Heart rate as a determinant of cardiac function: Basic mechanisms and clinical significance

270 Pages·2000·6.297 MB·English

by  H. R. Kirchheim, A. Just, H. Ehmke (auth.), Prof. Dr. G. Hasenfuss, Prof. Dr. H. Just (eds.)

G. Hasenfuss . H. Just (Eds.) • Heart rate as a determinant of cardiac function
G. Hasenfuss . H. Just
Editors
Heart rate
as a determinant
of cardiac function
Basic mechanisms
and clinical significance
t
Springer
Prof. Dr. G. Hasenfuss
Abteilung Kardiologie und Pneumologie der Universitat Gottingen
Robert-Koch-StraBe 40,37075 Gottingen, Germany
Prof. Dr. H. Just
Medizinische Fakultat, Ethik Kommission
Elsasser StraBe 2a, Haus la, 79110 Freiburg, Germany
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ISBN-13: 978-3-642-47072-1 e-ISBN-13: 978-3-642-47070-7
DOl: 10.1007/978-3-642-47070-7
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Introduction
Numerous studies have indicated that in a variety of cardiac diseases the influence of heart
rate on cardiac function is altered and that both heart rate and heart rate variability are of
great relevance for the prognosis of cardiac patients.
Heart rate is an important determinant of cardiac function. In humans and most animal
species, increased heart rate during exercise enhances cardiac output through an increased
number of beats per minute as well as by its action on myocardial performance. The latter
effect, termed the force-frequency relation, strength-interval relation or TREPPE (staircase)
phenomenon was first observed by Bowditch in the isolated frog heart. Recent studies
demonstrated that in failing human myocardium the force-frequency relation is flattened or
inversed. The altered force-frequency relation results from disturbed function at the level
of the myocyte due to disturbed calcium homeostasis. The latter may be the consequence
of altered transsarcolemmal calcium influx, altered sarcoplasmic reticulum calcium uptake
and release as well as of altered sarcolemmal sodium-calcium exchange. Knowledge of the
subcellular defects underlying disturbed calcium homeostasis may allow the development
of new therapeutic strategies to treat heart failure patients. In addition, the finding of an
altered force-frequency relation in the failing human heart may suggest that heart rate
reduction is of critical importance for patients suffering from heart failure. In this regard,
the beneficial effects of j3-blockers as well as of amiodarone observed in patients with con
gestive heart failure may be partially related to the effect of those agents on heart rate.
During the last decade many studies also demonstrated that heart rate and heart rate vari
ability have significant impact on arrhythmogenesis and prognosis in patients with cardiac
diseases. In patients with heart failure, heart rate is increased and heart rate variability and
baroreceptor reflex sensitivity are decreased. All three changes reflect a relative increase of
the sympathetic over the parasympathetic nervous system. The mechanisms underlying this
autonomic imbalance are complex and not completely understood. Heart rate variability as
a reflection of the balance of the sympathetic and parasympathetic nervous system is related
to electrical stability of the myocardium. Increased vagal activity is associated with
increased heart rate variability and a decrease in the high frequency band in the spectral
analysis of heart rate variability. Most clinical studies observed an increase in heart rate and
in low to high frequency ratio in the spectral analysis of heart rate variability prior to spon
taneous episodes of ventricular tachycardia in patients after myocardial infarction. The latter
indicates a decrease in vagal relative to sympathetic tone. Heart rate variability was also
shown to be a good and independent predictor of mortality of patients after myocardial
infarction. Furthermore, it was observed that heart rate variability is reduced in patients with
heart failure within 24 hours before onset of ventricular tachycardia. Whether or not phar
macological agents which influence heart rate and heart rate variability may be associated
with altered prognosis is not known yet.
In the Gargellen Conference "Heart rate as a determinant of cardiac function - Basic
mechanisms and clinical significance" international experts in this field were brought
together to elaborate on the interrelation between heart rate and myocardial function,
arrhythmias, prognosis, and therapy of patients with cardiac diseases. Basic mechanisms
as well as clinical relevance and therapeutic consequences were critically discussed.
Gottingen, May 2000 G. Hasenfuss
Contents
Introduction ............................. ........................... V
Regulation of heart rate
Physiology and pathophysiology of baroreceptor function and
neuro-hormonal abnormalities in heart failure
Kirchheim, H. R., A. Just, H. Ehmke ... .... .. ... .. .. ........... ........ .
