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CHAPTER 23  Structure and Function of the Heart

Myocardial Mechanics: Myocardial Receptors
and Responses to Drugs
Cardiac myocytes express a- and b-adrenoceptors that mediate
the responses to endogenous and exogenous catecholamines
and therefore are involved in the rapid regulation of myocardial
function. They can also be inhibited by adrenergic-blocking
agents such as b-blockers and are a target in treating heart
failure and arrhythmias. a1-Adrenoceptors appear early in gestation and in many species reach their highest density in the
neonate.3,4,72 In contrast, b-adrenoceptors increase progressively with age. b1, b2, and b3 are present on myocytes, but
b1-adrenoceptors are described as the predominant receptor
subtype in cardiac myocytes.73,74 In addition, histamine H2,
vasoactive intestinal polypeptide (VIP), adenosine A1, acetylcholine M2, and somatostatin receptors have been identified.
They act on the myocyte’s contractile apparatus through one of
two main pathways.
The major pathway involves membrane-bound receptor–G
protein–adenylate cyclase complexes. G proteins include the Gs
(stimulatory) and Gi (inhibitory) proteins.75 When agonists
stimulate b-adrenergic receptors, the G proteins undergo a conformational change. The changes induce the Gs protein to
exchange its guanosine diphosphate (GDP) for guanine triphosphate (GTP). The Gs-a-GTP complex interacts with adenylate
cyclase to convert ATP to cyclic adenine monophosphate
(cAMP), which activates a variety of protein kinases to phosphorylate proteins, including voltage-dependent calcium channels, phospholamban, and troponin I. Consequently, calcium
entry during depolarization and during uptake of calcium into
the sarcoplasmic reticulum storage pool is increased, thus increasing contractility. The Gs-a-GTP complex has intrinsic
GTPase activity that converts GTP to GDP. In this way, as long
as receptors are occupied by the agonist, the Gs cycle produces
increasingly more cAMP, amplifying the stimulatory signal. The
Gi protein complex undergoes a similar cycle when adenosine or
acetylcholine receptors are stimulated. However, activating Gi
protein reduces cAMP formation and decreases contractility.

b2-adrenergic receptors also couple to Gi in addition to Gs.76
Gi in this context is thought to oppose the effects of Gs to some
degree, including limitation of the acute positive inotropic response to adrenergic stimulation and offering some protection
from apoptosis.77–79
In heart failure, the number of b1-adrenergic receptors are
downregulated, and b2-adrenergic receptors are uncoupled from
G proteins.35,73,74,80,81 These changes make the myocardium less
responsive to circulating or locally released catecholamines and
play a role in the reduced contractility observed in heart failure.
Treating heart failure with b-adrenergic blocking agents has been
shown to reverse the receptor changes and has also been associated
with improved function of muscle strips in adult patients.82–85
b3-adrenoceptors, the minor isoform in the heart, can activate
different signaling pathways; their role in heart failure therapy is
a recent topic of study.86,87
Milrinone is an agent that stimulates contractility by inhibiting phosphodiesterases and increasing cAMP. Although previously thought to be ineffective in the newborn,88 a multicenter
randomized trial89 and subsequent widespread use has confirmed
its efficacy in the neonatal population.90,91 Because contractile
mechanisms are almost fully developed at birth, the majority of
mechanisms controlling contractility (except for changes in the
source of calcium) are in place at birth.

193

Myocardial Mechanics: Integrated Muscle
Function
Relationship Between Muscle Strips and Intact Ventricles
With preload, stretching a muscle strip is equivalent to end-diastolic
fiber length of the intact ventricle. This length can be measured by
various devices in animals; however, in the intact human ventricle,

it is best related to end-diastolic diameter or volume. Frequently,
end-diastolic pressure has been used interchangeably with enddiastolic volume as an index of preload, but this usage can be misleading if the distensibility of the ventricle changes or if pressure
outside the heart (pericardial or intrathoracic) rises.92–95
Afterload is more complicated in the intact ventricle, commonly defined as the pressure or load against which the heart
contracts to eject blood. Often, aortic systolic pressure is equated
with afterload. However, in the muscle strip, afterload represents
the force exerted by the muscle during contraction; in physical
terms, force 5 pressure 3 area.71,96–98 Therefore, afterload accounts for the distribution of pressure over the surface to which
the force is applied. When the force is applied to a thick spherical
chamber, it is more accurately described by the Laplace wall stress
relationship:
Wall Stress ( ) 

