THE CARDIOVASCULAR SYSTEM

Heart Block

A 48-year-old man, who engaged in regular physical exercise, went to see his physician because of
recurrent headaches. Physical examination revealed that the patient had a mean heart rate of 55
beats/min. His physician noted that the patient's cardiac rhythm varied substantially with the phases of
respiration; the heart rate increased during inspiration and decreased during expiration.

1. What changes in cardiac sympathetic and parasympathetic activity take place during the respiratory
cycle?

Action potentials recorded from efferent nerve fibers to the heart in experimental animals indicate that
sympathetic activity increases and vagal activity decreases during inspiration. The opposite changes
take place during expiration.

2. Are the respiratory fluctuations in heart rate produced by the rhythmic changes in sympathetic activity,
in parasympathetic activity, or both?

The physician diagnosed this patient's headaches as migraine. He advised the patient to take
propranolol, a ¦Â-adrenergic receptor antagonist, to relieve the headaches. The physician noted that
after the patient had taken the propranolol, the mean heart rate diminished very slightly, and the
respiratory fluctuations in heart rate were not appreciably different from those observed before the
propranolol was taken.

The changes in activity in both divisions of the autonomic nervous system would tend to contribute to
the respiratory sinus arrhythmia (i.e., to the observed alterations in heart rate throughout the
respiratory cycle). However, when atropine (which blocks the cardiac effects of the vagal activity) is
given, the respiratory sinus arrhythmia usually disappears entirely. However, when propranolol (which
blocks the cardiac effects of the sympathetic activity) is given, the respiratory sinus arrhythmia is
scarcely affected.

The vagal influence usually predominates over the sympathetic influence as a mediator of respiratory
sinus arrhythmia for several reasons. First: in normal resting individuals, vagal activity is usually
substantial, whereas sympathetic activity is usually minimal. Second, this disparity in activity is
usually exaggerated in people who exercise regularly. Third, and probably most important, the time
courses of the vagal and sympathetic effects on the heart are entirely different. The vagal effects
produce their responses very quickly (relative to the duration of a respiratory cycle), and the vagal
responses also decay very quickly after vagal activity ceases. Conversely, the onset and decay of the
cardiac responses to sympathetic activity are much more sluggish. Periodic changes in sympathetic
activity associated with the respiratory cycle cannot produce appreciable changes in cardiac function
within the usual time course of a respiratory cycle, because the cardiac changes develop so slowly at

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 the beginning of any brief period of sympathetic activity and the cardiac changes also decay very
slowly after the sympathetic activity ceases.

3. Does the failure of propranolol to induce a substantial change in mean heart rate or in the respiratory
fluctuations in heart rate necessarily signify that the patient's cardiac sympathetic neural activity was
negligible at the time he was being examined?

Three years later, the patient began to experience frequent episodes of chest pain on exertion. The
patient's cardiologist recommended a diagnostic cardiac catheterization. His aortic pressure (Pa) and
his electrocardiogram (ECG) were recorded during the procedure; one segment of the record is shown
in Fig. 25-1. As the cardiac catheter was being manipulated, it initiated several premature ventricular
depolarizations, one of which (designated R') is shown in this figure.

The failure of propranolol to induce any substantial change in mean heart rate or in the respiratory
fluctuations in heart rate does not necessarily signify that the activity in the cardiac sympathetic
nerves was negligible. The slow heart rate (55 beats/min) and the prominent respiratory sinus
arrhythmia suggest that the vagal tone in this patient was considerable. Under such conditions, the
vagal influence on heart rate would predominate, even if sympathetic activity also was substantial.
The summation of sympathetic and vagal effects on heart rate is highly nonlinear. One of the principal
mechanisms responsible for the vagal predominance is that the acetylcholine released from vagal
nerve endings acts to inhibit the release of norepinephrine from neighboring sympathetic nerve
endings. Thus even if sympathetic neural activity were substantial, the sympathetic nerve endings
might not release much norepinephrine if the tissue concentration of acetylcholine were appreciable in
the region of the sympathetic nerve terminals. Under such conditions, propranolol would probably
have little influence on heart rate.