Heart rate and myocardial function
A mechanistic analysis of the force-frequency relation in non-failing
and progressively failing human myocardium
Alpert, N. R., B. 1. Leavitt, F. P. Ittleman, G. Hasenfuss, B. Pieske,
L. A. Mulieri .. .. ..... .. ........................................ ..... 37
Post-rest contraction amplitude in myocytes from failing human ventricle
Davia, K., S. E. Harding .............................................. 53
Influence of SR Ca2+-ATPase and Na+-Ca2+-exchanger on the force-frequency
relation
Schillinger, W., S. E. Lehnart, J. Prestle, M. Preuss, B. Pieske, L. S. Maier,
M. Meyer, H. Just, G. Hasenfuss ... ..... .. ... ....... .. ... .... ........... 63
Force-frequency relations in nonfailing and failing animai myocardium
Crozatier, B. ... ................... ............. ......... .... .. ...... 77
Influence of stimulation frequency on subcellular systems
Heart rate as a determinant of L-type Ca2+ channel activity:
Mechanisms and implication in force-frequency relation
Lemaire, S., C. Piot, F. Leclercq, V. Leuranguer, J. Nargeot, S. Richard 85
Electrophysiologieal aspects of changes in heart rate
Ravens U., E. Wettwer ....................................... ......... 99
Influence of Forskolin on the force-frequency behavior in nonfailing
and endstage failing human myocardium
Pieske B., S. Trost, K. Schlitt, K. Minami, H. Just, G. Hasenfuss .............. 109
VIII Contents
Modulation of the force-frequency relation
Effect of inotropic interventions on the force-frequency relation
in the human heart
Bavendiek U., K. Brixius, G. Munch, C. Zobel, J. Muller-Ehmsen,
R. H. G. Schwinger .................................................. 125
Effects of cytokines and nitric oxide on myocardial E-C coupling
Haque R, H. Kan, M. S. Finkel.......................... .. .. .. ......... 141
Relevance of heart rate on hemodynamics and energetics
Adrenergic regulation on the force-frequency effect
Ross, J. Jr. .......................................................... 155
Influence of left ventricular pressures and heart rate on myocardial
high-energy phosphate metabolism
Neubauer, S. ........................................................ 167
Force-frequency relation in patients with left ventricular hypertrophy
and failure
Kass, D. A. ......................................................... 177
Prognostic relevance of heart rate
Heart rate variability and electrical stability
Fetsch, Th., L. Reinhardt, Th. Wichter, M. Borggrefe, G. Breithardt 189
Rate-dependence of antiarrhythmic and proarrhythmic properties
of class I and class III antiarrhythmic drugs
Weirich, J., H. Antoni. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Autonomic control of heart rate: Pharmacological and nonpharmacological
modulation
Vanoli, E., D. Cerati, R F. E. Pedretti .................................... 215
Therapeutic relevance of heart rate control
Left ventricular restoring forces: Modulation by heart rate and contractility
LeWinter, M. M., J. Fabian, S. P. Bell .................................... 231
Beta-blocker treatment in heart failure. Role of heart rate reduction
Lechat, P. .......................................................... 239
Digitalis therapy - Relevance of heart rate reduction
Erdmann, E. ........................................................ 251
~-Blocker treatment of chronic heart failure with special regard to carvedilol
Maack, C., M. B6hm ................................................. 257
Physiology and pathophysiology of baroreceptor function
and neuro-honnonal abnonnalities in heart failure
H. R. Kirchheim, A. Just, H. Ehmke
Physiologisches Institut, Universitat Heidelberg
Introduction
This review deals with the neuro-hormonal changes in congestive heart failure, a syndrome
that is usually initiated by a reduction of cardiac output. In order to do this, we should like
to 1) summarise previous and more recent evidence for a number of these neuro-hormonal
derangement's, 2) review the experimental evidence for an abnormality in the function of
the arterial- and cardiopulmonary baroreceptor reflexes and 3) discuss, whether this
abnormality or an interaction with renal mechanisms might cause the neuro-hormonal
derangements in congestive heart failure.
Evidence for a reduced "vagal tone"
in congestive heart failure
Before presenting evidence in favor of a loss of resting "vagal tone" in heart failure, the
physiology of the baroreflex and the respiratory influences on cardiac vagal activity need
to be briefly reviewed.
Vagal preganglionic neurones innervating the heart (vagal cardiomotor neurones) are
predominantly located in the ventrolateral part of the rostral nucleus ambiguus (NA).
Baroreceptor influences are probably transmitted to these neurones through projections
from the nucleus tractus solitarii (NTS) to the NA. A species dependent number of vagal
preganglionic neurones located in the dorsal motor nucleus of the vagus (DMV) have also
been described, but little is known whether they differ in function from those neurones in
the NA (for references: see 22, 24).
Baroreceptor influence on vagal cardiomotor neurones
Baroreceptor stimulation causes excitation of vagal cardiomotor neurones and bradycardia
(70, 98, 105). The central latency of this baroreflex excitation amounts to 20-110 ms only
(24). Furthermore, these vagal cardiomotor neurones are more sensitive to the barorecep
tor input than sympathetic neurones although they have a higher threshold than the latter
(95). Recordings of efferent cardiac vagal activity have shown that in the anaesthetized
2 H. R. Kirchheim et al.
1300 g ascending 35 s; 1.0 mg Nitro.