Pr
2h

where P is the transmural pressure across the wall of the chamber,
r is radius of curvature, and h is wall thickness. Because the left
ventricle is not a regular sphere, particularly in systole, the Laplace
formula is an oversimplification.99 A fairly simple and accurate
formula was developed by Grossman and colleagues100:
Wall Stress (  ) 

Pr
h

2h  1  
2r 


Note that if the left ventricle dilates acutely, wall stress rises markedly because r gets bigger and h gets smaller.
The major findings from studies of muscle strips have been
confirmed in intact ventricles. Increasing preload increases the
pressure generated by an isolated ventricle that is not allowed to
eject, as observed in the 20th century by Otto Frank. If the ventricle is allowed to eject, then increased preload allows the heart
to eject the same stroke volume against an increased afterload or
to eject a greater stroke volume against a constant afterload. This
is the Starling component of the Frank-Starling law.101,102 The
mechanism of this response is twofold: (1) lengthening the sarcomere places the myosin and actin fibrils closer together for stronger interaction and (2) increased calcium sensitivity is mediated in
some way by titin stretching.30 Therefore, stretching the sarcomere to its optimal length (see Fig. 23.3C) will increase contractility. Beyond that length, further stretching (or preload) can be
detrimental as the end-diastolic pressure increases without a significant change in the stroke volume. There is evidence that in
failing hearts, this relationship between preload and developed
tension may be absent.103
The force-frequency relationship is a property of the cardiomyocyte whereby heart rate modifies contractility. Heart rates up to an
optimal heart rate increase the force of contractility beyond which
force decreases. The force-frequency relationship can be determined in intact hearts104,105 by examining the response of the


S E C T I O N I V   Pediatric Critical Care: Cardiovascular

Pressure-Volume Loops
If LV pressure and volume are measured simultaneously, the resulting pressure-volume loop gives information about ventricular
performance and can be used to assess myocardial contractility in
the intact heart.
The modern approach to analyzing these loops is based on the
elastance concept of Suga and Sagawa.109–111 Elastance is the ratio
of pressure change to volume change (the reciprocal of compliance). Consider an isolated ventricle that can be filled to different
volumes. At each volume, the ventricle is stimulated to contract
and generates a peak systolic pressure (Fig. 23.4A). As volumes
increase (1 n 2 n 3), so do the peak systolic pressures generated,

and the relationship is linear (Frank’s law). The line joining the
peak pressures intercepts the volume axis at a positive value,
termed V0, that indicates the unstressed volume of the ventricle.
The equation for this line is as follows:
Pes  E es (Ves  V0 )
where Pes is end-systolic pressure, Ees is slope of the line, the endsystolic elastance or the maximum elastance (Emax), Ves is endsystolic volume, and V0 is unstressed volume. If contractility
increases (more calcium enters the cells), the ventricle can generate
greater pressures at any given volume, thereby generating a steeper
pressure-volume line (higher value of Ees; purple line I in Fig. 23.4A).
If contractility decreases, the ventricle generates lower pressures at
any given volume, and the pressure-volume line is less steep
(lower value of Ees; blue line D in Fig. 23.4A).
The typical pressure-volume loop shown in Fig. 23.4B is characterized by four phases marked by the opening and closing of the
AV and arterial valves: diastole starts when the aortic and pulmonary valve close and the ventricular pressures fall owing to muscle
relaxation; initially, with the AV valves closed, the isovolumic relaxation phase occurs since both inlet and outlet valves are closed
with no change in ventricular volume. This phase is followed by
opening of the AV valve when atrial pressures are higher than ventricular pressures and initiation of ventricular filling. During diastolic filling, volume increases and diastolic pressure rises slightly
because of the increase in passive tension. At the end of diastole,
when the ventricular pressures surpass atrial pressure, AV valves
close and isovolumic contraction starts. In this phase, ventricular
pressure rises with no change in volume. When ventricular pressure exceeds aortic pressure, the aortic valve opens, blood is
ejected, and ventricular volume decreases. Ejection ends, and pressure falls to diastolic levels as isovolumic relaxation occurs and the
cardiac cycle restarts. The decrease in volume during ejection is the
stroke volume, which, divided by the end-diastolic volume, gives
the ejection fraction; normally, ejection fraction is greater than 65.
If afterload is suddenly increased by raising aortic pressure, the
normal heart responds as shown in Fig. 23.4B. In the first beat
after the increase, the ventricle must generate a higher pressure
before the aortic valve opens (loop 2; orange line). It then ejects but

