Cardiopulmonary Physiology
Millersville University
Dr. Larry Reinking
Chapter 6 - Regulation of Cardiac Pumping
Cardiac output can change from a resting value of about 6 L/min to more than 20 L/min
during vigorous exercise. These changes are mediated by external factors such as circulating
catecholamines and nervous input to the heart (extrinsic regulation) or by the heart itself
(intrinsic regulation). The ability of the heart to regulate, without nerves, is really quite
surprising. In racing greyhounds, denervation of the heart has little effect on cardiac output and
results in only a 5% reduction in running performance. Cardiac output increases satisfactorily
during exercise in heart transplant patients. At rest, in humans, heart performance is actually
inhibited by nervous input. When both divisions of the autonomic nervous system are blocked,
the heart rate in young adults increases from a resting 70 beats/min to 105 beats/min. This
chapter will examine these factors that regulate cardiac pumping.
Muscle Preload and Afterload
The concepts of preload and afterload are important for understanding striated muscle
performance. We will again refer to skeletal muscle as a basis for comparison. The following
illustrates a classical skeletal muscle experiment that, perhaps, you have performed.
Figure 6.1 Work Performed with Preload and Afterload in Skeletal Muscle
work performed
b
res t
pre-load
a
co ntraction
sarcomeres
point a
pre-load
c
point b
res t
after-load
after-load
co ntraction
point c
load
In this experiment an isolated skeletal muscle is stimulated and lifts a load. Under
preload conditions, the muscle is presented with the load, and is stretched, before contracting.
With after-load, the load is supported and the muscle will not be stretched prior to contraction.
As seen above, skeletal muscles perform poorly when afterloaded.
The shape of the preload curve is due, mainly, to the geometry of the sarcomeres. At point
a, the muscle has only been slightly stretched by the preload and the sarcomeres are ‘crunched’.
As a result, few cross bridges will be able to form and muscle contraction is weak. Optimal
stretching and cross-bridging occurs at point b, resulting in the most forceful contraction.
Further loading over stretches the sarcomeres, fewer cross-bridges form, and muscle contraction
is weaker (point c). Afterloaded muscle, due to the lack of stretching, will have sub optimal
cross-bridge geometry and poor contractile performance for all loads.
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Cardiac muscle experiences preload and afterload conditions. Preloading occurs during
diastolic filling when the ventricular walls stretch. Afterload work is encountered when the
semilunar valves open and the heart encounters arterial pressure and resistance. Hypertension,
elevated arterial pressure, represents additional afterload. Like skeletal muscle, cardiac muscle
performs poorly when presented with a large afterload.
INTRINSIC REGULATION (AUTOREGULATION)
An isolated heart will regulate its cardiac output to match venous return. In other words,
the heart will pump out exactly what it receives. This is referred to as intrinsic regulation of
myocardial contractility. These controls can be directly related to changes in muscle fiber length
(categorized as heterometric autoregulation) or to other intrinsic, length independent causes
(termed homeometric autoregulation). The strength of cardiac contraction is reflected by the
volume of blood ejected with each beat (the stroke volume). In an isolated heart, cardiac output
is the product of the stroke volume (SV) and the heart rate (HR).
CO = SV . HR
Equation 6.1
Thus, intrinsic regulation can be accomplished by altering either the stroke volume, heart rate or
both.
Frank-Starling Law (Starling’s Law of the Heart)
This principle describes the relationship between end-diastolic length of myocardial
fibers and left ventricular work.
Cardiac
Performance
Curve
cardiac output
left ventricular work
Figure 6.2 Cardiac Performance and End-diastolic Volume
s ymp.
s tim.
paras ympathetic
s timulation
end-diastolic volume
rt. atrial press. or venous press.
This relationship can be explained in terms of sarcomere geometry, in a fashion
analogous to skeletal muscle example on the previous page. As the ventricular volume increases
during diastolic filling, the muscular walls are stretched, altering the length of the myocardial
sarcomeres. The length of the sarcomeres affect the ability to cross bridge, and as a consequence,
the contractile ability and stroke volume change. At a low end-diastolic volume, the heart will
have poor contractility (low stroke volume) due to ‘crunched’ sarcomeres. End-diastolic volume
represents the preload condition for the ventricular myocardium.
