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Cardiology: An Integrated Approach >

Chapter 5: Cardiac Output and the Pressure-Volume

Relationship
Kristen Millado; Margaret Chi; Adel Elmoselhi

Learning Objectives
Learning Objectives

By the end of this chapter the student will be able to:

Explain the main factors that regulate cardiac output, heart rate, and stroke volume including the autonomic nervous system.

Describe the impact of preload, a erload, and contractility on cardiac output.

Explain the various methods used for measuring cardiac output.

Integrate the myocardial structure with the contraction of the heart.

Explain the coupling of electrical excitation with the contraction of the heart.

Describe the regulation of [Ca2+]i and its impact on contractility.

Describe the e ects of the autonomic nervous system on contractility.

Identify the importance of the Frank-Starling relationship on cardiac output.

Describe the relationship between cardiac and vascular curves and their coupling.

Explain pressure and volume in the heart during the cardiac cycle through a ventricular pressure-volume loop.

Describe how preload, a erload, and contractility a ect the pressure-volume loop.

Introduction
Cardiac output (CO) is the total volume of blood ejected by the ventricles per minute. It is approximately 5 L/min at rest in an average healthy individual
(70 kg man) and it can increase up to 20 to 25 L/min during maximum exercise. CO is critical to maintain a su icient blood supply to all body tissues,
especially to the brain and other vital organs during various stressful conditions. At all times, the CO of the right ventricle going to the pulmonary
circulation is equal to the CO of the le ventricle going to the systemic circulation. Furthermore, the venous return to both sides of the heart equals their
CO. This precise control of CO depends on the regulation of heart rate and stroke volume. In this chapter, the various mechanisms that regulate CO, heart
rate, and stroke volume as well as the pressure-volume relationship will be discussed.

Regulation of Cardiac Output

Cardiac output varies based on the body’s requirements and depends on the heart rate (beats per minute) and the stroke volume (blood volume
pumped per heartbeat) as follows:

Cardiac output = Heart rate × Stroke volume

 

On average, the heart rate is equal to 70 beats per minute and the stroke volume is approximately 70 mL/beat. Thus, the CO is 4900 mL/min or
approximately 5 L/min. This means that each minute the right ventricle pumps 5 L of blood to the lungs and the le ventricle pumps 5 L of blood to the
systemic circulation, which is approximately the total volume of blood in the body (~5-5.5 L). During exercise of an average untrained individual, CO can
reach 20 to 25 L/min; however, it can further increase to almost 40 L/min in a trained athlete during endurance exercise. The di erence between CO at
rest and during maximum exercise is referred to as cardiac reserve. This variability of CO is based on the body’s demand and is regulated via several
mechanisms as discussed below (Fig. 5.1).

Figure 5.1
Main factors regulating cardiac output.

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Heart Rate and Its Regulation

The heart rate (HR) is determined by the balance between sympathetic and parasympathetic activation, normally, on the sinoatrial (SA) node of the
heart. The SA node is the heart’s natural pacemaker and fires intrinsically at approximately 100 beats per minute in a healthy adult without any neural
influences. In a normal resting state, parasympathetic activation dominates the stimulation of the SA node to lower the heart rate to approximately 70
beats per minute. Furthermore, depending on a person’s state, sympathetic stimulation (“fight-or-flight” response) can increase the heart rate while
parasympathetic activation (“rest-and-digest” state) can decrease it.

Positive Chronotropic E ects (Sympathetic Stimulation) Increases Heart Rate

Norepinephrine released from the sympathetic nerve endings activates the β1 receptors in the SA node. Activation of the β1 receptors in the SA node

leads to an increase of inward Na+ and Ca2+ movement via enhanced “funny” Na+- and T-type voltage-gated Ca2+ channels. This speeds the
depolarization phase of the SA node’s action potential by reaching the threshold faster, that in turn increases the heart rate. Furthermore, sympathetic
stimulation reduces the AV nodal delay and increases the conduction of the action potentials throughout the conductive system.