Pressure

I
2

3

1

V0

A

D

1

2

3

Volume
I

Pressure

maximal rate of change of pressure (dP/dt max) in the ventricles
after premature beats. The results in intact ventricles and muscle
strips are similar. Subsequently, Seed and colleagues106 applied
this technique to humans with normal or abnormal LV function

and found an optimal R-R interval of 800 ms. This response is
mediated by an increase in the intracellular calcium in normal
hearts but is limited in the setting of ventricular dysfunction. As
with preload, the force-frequency relationship may be abnormal
in failing hearts.107,108

2

3

1

D
EDV

V0

B

1

2

3

4

Volume

Pressure

194

2

3

1

EDV
EDV

V0

C

1

2

3 I

II

III

Volume

• Fig. 23.4  ​Concept of ventricular elastance. (A) Isolated ventricle contracting at volumes 1, 2, and 3, generating corresponding pressures.
Purple line I indicates results at increased contractility. Blue line D indicates

results at decreased contractility. (B) Ventricular pressure-volume loops
achieving end-systolic pressures of 1, 2, and 3 at corresponding volumes.
Purple line I indicates results at increased contractility, with greater endsystolic pressures at each volume. Blue line D indicates results at decreased contractility. From a given end-diastolic volume, either the same
ejection fraction is delivered at a lower end-systolic pressure (dotted
line 1) or the same end-systolic pressure is achieved but at a much
smaller stroke volume and ejection fraction (line 4). (C) As a consequence
of afterload increase, the ventricular end-diastolic volumes (EDV) increase,
then stroke volume can be maintained, even though ejection fraction decreases. If contractility is decreased (blue line), then stroke volume can be
maintained only with increasing end-diastolic pressures. 1, 2, 3, Endsystolic volumes and pressures at normal contractility; I, II, III, end-systolic
volumes at decreased contractility; V0, resting (unstressed) volume.
cannot eject the same stroke volume. In fact, the end-systolic volume is that which is appropriate for the higher pressure (compare
Fig. 23.4B, end-systolic volume at 1 and 2 in the orange line). If
different afterloads are used, the end-systolic pressure-volume
points define a sloping line that is the same as the line obtained in
the isolated heart at those same volumes. This is the maximal ventricular elastance (Ees) or end-systolic elastance (Ees) line. If ventricular
contractility increases, then the ventricle can attain higher ejection
pressures at any given volume, and the end-systolic pressure-volume
points lie on a steeper line that lies above and to the left of the normal
line (purple line I in Fig. 23.4B). If ventricular contractility decreases,
then the end-systolic pressure-volume line lies below and to the right
of the normal line (blue line in Fig. 23.4B). Note from Fig. 23.4B
that, from a given end-diastolic volume, the ventricle with impaired
contractility can either eject the original stroke volume at much
reduced pressures or eject at a normal pressure only by reducing its
stroke volume drastically (loop 4).


