49] James TN, Sherf L, Fine G, Morales AR. Comparative ultrastructure
of the sinus node in man and dog. Circulation 1966;34:139–163.
184
Determinants of the intrinsic heart rate in man
[50] Davies MJ, Pomerance A. Quantitative study of ageing changes in
the human inoatrial node and internodal tracts. Br Heart J
1972;34:150–152.
[51] Alings AM, Bouman LN. Electrophysiology of the aging rabbit and
cat sinoatrial node. A comparative study. Eur Heart J 1993;14:1278–
1288.
[52] Bouman LN, Opthof T, Mackaay AJC, Bleeker WK, Jongsma HJ.
On the intrinsic cardiac rhythm. In: Bouman LN, Jongsma HJ,
editors, Cardiac rate and rhythm, Boston / Dordrecht / Lancaster:
Martinus Nijhoff, 1982, pp. 483–493.
[53] Opthof T, Mackaay AJC, Bleeker WK et al. Dependence of the
chronotropic effects of calcium, magnesium and sodium on temperature and cycle length in isolated rabbit atria. J Pharmacol Exp Ther
1980;212:183–189.
[54] Trautwein W, Uchizono K. Electron microscopic and electrophysiologic study of the pacemaker in the sinoatrial node of the
rabbit heart. Z Zellforsch 1963;61:96–109.
[55] Nilsson E, Sporrong B. Electron microscopic investigation of
adrenergic and non-adrenergic axons in the rabbit SA-node. Z
Zellforsch 1970;111:404–412.
[56] Yamauchi A. Ultrastructure of the innervation of the mammalian
´
heart. In: Challice CE, Viragh
S, editors, Ultrastructure of the
mammalian heart, London: Academic Press, 1973, pp. 127–172.
[57] King TS, Coakley JB. The intrinsic nerve cells of the cardiac atria of
mammals and man. J Anat 1958;92:353–379.
[58] Meek WJ, Eyster JAE. Experiments on the origin and propagation of
the impulse in the heart. Am J Physiol 1914;34:368–383.
[59] Toda N, West TC. Interaction between Na, Ca. Mg and vagal
stimulation in the S.-A. node of the rabbit. Am J Physiol
1967;212:424–430.
[60] Bouman LN, Gerlings ED, Biersteker PA, Bonke FIM. Pacemaker
¨
shift in the sino-atrial node during vagal stimulation. Pflugers
Arch
1968;302:255–267.
[61] Toda N. Cholinergic actions in the sinoatrial node of the reserpinepretreated rabbit. J Pharmacol Exp Ther 1968;159:290–297.
[62] Spear JF, Kronhaus KD, Moore EN, Kline RP. The effect of brief
vagal stimulation on the isolated rabbit sinus node. Circ Res
1979;44:75–88.
[63] Toda N, Shimamoto K. The influence of sympathetic stimulation on
transmembrane potentials in the S-A node. J Pharmacol Exp Ther
1968;159:298–305.
[64] Geesbrecht JM, Randall WC. Area localization of shifting cardiac
pacemakers during sympathetic stimulation. Am J Physiol
1971;220:1522–1527.
[65] West TC. Ultramicroelectrode recording from the cardiac pacemaker. J Pharmacol Exp Ther 1955;115:283–290.
[66] Mackaay AJC, Opthof T, Bleeker WK, Jongsma HJ, Bouman LN.
Interaction of adrenaline and acetylcholine on cardiac pacemaker
function. Functional inhomogeneity of the rabbit sinus node. J
Pharmacol Exp Ther 1980;214:417–422.
[67] Mackaay AJC, Opthof T, Bleeker WK, Jongsma HJ, Bouman LN.
Interaction of adrenaline and acetylcholine on sinus node function.
In: Bouman LN, Jongsma HJ, editors, Cardiac rate and rhythm, The
Hague / Boston / London: Martinus Nijhoff, 1982, pp. 507–523.
[68] Tranum-Jensen J. The fine structure of the sinus node: a survey. In:
Bonke FIM, editor, The sinus node. Structure, function and clinical
relevance, The Hague / Boston / London: Martinus Nijhoff Medical
Division, 1978, pp. 149–165.