Negative Chronotropic E ects (Parasympathetic Stimulation) Decreases the Heart Rate

Acetylcholine (ACh) release from the parasympathetic nerve endings bind to muscarinic receptors in the SA node to decrease the heart rate as a result of
(1) slowing down the rate of spontaneous depolarization as a result of a decreased Na+ inward current via Na+ “funny” channels—this occurs through
coupling of the muscarinic receptors with the Gi proteins that consequently inhibits adenylyl cyclase; (2) hyperpolarization of the resting potential

because of the increase of the K+ permeability and the outward current via the K+-ACh channels; and (3) a decreased Ca2+ inward current as a result of
decreasing functional Ca2+ channels. Thus, more depolarization is needed to reach the threshold and fire an action potential.

Stroke Volume and Its Regulation

Stroke volume (SV) is the volume of blood ejected from each ventricle during the contraction in 1 heartbeat. It is equivalent to the di erence between
the volume of blood in the ventricle just before the contraction (end-diastolic volume) and the volume of blood le in the ventricle a er the contraction
(end-systolic volume).

Stroke volume (mL) = End-diastolic volume (mL) – End-systolic volume (mL)

 

SV is regulated by preload, a erload, and contractility as shown in Fig. 5.1—each parameter will be described in stroke volume and its regulation section.
In experimental studies, intact isolated hearts have shown that an increased ventricular volume during diastole leads to an increase in the stretching of
the muscle fibers, and, as a result, an increase in the force of the contraction and stroke volume. This relationship between the length of the muscle
before stimulation (ie, preload) and the tension developed is the basis of the previous observation in the intact heart and is called the Frank-Starling
relationship. This relationship explains an important aspect of the intrinsic mechanism of the heart to pump the same volume of blood that it will
receive. An increase in the venous return to the heart (or an increased preload) increases the diastolic ventricular filling and consequently increases the
cardiac output.

A erload is a fixed load that the cardiac muscle needs to overcome in order to shorten during an isotonic contraction. The greater the load, the less the
shortening of the muscle during a contraction. Intact heart tissue, larger volume loads, or resistance against a ventricular contraction, make it harder to
eject the blood out of the ventricle. As a result, the ventricular pressure increases to overcome the higher load or resistance against the contraction. A

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decreased a erload has the opposite e ect, as the heart does not have to pump as hard to get blood through to the rest of the body. Classic clinical
examples of increased a erload are hypertension and aortic stenosis.

With increased myocardial contractility, the heart is also able to increase stroke volume by pumping more blood out during systole, independent of the
preload and the a erload. Contractility depends on the neural or hormonal influences on the intracellular Ca2+ concentration and cross-bridge cycling.
For example, sympathetic stimulation and release of norepinephrine enhances contractility in various stress conditions. Furthermore, several
pharmacological substances increase myocardial contractility, such as digitalis and catecholamine drugs, which are usually used in cases of heart
failure.

Preload

Preload in the heart can be defined as the stretching of the myocardial muscle fibers just prior to a contraction or ventricular wall tension at the end of
diastole. The importance of preload was described by Frank and Starling in an experimental model, which showed that within a physiologic range, the
more the ventricle is distended and filled with blood during diastole, the more the ventricle contracts, and more blood is ejected in the next systole. This
relationship is depicted graphically in Fig. 5.2, and is known as the ventricular function curve or the Frank-Starling curve. Thus, within physiological
limits, the more blood returning to the heart as venous return, the more blood pumped from the heart as cardiac output.

Venous return = Cardiac output (within physiological range)

 

Figure 5.2
Relationship between preload and cardiac output.

There are several indices or markers that can be measured to reflect the values of the preload such as the ventricular end-diastolic volume (EDV),
ventricular end-diastolic pressure (EDP), le atrial pressure, pulmonary venous pressure, and pulmonary wedge pressure. A clinical example of a
decreasing preload is a severe hemorrhage or dehydration that can result in a reduction of stroke volume or cardiac output. For example, excessive IV
fluid infusion can lead to an increased preload and consequently increase the stroke volume.

A erload

A erload is defined as the ventricular wall stress during the ejection phase of systole or the resistance that the ventricle needs to overcome in order to
eject its content. Clinically, it is the amount of aortic pressure that the heart ejects blood against in order to empty the le ventricle. A erload is
determined by several factors, including wall stress, aortic pressure, and total peripheral resistance.

Wall stress is equal to the ventricular pressure (P), multiplied by the ventricular radius (r), and divided by 2 times the wall thickness (h), as shown below.
Wall tension, on the other hand, is the same as wall stress but without consideration of the wall thickness.