CHAPTER 23  Structure and Function of the Heart

In beats that follow a sudden increase in afterload, the ventricles adjust (Fig 23.4C). Because of the reduced stroke volume in

the first beat following afterload increase, the end-systolic volume
is larger than normal. During diastole, however, a normal stroke
volume enters the ventricle so that end-diastolic volume increases
(loop 2 in Fig. 23.4C). In normal ventricles, the increased enddiastolic fiber length causes little increase in diastolic pressure.
The pressures during ejection and the end-systolic pressurevolume point are unchanged, but stroke volume and ejection
fraction increase. After a few more cycles, a new equilibrium is
established (loop 3) in which the ventricle ejects a normal stroke
volume at the higher afterload. However, the ejection fraction is
subnormal because, although the stroke volume is normal, the
end-diastolic volume is increased. The ventricle has adapted to the
higher afterload by increasing end-diastolic fiber length, a phenomenon described by Starling and discussed by Ross96,97 under
the term preload reserve. If the ventricle has decreased contractility
(dashed loops, blue line in Fig 23.4C), the same pattern of response
occurs but with some important differences. With decreased contractility, the ventricle cannot eject a normal stroke volume from
a normal end-diastolic volume. Compensation results in a larger
than normal increase in end-diastolic volume, even at normal afterloads. Any increase in afterload causes a further increase in
end-diastolic volume; this increase causes diastolic pressures to
rise to high values that cause pulmonary congestion. The normal
preload reserve has been used up in the attempt to eject a reasonable stroke volume against a modestly increased afterload. In more
depressed hearts, even normal afterloads cannot be handled by the
ventricle without a pathologically raised diastolic pressure in the
ventricles or a drastic decrease in stroke volume. Note that in
these hearts, because of the relatively flat slope of the maximal
ventricular elastance line, a slight reduction of afterload produces
a relatively large increase in stroke volume and a relatively large
decrease in ventricular end-diastolic volume and pressure. This is
one of the mechanisms for cardiac improvement with afterload
reduction in the setting of systolic dysfunction.
The normal RV pressure-volume curve is triangular, unlike the
more rectangular LV pressure-volume curve described earlier.112

This difference is accounted for by a relative lack of isovolumic
contraction and relaxation times in the right ventricle. The normally low afterload of the right ventricle and the high compliance
of the outflow portion of the ventricle allow ejection to begin almost instantaneously after the onset of contraction and proceed
through pressure decline so that there is near complete emptying
of the ventricle by the end of systole and the ejection time of the
right ventricle thus spans the entire period of systole. An important consequence of this relationship is that even small increases
in RV afterload begin to make the RV pressure-volume curve resemble the normal LV pressure-volume curve, with isovolumic
contraction and relaxation times becoming more prominent.113
Ejection fraction is reduced, although stroke volume may be
maintained due to RV dilation,114 and the thin-walled right ventricle may handle this new physiology quite poorly.

Assessing Myocardial Contractility: Systolic Ventricular
Function
An index of contractility must reflect the ability of the ventricle to
perform work independent of changes in preload and afterload.
Contractility can be defined as the alterations in cardiac function
that occur secondary to changes in cytosolic calcium availability
or sarcomere sensitivity to calcium. Thus, b-adrenergic agonists or
phosphodiesterase inhibitors, which increase cytosolic calcium,

195

are positive inotropic agents. However, quantifying contractility
in the intact heart is difficult115 because all indices of contractility
are indices of overall performance of cardiac function and are not
independent of loading conditions and heart rate. The relationship between loading conditions and contractility is complex
since the handling of calcium within the myocyte is influenced by
(1) the myocardial fiber length, which, in turn, depends on the
preload (Frank-Starling mechanism)116; and (2) afterload, as it has
been demonstrated that contractility increases in response to a rise

in the afterload.117 Despite these limitations, the methods we currently have to assess contractility can be divided into those occurring in early systole during isovolumic contraction (isovolumic
phase indices) and those that occur later, during ejection (ejection
phase indices).
Isovolumic Phase Indices