The major determinant of end-diastolic volume is the ‘filling pressure’ of the heart which
can be measured as the right atrial pressure or by the nearly identical central venous pressure.
Since these pressures are much easier to determine, they are typically used in place of enddiastolic volume. Cardiac output is directly related to the work of the heart. Using these
replacement terms, the more common form of the Frank-Starling law is seen in the graph at the
right of Figure 6.2. The relationship depicted in these graphs is also called the cardiac
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performance curve. Note that cardiac performance (i.e., strength of contractility) can be altered
by autonomic stimulation. A shift to the left indicates an increase in cardiac performance while a
shift to the right is a decrease in performance. Thus, the Frank-Starling relationship is really a
family of curves that depend on extrinsic input.
Cardiac Preload is related to
Cardiac Afterload is related to
end-diastolic sarcomere length
diastolic pressure
end-diastolic ventricular volume
vascular resistance
filling pressure
Stretch of Branched Myofibers
A simple geometrical relationship may also contribute to the above heterometric effect as
illustrated by this exaggerated drawing of ventricular myocardial fibers:
Figure 6.3 Geometry of Stretched Myocardial Fibers
low end-diastolic volume
high end-dias tolic volume
At low end-diastolic volume there is little stretch on the myofibers and they do not pull in
the same direction. At higher end-diastolic volume the ventricular walls are stretched causing the
branched fibers to be closer to parallel. During contraction, these fibers shorten in the same
general direction and may create a more efficient contraction.
Limitations of the Frank-Starling Principle
The Frank-Starling law is a cornerstone of cardiology, however, it does have some short
comings. Consider the following example. A fresh rat heart, when dropped into a beaker of
warm saline, will ‘jet around’ in the solution like a tiny squid. The Frank-Starling principle
emphasizes that ventricular filling is a function of venous pressure. However, in the case of the
isolated rat heart, there is no filling pressure! The Frank-Starling law was developed using
isolated hearts and probably does not may take into account all the factors at play in vivo.
Actually, the heart may also act as a suction pump. At the end of systole some energy
may be stored in the elastic components of the ventricular walls. During the rapid inflow period
the walls rebound an suck blood into the ventricle. The anatomical arrangement of collagen and
elastic fibers around the myofibers is consistent with this idea. Also the heart moves within the
chest. As blood is ejected upward, during systole, the heart is forced downward (i.e., Newton’s
law of motion). During diastole the heart rebounds, a motion that would augment ventricular
filling. This last concept would be similar to filling a plastic bag by sweeping it through a tub of
water.
The Frank-Starling law best describes cardiac function in depressed hearts where the
cardiac performance is low and venous pressure is high. In healthy hearts, the Frank-Starling
principle is at play but other factors such as suction filling probably contribute to overall cardiac
function.
Heart Rate Effect
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The previously described intrinsic controls alter stroke volume. The other way to regulate
cardiac output, of course, is to alter heart rate. An increase in atrial filling will initiate a reflex
response that causes heart rate to increase as much as 75%. Part of this response is due to
stretching of the SA node which, in turn, can cause the rate of pacemaker firing to increase by up
to 15%. The remainder of this response is due to vagal signals, from the atria to the brain, and
the activation of sympathetic input to the heart. This portion of the heart rate response is called
the Bainbridge reflex and is, actually, an extrinsic type control. Also, the stretching of the atria
releases peptide hormones into the circulation (more on this in later chapters).
Rate Induced Regulation
The previous control dealt with heart rate as a response. However, a change in heart rate
will induce a change in the force of contractility. In an experimental situation, a strip of
ventricular muscle will increase its force of contraction when the rate of stimulation increases
(for skeletal muscle this called the staircase effect or Treppe). This response appears to be
caused by an accumulation of intracellular calcium, which as we saw in Chapter 4, increases
cross-bridging and the force of contraction. This length independent control is a type of
homeometric autoregulation.
EXTRINSIC REGULATION
As shown previously, the Frank-Starling relationship is modified by the parasympathetic
and sympathetic divisions of the autonomic nervous system. This autonomic input originates
from the medulla oblongata and is the result of the processing of signals from a variety of
systemic regulatory mechanisms. At rest, parasympathetic influences predominate over
sympathetic effects.