Wall stress = (P × r) / 2h
 

Wall stress is estimated from the law of Laplace as an increase in the ventricular pressure or the radius of the ventricle. This means that ventricular
dilation will increase the wall stress. However, increased wall thickness reduces the wall stress because the force is divided into a larger thickness per

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unit of pressure. For example, a hypertrophied le ventricle acts as a compensatory mechanism for increased a erload and as a result reduces wall
stress. Classic examples of increased a erload include high blood pressure and aortic stenosis.

Contractility

Contractility or inotropy is the property that accounts for the changes in the strength of myocardium contraction independent of the preload and the
a erload. It is a ected by the neurotransmitters or hormonal influences and is mainly mediated by the change of the intracellular calcium concentration
in the cardiomyocytes.

In experimental studies, the main index for contractility is o en the change in pressure versus the change in time (dp/dt). However, in a clinical setting,
the index used for contractility is called the ejection fraction. The ejection fraction is the fraction of the end-diastolic blood volume ejected from 1
ventricle in 1 beat and calculated as follows:

Ejection fraction = Stroke volume/End-diastolic volume= 70/110 = 0.64 or 64%

 

In a healthy individual, the normal range of the ejection fraction percentage is between 55 and 75. The e ect of increased contractility on the stroke
volume or the cardiac output will be discussed in the Frank-Starling Relationship in following section.

The activation of sympathetic activity, for example, during exercise or the administration of positive inotropic drugs, not only results in increased cardiac
contractility but also enhanced relaxation. Overall, exercise or positive inotropic drugs cause the heart to be more e icient during systole and diastole
through (1) increased dp/dt, thus increasing the slope of the contraction and the rate of pressure development; (2) an increased peak in the le
ventricular pressure; (3) an increased rate of relaxation due to the enhanced rate of Ca2+ sequestration; and (4) a decreased systolic interval and more
contractions during certain time periods.

Therefore, the cardiac output increases to provide more blood supply to the active muscles during exercise, or attempts to return the cardiac output
toward normal, for example in heart failure.

Measurement of Cardiac Output

There are several invasive and noninvasive methods that are used to measure cardiac output. Noninvasive methods that are increasing in development
and more commonly accepted clinically include Doppler ultrasound, echocardiography (ECG), pulse pressure methods, and magnetic resonance
imaging (MRI). An invasive method includes intracardiac catheterization based on the conservation of mass using the Fick principle. Briefly, by
rearranging the following equations:

Contractile Apparatuses in the Myocardium

This section will focus on contractility of the myocardium, which is the muscular layer of the wall of the heart. Cardiac muscle is composed of numerous
myocardial cells working in conjunction with one another to pump blood throughout the body. On a microscopic level, each myocardial fiber is broken
down into bundles of myofibrils as shown in Fig. 5.3. Along the length of a myofibril is a series of sarcomeres, which are the smallest basic contractile
unit of the heart muscle.

Figure 5.3
A. Cardiac muscle structure. Diagram of cardiac muscle cells indicates characteristic features of this muscle type. The fibers consist of separate cells with
interdigitating processes wherein they are held together. These regions of contact are called the intercalated disks (IDs), which cross an entire fiber
between two cells. The transverse regions of the step-like ID have abundant desmosomes and other adherent junctions, which hold the cells firmly
together. Longitudinal regions of these disks contain abundant gap junctions, which form “electrical synapses” allowing contraction signals to pass from

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cell to cell as a single wave. Cardiac muscle cells have central nuclei and myofibrils that are less dense and organized than those of skeletal muscle. Also
the cells are o en branched, allowing the muscle fibers to interweave in a more complicated arrangement within fascicles that produces an e icient
contraction mechanism for emptying the heart. B. Cardiac muscle is composed of irregular branched cells bound together longitudinally by intercalated
disks and shows strong, involuntary contractions. (Reproduced, with permission, from Mescher AL: Junqueira’s Basic Histology Text and Atlas. 14th ed.
New York: McGraw-Hill, 2016.)

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Similar to skeletal muscle, these sarcomeres abide by the sliding filament model. When contraction occurs, cross-bridges form between the actin and
the myosin allowing adjacent filaments to slide across one another. This results in a shortening of the sarcomere and thus the myofibril and the muscle
contract. The 2 types of filaments involved in this process are thick and thin filaments. Thick filaments are composed of myosin and thin filaments are
composed of actin, troponin, and tropomyosin.