The maximal rate of change of ventricular pressure (dP/dt max) is
achieved during the isovolumic contraction, before the aortic
valve opens, and is relatively unaffected by changes in preload. It
can be measured by invasive pressure tracing or, indirectly, from a
continuous-wave Doppler tracing of a mitral regurgitation jet by
echocardiography. However, the index is markedly affected by
changes in afterload. Thus, it must be used with caution when
afterloads are very different. This method is more useful for measuring acute changes in contractility than for assessing absolute
contractility.
Ejection Phase Indices

The index of contractility most commonly used today is the
maximal (end-systolic) ventricular elastance of Suga and Sagawa,
which is defined by the slope of the end-systolic pressure-volume
relationships. Measurements must be obtained at several different
levels of afterload, and either ventricular volumes must be measured or echocardiographic dimensions must be used as substitutes for volumes.71,98 Several studies have shown that the maximal elastance line often is not linear, as previously stated,118,119
but the values of elastance in the midrange of pressures are accurate enough to use the slope of the end-systolic pressure-volume
relationship as a parameter of left ventricular contractility.119
The LV end-systolic wall stress-velocity of fiber shortening
relation as a single beat index of contractility has also been used.
This index is not exempted from limitations, which arise from
the need to adjust for changes in afterload,120 and single-point
determinations are of little use since the relationship is not linear
(Fig 23.5).117
Echocardiographic measurements of ventricular function are

most commonly used in clinical situations. These are load-dependent measurements of contractility. These techniques measure
global and regional function. They can be subdivided into those
that are based on dimensional and volume changes (i.e., shortening and ejection fraction, RV fractional area change) and those that
are Doppler based (such as dP/dt max).121 M-mode–generated
ejection fraction is a popular method used in children to assess
LV function noninvasively. Even though it is useful, it is a loaddependent measurement and is less accurate in the setting
of mitral regurgitation, dysynchrony, regional wall motion abnormalities, and LV dilation (see Chapter 31 for more details).
M-mode–derived tricuspid annular plane systolic excursion
(TAPSE) is also an easily derived measurement of RV systolic
function. Cardiac magnetic resonance imaging can be considered
as an additional imaging modality if more accurate ventricular
volumes and measurements of systolic function are required.


196

S E C T I O N I V   Pediatric Critical Care: Cardiovascular

1.6

Vcfc = −0.0044 σes + 1.23
r = −0.84
n = 118

Rate corrected Vcf (circ/s)

1.4
+2SD
1.2

Mean
−2SD

1.0

0.8

0.6
0

20

40

60

80

100

120

LV end-systolic wall stress
(g/cm2)

A

* Low afterload

B

*

End-systolic wall stress

1*

* Low afterload

Normal afterload
High afterload

Normal afterload
High afterload

Mean Vcfc

2

*

Mean Vcfc

Mean Vcfc

1

End-systolic wall stress

2

*

End-systolic wall stress

• Fig. 23.5  ​(A)

Relationship between rate-corrected mean velocity of fiber shortening (Vcf) and left ventricular (LV) end-systolic wall stress. (B) Possibility of misinterpreting the relationship between mean velocity of fiber shortening and end-systolic wall stress. Left, Data point 1 is more than two standard deviations
(SD) above normal relation (taken from left panel), suggesting increased contractility. Data point 2 is within
the normal range, suggesting normal contractility. Middle, Alternative explanation for point 1 is that contractile state is normal, but points obtained at very low afterloads follow a hyperbolic, not a linear, relationship. Right, Alternative explanation for point 2 is that contractility is decreased. However, because of the
hyperbolic relationship and the low afterload, it appears within the “normal” linear range. (A, From Colan
SD, Borow KM, Neumann A. Left ventricular end-systolic wall stress-velocity of fiber shortening relation:
a load-independent index of myocardial contractility. J Am Coll Cardiol. 1984;4:715–724. B, Modified from
Banerjee A, et al. Nonlinearity of the left ventricular end-systolic wall stress-velocity of fiber shortening
relation in young pigs: a potential pitfall in its use as a single-beat index of contractility. J Am Coll Cardiol.
1994;23:514–524.)