.6 ascending 30 s; 0.5 mg Nitro. 0o ·
1200 0 ascending 34 5; 1.0 mg Nitro.
ascending 10 5; 50 Ilg Phen .
1100
- . Y~a+b x'(r~0.86)
S 1000 g6 g
Koch'sdata( 1931) g
'C"; 900 ---- logistic function (r = 0.98)
..s',"
800
'" 700
CO
tl
600
'"
:I:
500
400
300
50 60 70 80 90 100 110 120 130 140 150
Systolic Blood Pressure ( mmHg )
Fig. 1 Relationship between systolic blood pressure and heart beat interval in conscious (our own data) and in
anaesthetized dogs (Koch's data). In conscious dogs, blood pressure was either decreased by an i.v. injection of
Nitro-glycerine (Nitro; open triangels, open circles) or increased by a bolus injection of Phenylephrine (phen.;
filled circles). Nitro-glycerine-experiments: After systolic pressure had dropped to a minimum of 72-94mmHg,
systolic pressure and the first heart beat interval to follow were recorded for 30-35 seconds with increasing pressure
(ascending). Phenylephrine-experiments: Systolic pressure and the first heart beat interval to follow were recorded
for 10 seconds with increasing pressure (ascending). The data were approximated by the power function Y = a +
be (r = 0.86). Koch's data: Heart beat interval versus carotid sinus pressure in anaesthetized dogs (right carotid
sinus preparation; left sinus nerves and both aortic nerves cut) as reported by Koch (92). The data were approxi
mated by a 4-parameter logistic function (Y = a+b / (X/C)d; r = 0.98). ----: 122 ± 4 (SEM) beats/min: Intrinsic heart
rate as evaluated from 11 conscious dogs (see text).
animal these efferents show very little central activity unless blood pressure exceeds
140-150 mmHg (70, 71, 98). In Koch's data, which were also obtained during anaesthesia,
heart rate is reduced below the intrinsic heart rate of a dog's sinus node (122 ± 4 beats/min)
when systolic blood pressure increases above 125 mmHg (Fig. 1). Both observations may
be limited by anaesthesia, which reduces "vagal tone" (see below). In our experiments in
conscious dogs, heart rate is reduced below the intrinsic heart rate at a systolic blood
pressure of 110 mmHg already (Fig. 1). Finally, experiments in which vagal cardiomotor
neurones and cardiac sympathetic neurones were stimulated electrically have clearly shown
that the response of the vagal neuroeffector junction (sinus node) is much faster (a change
may be complete within 3-4 seconds) than the response to sympathetic stimulation (a
maximum response may require 25-35 seconds). The "off-response" of the vagal neuro
effector junction is also much fasterthan their sympathetic counterpart (170, 175, 176). This
has the important physiological advantage of increasing both heart rate and cardiac output
within a few seconds, for instance at the onset of exercise.
Respiratory influences on cardiac vagal activity
Respiratory variations of heart rate were first described by Carl Ludwig in 1847 (for refer
ence see 21). Early workers agreed that the arrhythmia was abolished by division of the
Physiology and pathophysiology of baroreceptor function 3
cervical vagus nerves, thus, providing evidence as to its neural origin. Later work revealed
that both central and pulmonary reflex mechanisms were involved and that the efferent path
way is largely vagal in both animals and man (21). Respiratory arrhythmia is quite striking
in humans, in conscious and in morphine-chloralose-anaesthetized dogs but is weak or
absent in conscious cats, rabbits, and rats. However, even in species normally presenting
clear sinus arrhythmia, it is suppressed by various anaesthetic agents with vagolytic prop
erties (21, 62, 70). In chloralose-anaesthetized dogs, central cardiac vagal activity ("vagal
tone") is still present after elimination of all afferents running in the vagi, the aortic, and
the sinus nerves (92). Central respiratory activity originating from medullary neurones
strongly influences vagal cardiomotor discharge, which shows a pattern inverse to sympa
thetic efferent activity with a maximum occurring during expiration (71, 98, 105). Record
ing cardiac vagal efferent nerve activity Katona and co-workers (78) showed that respira
tory sinus arrhythmia in the spontaneously breathing dog is due to a complete cessation of
vagal efferent activity during the inspiratory phase of each respiratory cycle. The presence
of this central "vagal tone", i.e., resting activity in the cardiac vagal efferent fibers, is an
important prerequisite for the demonstration of respiratory arrhythmia. Iriuchijima and
co-workers, also recording the activity of vagal cardiomotor neurones, observed that vagal
efferent cardiomotor fibers could only be activated by the baroreceptor input during
expiration (71). This is in line with the previous observation that the vagally transmitted
bradycardia by electrical stimulation of the carotid sinus nerve was minimal at the early
phase of inspiration and maximal at early expiration (94). In man Eckberg and collabora
tors found that a baroreceptor stimulus by brief neck suction increased the heart beat interval
by 30 ms (minimum) during inspiration and by 220 ms (maximum) during early expiration
(36).