Parasympathetic Input
Parasympathetic input to the heart is primarily to the nodal tissue via the right and left
vagus nerves. Thus, the primary effects of parasympathetic stimulation will be on heart rate
(chronotropic effect). The right vagus principally innervates the SA node, while the left vagus
primarily supplies the AV node. Acetylcholine, the parasympathetic neurotransmitter, slows the
rate of pacemaker firing and slows conduction through the AV node (see chapter 4 for
mechanism). Thus, we can say that parasympathetic input induces bradycardia or has negative
chronotropic effect. Secondary effects (all inhibitory) include decreased contractile strength,
depressed myocardial metabolism and, possibly, coronary artery constriction. Acetylcholine’s
affect on the heart is mediated by muscarinic type cholinergic receptors and is blocked by
atropine . Cardiac nodal tissue has a high levels of cholinesterases and, therefore, the effects of
parasympathetic stimulation are short lived.
Sympathetic Input
Sympathetic nerves to the heart originates from several thoracic and one or two cervical
segments of the spinal cord. Both the myocardium and nodal tissue are innervated by these
fibers. In many species, the left and right sides of the sympathetic chains differentially innervate
the working myocardium or the nodal tissue. This also probably true in humans. In addition to
norepinephrine released by the nerve endings, the heart will also be influenced by circulating
epinephrine. The adrenergic receptors are principally of the 1 type (i.e., isoproterenol is more
active than norepinephrine or epinephrine) and are inhibited by beta blockers such as propranolol
and atenolol. Degradation of catecholamines is limited in heart tissue and therefore the effects of
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sympathetic stimulation decay rather slowly. The main cardiac effects of catecholamines are
increased contractility (positive inotropic effect) and increased heart rate (tachycardia or a
positive chronotropic effect). Secondary effects include an increased myocardial metabolism
and, possibly, dilation of the coronary arteries.
Table 6.1 Summary of Autonomic Effects on the Heart
Parameter
Nervous input
Neurotransmitter
Receptor
Antagonist
Agonist
Persistence of effect
Heart rate effect
Contractility effect
Myocardial metabolism
Coronary arteries
Parasympathetic
Sympathetic
vagus nerves
sympathetic chains
acetylcholine
norepinephrine (+ circulating epi)
muscarinic
1 adrenergic
atropine
propranolol, other 1 blockers 
muscarine
isoproterenol > epi = norepi
decays rapidly
decays slowly
negative chronotropic (1°)
positive chronotropic (1°)
negative inotropic (2°)
positive inotropic (1°)
depressed (2°)
elevated (2°)
constriction (2°) ??
dilation (2°) ??
1° = primary effect
2° = secondary effect
cardiac output
Limit of Heart Rate Effect on Cardiac Output
As stated previously, cardiac output increases with beating frequency for an isolated
heart. This relationship, however, will apply only over a limited range:
Figure 6.4
Heart Rate and Cardiac Output
heart rate
At lower heart rates this relation holds, however, at higher heart rates the cardiac output
plateaus and then declines. A rapid heart rate is accompanied by a shortened cardiac cycle and a
shortened period of diastolic filling. As we saw above, less filling results in a decreased
contractility. In humans, the peak for this type of curve occurs in the range of 130-170
beats/min. Above 170 beats/min ventricular filling is severely compromised and cardiac output
drops. In an intact human, other factors such as changes in peripheral resistance will complicate
this relationship.
CARDIAC OUTPUT AND VENOUS RETURN
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During the discussion of the Frank-Starling law, we examined the effect of venous
pressure on cardiac output. Now we will examine the converse; the effect of cardiac output on
venous pressure. Cardiac output alters venous pressure because as the heart pumps, the recoiling
ventricles ‘draw’ on the venous supply. If we were interested in the effect of cardiac output on
arterial pressure we could simply refer to an equation from Chapter 3 (Equation 3.11):
Pa = (CO . RT)+Pv.
It would seem logical that we could rearrange this equation for venous pressure (Pv).