Assessing Myocardial Relaxation: Diastolic Ventricular
Function
Diastolic function refers to the rate and extent of ventricular relaxation.93,122 Many forms of heart disease manifest abnormalities
of both systolic and diastolic function, but one or the other form
of dysfunction may predominate and impact optimal therapy.123
Diastolic dysfunction results in increased ventricular diastolic
pressure at normal or even low ventricular volume122 either from an
increase in passive stiffness of the ventricles from chronic infiltrates
(e.g., amyloid), myocardial scars, constrictive pericarditis, or diffuse
myocardial fibrosis, or from impaired relaxation or AV dyssynchrony. Diastolic relaxation of ventricular muscle associated with
rapid release of calcium from troponin and its subsequent uptake by
the sarcoplasmic reticulum allows actin-myosin cross-bridges to dissociate and the sarcomeres to lengthen, permitting the ventricle to

relax. Impairment of calcium removal due to abnormalities in
major contractile proteins or transport processes decreases the
rate and extent of relaxation.69,124 Many heart diseases, including
ischemia, impair calcium metabolism and diastolic ventricular
function.40,43,105,125 The most common methods to assess diastolic
function are invasive measurement of end-diastolic LV pressure in
the catheter laboratory or noninvasively by measurements of tissue
Doppler indices, ventricular inflow, and systemic and pulmonary
venous Doppler profiles. Assessing diastolic function noninvasively
remains challenging in children.126,127 One can measure diastolic
function more accurately using micromanometer-tipped catheters to
assess the time constant of diastolic relaxation (Tau), which has been
associated with clinically relevant events such as duration of intensive
care and hospital stay after the Fontan operation.128 However, this
primarily remains a research tool owing to complexity and expense.


CHAPTER 23  Structure and Function of the Heart

Pericardial Function
The parietal pericardium is a fibrous membrane that surrounds
the heart and is separated from the epicardium by a thin layer of
fluid. Owing to its nonelastic properties, the pericardium enhances mechanical interactions of the cardiac chambers and limits
acute cardiac dilation.129 Thus, if the ventricles enlarge because of
sudden volume load or myocardial depression, the pericardium
becomes tense and restrains further enlargement of the ventricles.94,95 This is seen with acute myocardial ischemia, where LV
diastolic pressure can increase without much change in ventricular volume because of tension from the pericardium. In this setting, changes in the diastolic pressure-volume relationship reflect
both myocardial stiffness and pericardial constraint.92,93,130–132
Transmural pressure is the difference between intracavitary and
extracavitary pressure (intracardiac pressure–pericardial pressure).

Pericardial pressure reflects intrapleural pressure during the respiratory cycle,133 which oscillates around –5 cmH2O in a spontaneously breathing patient in the absence of pericardial disease. With
each inspiration, the pleural pressure becomes more negative and
the pericardial pressure drops, which increases cardiac transmural
pressure and facilitates filling of the right heart. Mechanical
ventilation increases pleural and pericardial pressure, reduces
transmural pressure and impedes filling of the right heart.134 This
reduction in transmural pressure is detrimental for right heart
filling but decreases both ventricular and aortic transmural pressure, decreasing wall stress/afterload and therefore improving
stroke volume. In volume-replete patients, increased intrathoracic
pressure will primarily assist the left ventricle. However, this benefit
may be lost or it may even be detrimental to use positive-pressure
ventilation in the volume-depleted patient. This afterload reduction and a decrease in metabolic demands due to less respiratory
effort are the basis of using positive pressure, either noninvasive or
invasive, ventilation in the setting of heart failure.135 Furthermore, in those with significant work of breathing, such as patients
with pulmonary edema, the inspiratory pleural pressure is likely
to be much more negative than in healthy people. This serves
to significantly increase LV transmural pleural pressure and
potentially make the use of positive-pressure ventilation more
beneficial.
Ventricular Interactions
Ventricular interactions independent of humoral, neural, or circulatory effects are called ventricular interdependence and can be divided into diastolic and systolic ventricular interactions.131,136
They occur because of anatomic associations between the ventricles, interventricular septum as a shared septal wall, and enclosure
within the pericardium.
In normal circulation, diastolic ventricular interactions are responsible for changes in the pulse pressure during spontaneous
ventilation. During inspiration, RV filling and volume increase,
and the septum moves slightly toward the left, increasing LV enddiastolic pressure and decreasing LV end-diastolic volume and
therefore decreasing stroke volume. These effects reverse during
exhalation, increasing stroke volume. This mechanism is the basis
of pulsus paradoxus in conditions that accentuate ventricularventricular interactions such as cardiac tamponade or asthma. In
the failing right ventricle, dilation of the right ventricle pushes the