Dependence of respiratory arrhythmia and baroreflex bradycardia
on "vagal tone"
That respiratory sinus arrhythmia increases with an increasing heart beat interval was
reported as early as 1935 (147). Consequently, the standard deviation of the heart beat
interval, which more recently is used as an index of respiratory arrhythmia, also increases
with an increasing baseline heart beat period. The relationship between the respiratory vari
ation in the heart beat interval and baseline heart beat was found to be nearly quadratic (93,
145). This was confirmed by Katona and Jih (79), who found that a linear correlation was
less appropriate. In their experiments, the respiratory variations of heart rate period reached
a minimum at a heart rate period of around 550 ms (= l20/min), which is close to a dog's
intrinsic heart rate (see below). These results clearly suggest that the degree of respiratory
sinus arrhythmia may be used as a non-invasive indicator of the degree of prevailing central
parasympathetic "vagal tone" (79).
The slope of the relationship between systolic pressure and heart beat interval after the
intravenous injection of a vasoconstrictor drug (called "baroreflex sensitivity" according to
the "Oxford" -method) is also a function of the baseline heart beat interval (10, 12, 16, 51,
67,161).
Reduced "vagal tone" in heart failure
The tachycardia in patients suffering from heart failure was alreay known to E. Starling
(154), but, because of the early recognition of sympathetic overactivity, traditionally was
4 H. R. Kirchheim et al.
assigned to an enhanced cardiac sympathetic tone. Indirect evidence for a reduced resting
vagal discharge to the heart was provided by the observation that patients with a diseased
myocardium showed a depressed respiratory arrhythmia (145). Calculating an arrhythmia
index this author also reported that respiratory arrhythmia was dependent on age as well as
on the resting heart rate. Using microneurography to record muscle sympathetic nerve dis
charge in healthy subjects and in patients with heart failure, Porter and collaborators noted
a strong central respiratory modulation of sympathetic outflow, but very few signs of
changes in vagal outflow, i.e., no respiratory arrhythmia (131). Short baseline R-R inter
vals and small standard deviations of the R-R interval indicating a decreased level of vagal
cardiac nerve activity were also noted in heart failure (2,131,144,151,153). In some of
the patients studied by Porter and co-workers the standard deviations of the R-R interval
were almost as small as in heart transplant patients (denervated donor, denervated recipi
ent) (3, 144). Smith and collaborators reported that the correction of heart failure by trans
plantation (denervated donor, innervated recipient) restored the parasympathetic control
toward normal (151). More direct evidence for a reduced "vagal tone" in heart failure was
provided by Eckberg and co-workers. Patients with coronary heart disease and idiopathic
cardiomyopathy experienced the same degree of bradycardia (-9 to -10 beats/min) as con
trol subjects when given propranolol intravenously, but less tachycardia after intravenous
atropine sulphate (+34 beat/min versus + IS beats/min). The authors therefore suggested that
in patients with heart disease the baseline vagal tone from the central nevous system was
diminished (35). Similar data after intravenous application of atropine (10 f.lg/kg) were
reported by Porter and co-workers, who observed that heart rate increased to the same level
(89-92 beats/min) in both groups of subjects, but started from a lower baseline level
(65 beats/min) in the healthy subjects as compared to patients suffering of heart failure
(77 beats/min) (131).
Increased sympathetic nerve activity
in congestive heart failure
Before presenting evidence in favor of an increased sympathetic nerve discharge to several
target organs in heart failure, a few remarks should be made with regard to the origin of
resting sympathetic nerve activity.
It is clear now that neurones in the rostral ventrolateral medulla (RVLM) are tonically
active and generate a large component of the resting sympathetic activity in anaesthetized
animals (for references see 22). A question which still remains unanswered is how this tonic
activity in the RVLM neurones is generated. Three different mechanisms have been
proposed (for references see 22): 1) One suggestion is that the RVLM sympathetic cells are
chemosensitive and are tonically excited even at normal levels of blood pH, p02' and pC02.
In support of this theory, the blood flow and capillary density within the RVLM have been
shown to be significantly greater than in surrounding areas. 2) Another suggestion is that
pacemaker cells in the RVLM are largely responsible for generating resting activity in
sympathetic neurones. 3) A third theory suggests than an ensemble of neurones (referred
to as "network oscillator") in the brain stem generates a basal level of activity which is then
transmitted to the RVLM sympathoexcitatory neurones.