4. Why did the premature ventricular depolarization (Fig. 25-1) not affect the aortic pressure tracing?

When a ventricular depolarization is very premature (as in R' in Fig. 25-1), the time for ventricular
filling is severely limited, the sarcomeres will not be stretched optimally, and therefore the
contractions will be weak (Frank-Starling mechanism). Furthermore, premature depolarization
affects the intracellular Ca++ distribution and hence the strength of contraction. During each
heartbeat, the Ca++ that dissociates from the contractile proteins is rapidly taken up by the
sarcoplasmic reticulum (SR) during relaxation. However, several hundred milliseconds must
elapse before that Ca++ is fully available to be released again by the SR. Hence, very premature
contractions are associated with a meager release of Ca++ from the SR, and therefore the
premature contraction is feeble. In the patient whose tracings are shown in Fig. 25-1, the
premature contraction evidently did not generate a sufficiently high intraventricular pressure to
force open the aortic valves and to eject blood into the aorta. Therefore the premature
contraction had no evident effect on the aortic pressure tracing.

5. Why did the ventricular contraction after the premature beat produce such a large aortic pulse pressure
(difference between maximum and minimum aortic pressures)?

About 1 year later, the patient developed 2:1 atrioventricular (AV) block (i.e., only alternate cardiac
impulses were propagated from atria to ventricles). The patient's ECG is shown in Fig. 25-2. Note that

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 before the patient was given atropine (top tracing), those P-P intervals that include an R wave are
shorter (0.7 s) than those that do not include an R wave (0.8 s).

The cardiologist gave the patient test injections of propranolol and of atropine to determine the role of
both divisions of the autonomic nervous system in the production of the AV block and of the
alternating P-P interval durations. The cardiologist found that propranolol had little effect either on the
2:1 AV block or on the alternation of the P-P intervals. He also observed that atropine had little effect
on the AV block, but it did cause the mean P-P interval to diminish (to 0.6 s), and the alternations of
the P-P intervals were no longer evident (bottom tracing).

The same factors operate, but in the opposite direction, to explain the large pulse pressure for the
contraction after the premature beat (Fig. 25-1). The long pause (compensatory pause) after the
premature beat allowed a prolonged filling time for the ventricles, and therefore the increased sarcomere
stretch augmented the cardiac contraction (Frank-Starling mechanism). Furthermore, the compensatory
pause also allowed more than sufficient time for the sarcoplasmic reticulum to release the Ca++ that had
been taken up during both the premature beat and the beat that preceded it. Therefore the contraction
that followed the premature beat could eject a supernormal stroke volume and thereby produce the large
arterial pulse pressure.

6. What is the most likely explanation for the alternating durations of the P-P intervals (Fig.25-2)?

The baroreceptor reflex is probably the principal mechanism responsible for the alternating P-P intervals
(Fig. 25-2) that are often observed in patients with 2:1 AV block. This distinctive rhythm, which is
referred to as ventriculophasic sinus arrhythmia, is characterized by cyclic fluctuations in arterial
blood pressure (Pa) associated with the alternating presence and absence of a ventricular contraction
during consecutive P-P intervals. During the cardiac cycles in which the ventricles contract and eject
blood, Pa rises from its diastolic value to its systolic value, and then begins to fall again. During such
a cycle, the arterial baroreceptors are stimulated by the rise in Pa, and after a brief delay, they
increase cardiac vagal activity and decrease cardiac sympathetic activity. During the alternate cycles,
the ventricles fail to contract, and therefore Pa falls below the level attained at the end of the
preceding cardiac cycle. Hence, vagal activity progressively diminishes and sympathetic activity rises.

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 Usually the reflex delay initiated by the systolic rise in Pa is sufficiently long that it does not prolong
the concurrent cardiac cycle. Instead, the ventricular contraction usually causes the subsequent
P-P interval (one that does not include an R wave) to be prolonged. Occasionally, however, the
temporal relation between the reflex delay and the cardiac cycle length is such that those P-P
intervals that do contain the R waves are the intervals that are prolonged, and the P-P intervals
that do not include an R wave are abridged.

7. How do you explain the abolition of the alternations by atropine (Fig. 25-2), but the absence of any
appreciable effect by propranolol?

Although the cyclic alternation in Pa does alter both vagal and sympathetic neural activity in each
cardiac cycle, the alternating changes in P-P interval can usually be abolished completely by
atropine, but propranolol will have little influence. The main reason for this is that vagally
mediated cardiac responses can be initiated and terminated rapidly, within the time constraints of
an ordinary cardiac cycle, whereas sympathetically mediated responses are much more sluggish
and cannot induce appreciable changes beat by beat.