septum to the left, decreasing LV volume and preload and shifting
the LV diastolic pressure-volume relationship upward137 and
decreasing cardiac output.94,138,139 Increasing LV afterload by
manipulation of systemic vascular resistance can potentially counteract septal displacement, improving ventricular-ventricular

197

interactions and overall cardiac output.140,141 In systole, due to
the shared interventricular septum, the left ventricle generates
20% to 40% of RV contractility,142 whereas only 4% to 10%
of LV systolic pressure is generated by the right ventricle. The
decrease in cardiac output that occurs with acute RV failure with
an intact pericardium is at least partially attributable to a decrease
in systolic LV performance.143

Neural Control of the Heart
The autonomic nervous system is the major determinant of
heart rate in the normal heart, through the balance of sympathetic and parasympathetic tone.144 Sympathetic fibers innervate
the atria, ventricle muscles, and the conduction system. Sympathetic activation releases norepinephrine through both the autonomic nervous system and humoral adrenaline from the adrenal
glands. Catecholamines bind to b1-adrenoceptors activating Gs
proteins, which results in increased heart rate (chronotropic effect), more rapid AV conduction (dromotropic effect), enhanced
contractility (inotropic effect), and faster relaxation (lusitropic
effect).145 The parasympathetic acetylcholine fibers mainly innervate the sinus and AV nodes. Vagal effects on the heart are
mostly demonstrated by changes in heart rate but minimal
direct effect on myocardial contractility. Parasympathetic stimulation may have an indirect effect on inotropy by reducing
effects of circulating catecholamines or sympathetic nerve stimulation. Conversely, blockade of muscarinic receptors can intensify
the myocardial contractile response to sympathetic stimulation.
In conscious animals, resting sympathetic tone is low, and
parasympathetic tone is high. Therefore, sympathetic blockade
has little effect on heart rate and myocardial contractility,

whereas parasympathetic blockade causes marked tachycardia.
On the other hand, many anesthetics depress the sympathetic
nervous system, leading to acutely decreased contractility and
bradycardia.
The carotid and aortic baroreceptors respond to changes in arterial blood pressure. Since basal sympathetic tone is usually low,
inhibiting sympathetic tone by raising aortic pressure has little effect on myocardial contractility, whereas a decrease in arterial pressure causes a reflex increase in sympathetic tone, with increases in
heart rate and contractility. Carotid and aortic chemoreceptors are
stimulated by low partial pressure of arterial oxygen, high partial
pressure of arterial carbon dioxide, and low pH, but only when
changes are significant, and even then the increase in myocardial
contractility is modest. The fetus seems to be less sensitive than the
adult to chemoreceptor stimulation.146
Innervation is not necessary for cardiac function, as evidenced
by those who have undergone cardiac transplantation. The response to exercise in the denervated heart is limited and mediated
by increases in circulating catecholamines and a rise in body temperature. In intact animals and humans, b-adrenoreceptor blockade blunts the heart rate increase with exercise and abolishes
inotropic response.144
Cardiac Output
Cardiac output (CO) is the volume of blood ejected by the heart
over one minute; therefore, CO 5 stroke volume (volume ejected
per contraction) 3 heart rate (contractions per minute).
Cardiac output in the fetus is determined mainly by heart rate
because of a limited capacity to increase stroke volume that results
mainly from decreased diastolic distensibility. Consequently, fetal
bradycardia is detrimental to blood flow and oxygen delivery. However, the fetal heart can respond to increased preload (Starling’s law)