This is not a valid approach because of the compliant nature of the venous circulation. Veins are
nearly twenty times more compliant than arteries and readily collapse when pressure drops below
zero. Thus, as cardiac output increases, the ventricles ‘draw’ more from the veins, venous
pressure drops and, at sometime, the veins collapse so that no further rise in cardiac output can
occur:
Figure 6.5
Effect of Cardiac Output on
Venous Pressure
The relationship shown above is called the vascular performance curve. Another
concept, the mean circulatory pressure is useful in our analysis. Mean Circulatory pressure
(Pmc) is the residual pressure that can be measured in the circulatory system when cardiac output
is zero. In other words, this is the pressure in the vessels if the heart stops. The value for Pmc is
about 7 mm Hg. Combining mean circulatory pressure with arterial compliance (Ca) and venous
compliance (Cv) gives us an equation for the relationship shown by the vascular performance
curve.
Equation 6.2
R  C  CO
Pv = Pmc -
T
a
Ca + Cv
If this concept is combined with the cardiac performance curve (i.e., Frank-Starling
relationship), we now have a powerful tool for understanding cardiac performance in an intact
individual:
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cardiac output
cardiac performance curve
Figure 6.6
'equilibrium point'
Combined Cardiac Performance
and Vascular Performance
Curves
vas cular performance curve
Pmc
0
7
Pmc = mean circulatory pressure
venous pressure
In Figure 6.6, 'equilibrium point' represents the actual value for cardiac output and venous
pressure (about 6 l/min and 2 mm Hg in young adults). This equilibrium point is a balancing act
between the cardiac performance curve and the vascular performance curve. If cardiac output
increases, venous pressure decreases, cardiac output then drops, venous pressure increases, .. etc.
Alterations of Performance Curves
The combined cardiac and vascular performance curves are helpful for predicting changes
in cardiac output, venous pressure during pathophysiological situations.
please consult graphs in lecture handout packet
1. Vascular Volume Changes - An increase in vascular volume (as might occur with an
accidental over infusion or during 'fluid forcing' in a trauma unit) causes the vascular
performance curve to shift to the right. As a result there will be a new equilibrium point and the
final result is increased cardiac output, increased venous pressure and increased mean circulatory
pressure. Increased vascular volume is also called hypervolemia. A decrease in blood volume,
hypovolemia (as might occur with blood loss or dehydration), causes a shift of the vascular
performance curve to the left. Cardiac output, venous pressure and mean circulatory pressure
will all decline.
2. Cardiac Failure - Cardiac failure is reflected in a shift of the cardiac performance curve to
the right. Initially, there will be a drop in cardiac output and rise in venous pressure. Cardiac
failure, however, will produce renal insufficiency and, therefore, fluid retention. As a result, the
vascular performance curve shift to the right. The final equilibrium point shows a large increase
in venous pressure, an increased mean circulatory pressure but little change in cardiac output.
3. Increased Cardiac Performance - A hyperdynamic heart (as during exercise or the result of
a cardiotonic drug) will have a vascular performance curve shifted to the left. In strenuous
exercise there may also be a significant changes in the vascular performance curve due to
vasodilation.
4. Changes in Vascular Resistance - Resistance changes alter the slope of the vascular
performance curve, mean circulatory pressure does not change. Vasodilation causes an upward
shift to the slope with the end results of increased cardiac output and increased venous pressure.
The changes for vasoconstriction via sympathetic stimulation cause the opposite changes.
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Vasoconstriction, however, will cause a severe after-load and a secondary shift in the cardiac
performance curve to the right.
Cardiac Output, Venous Return and Respiratory Activity
Since they share a common space with the lungs, the heart and great vessels are under the
influence of negative thoracic pressures. Negative pressure in the thorax is a few mm Hg but can
become many times this during forced inspiration. These pressure changes associated with
breathing will alter venous return to the ventricles.
During normal breathing, thoracic pressure drops during inspiration causing an expansion of the
vein cava and an increased venous return to the right heart. At the same time however, the
dropping thoracic pressure causes an expansion of the vessels in the lung, momentary pooling
occurs and left cardiac stroke volume drops. Thus, there is a slight variation in cardiac output in
synchrony with breathing.
Pulsus paradoxus is an alternating strong and weak pulse at the radial artery. It is reflection of
the above alternating stoke volume. This alternation of pulse is very minor in healthy individuals
but can become pronounced in some situations such as cardiac tamponade (compression of the
heart by fluid in the pericardial space or by a restrictive pericardium).
Valsalva maneuver is the forced expiration against a closed glottis. This maneuver will
increase thoracic pressure and hinder venous return.
Positive pressure ventilation also increases thoracic pressure, compresses veins and diminishes
cardiac return.
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