[69] Roberts LA, Slocum GR, Riley DA. Morphological study of the
innervation pattern of the rabbit sinoatrial node. Am J Anat
1989;185:74–88.
[70] Kostreva DR, Zuperku EJ, Purtock RV, Coon RL, Kampine JP.
Sympathetic afferent nerve activity of right heart origin. Am J
Physiol 1975;229:911–915.
[71] Malliani A, Lombardi F, Pagani M. Sensory innervation of the heart.
Prog Brain Res 1986;67:39–48.
[72] Beau SL, Hand DE, Schuessler RB et al. Relative densities of
muscarinic cholinergic and b-adrenergic receptors in the canine
sinoatrial node and their relation to sites of pacemaker activity. Circ
Res 1995;77:957–963.
[73] Rosenblueth A, Simeone FA. The interrelations of vagal and
accelerator effects on the cardiac rate. Am J Physiol 1934;110:42–
45.
[74] Roossien A, Brunsting JR, Nijmeijer A, Zaagsma J, Zijlstra WG.
Effects of vasoactive intestinal polypeptide on heart rate in relation
to vagal cardioacceleration in conscious dogs. Cardiovasc Res
1997;33:392–399.
[75] Woods WT, Urthaler F, James TN. Spontaneous action potentials of
cells in the canine sinus node. Circ Res 1976;39:76–82.
[76] Dale HH, Laidlaw PP, Symons CT. A reversed action of the vagus
on the mammalian heart. J Physiol 1910;41:1–18.
[77] Kabat H. The cardio-accelerator fibers in the vagus nerve of the dog.
Am J Physiol 1940;128:246–257.
[78] Donald DE, Samueloff SL, Ferguson D. Mechanisms of tachycardia
caused by atropine in conscious dogs. Am J Physiol 1967;212:901–
910.
[79] Rigel DF, Lipson D, Katona PG. Excess tachycardia: heart rate after
antimuscarinic agents in conscious dogs. Am J Physiol
1984;246:H168–H173.
[80] Henning RJ. Vagal stimulation during muscarinic and b-adrenergic
blockade increases atrial contractility and heart rate. J Autonom
Nerv Syst 1992;40:121–130.
[81] Roossien A, Brunsting JR, Nijmeijer A, Schuil HA, Zijlstra WG.
Mechanism of the decline in vagal acceleration in dogs in neuroleptanaesthesia. J Autonom Nerv Syst 1995;54:1–8.
[82] Levy MN. Sympathetic-parasympathetic interactions in the heart.
Circ Res 1971;29:437–445.
[83] Opthof T, Mackaay AJC, Bleeker WK, Jongsma HJ, Bouman LN.
Cycle length dependence of the chronotropic effects of adrenaline
and acetylcholine in the rabbit sinoatrial node. J Autonom Nerv Syst
1983;8:193–204.
[84] Zipes DP, Miyazaki T. The autonomic nervous system and the heart:
basis for understanding interactions and effects on arrhythmia
development. In: Zipes DP, Jalife J, editors, Cardiac electrophysiology. from cell to bedside, Philadelphia: W.B. Saunders, 1990, pp.
312–330.
[85] Takahashi N, Zipes DP. Vagal modulation of adrenergic effects of
canine sinus and atrioventricular nodes. Am J Physiol
1983;244:H775–H781.
[86] Inoue H, Zipes DP. Changes in atrial and ventricular refractoriness
and in atrioventricular nodal conduction produced by combinations
of vagal and sympathetic stimulation that result in a constant
spontaneous cycle length. Circ Res 1987;60:942–951.
[87] Schwartz PJ, Vanoli E, Stramba-Badiale M et al. Autonomic
mechanisms and sudden death. New insights from analysis of
baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation 1988;78:969–979.
[88] Coumel P, Leenhardt A. Mental activity, adrenergic modulation, and
cardiac arrhythmias in patients with heart disease. Circulation
1991;83:II58–II70.
[89] Rea RF, Martins JB, Mark AL. Baroreflex impairment and sudden
death after myocardial infarction. Circulation 1988;78:1072–1074.