Myosin contains myosin ATPase and is connected to the Z-line by titin (connectin).

Actin contains 2 strands arranged in an alpha-helical structure that contains a binding site for the myosin head.

Tropomyosin is a double-helical structure that occupies the myosin binding site on actin during the resting state. During the relaxation state, it prevents
binding of the myosin to actin.

Troponin is made up of 3 isoforms, troponin T (TnT), troponin I (TnI), and troponin C (TnC). TnT links troponin to actin and tropomyosin, TnI inhibits
ATPase activity that is necessary for contraction, and TnC binds Ca2+ ions.

The depolarization of 1 myocardial cell leads to subsequent depolarization of the adjacent myocardial cells in an all or nothing fashion, meaning when 1
cell is electrically excited, an action potential is propagated throughout the entire myocardium. The term “electrical syncytium” is o en used to portray
this interconnectedness of how both the atria act as 1 unit and also how both the ventricles act as 1 unit. Structures such as the sarcoplasmic reticulum,
T-tubules, and gap junctions facilitate this connection. The sarcoplasmic reticulum spans between the myofibrils and the T-tubular system, and the gap
junctions are located between the myocardial cells.

The sarcoplasmic reticulum acts as a storage for Ca2+ that is released upon electrical excitation.

The T-tubules are an invagination of the myocyte membrane at the Z-lines that help to propagate ion influxes inside the cells. T-tubules form triads with
the sarcoplasmic reticulum to facilitate the release of Ca2+ during a contraction.

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Intercalated disks are specialized structures that connect the ends of adjacent cells together. They consist of 2 types of membrane structures called
desmosomes and gap junctions. A desmosome is an adhering structure that mechanically aids to hold adjacent cells together considering the high
mechanical stress that occurs in the myocardium. Gap junctions are low resistance paths that allow for the propagation of the electrical action potential
to adjacent cells.

Excitation-Contraction Coupling and Intracellular Ca2+ Regulation

The conversion of the electrical potential to a physical muscle contraction is known as excitation-contraction coupling as shown in Fig. 5.4. In the heart,
the electric potentials originating from the sinoatrial node (SA node) dictate the heart rate. Initiation of an action potential leads to the activation of L-
type Ca2+ channels on the myocyte membrane. Via the T-tubular system, there is a small influx of Ca2+ from the extracellular space to the intracellular
space of the myocyte. This small amount of Ca2+, however, is not su icient to yield a contraction. Rather, it binds to ryanodine channel receptors on the
sarcoplasmic reticulum, which leads to the release of Ca2+ from sarcoplasmic reticulum stores inducing a large increase in the cytosolic Ca2+
concentration. Augmentation of the initial Ca2+ influx via a massive release from the sarcoplasmic reticulum is referred to as calcium-induced calcium
release (CICR).

Figure 5.4

Ca2+ fluxes in excitation-contraction coupling.

Cytosolic Ca2+ then binds to troponin C located on the thin filaments. This binding inhibits the action of troponin I and leads to a conformational change
in the tropomyosin, freeing the myosin head binding site on actin. Once the myosin binds to actin, it hydrolyzes its ATP. Energy obtained from the
phosphate bond generates the “power stroke” that results in the movement of the thin filament over the thick filament inward and thus a myocyte
contraction.

Following a contraction, ADP is released from the myosin and replaced by a new molecule of ATP. Myosin is then released from the actin binding site. At
this point, subsequent power strokes can be generated. To halt the contraction activity, a series of events need to occur including the inactivation of L-
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type Ca2+ channels and the movement of Ca2+ back into the sarcoplasmic reticulum via the Ca2+-ATPase pump (SERCA). Another important protein is
phospholamban which is located on the membrane of the sarcoplasmic reticulum. When phosphorylated, it leads to the reuptake of cytosolic Ca2+ from
the cytoplasm back into the sarcoplasmic reticulum, which results in relaxation of the myocardial cell. In addition to the Ca2+ uptake into the
sarcoplasmic reticulum, the Na+-Ca2+ exchanger and the ATPase Ca2+ pump in the sarcolemma remove the cytosolic Ca2+ outside the cell.

It is important to recognize that the contractility is directly correlated with the cytoplasmic intracellular Ca2+ concentration, which is mainly released
from the sarcoplasmic reticulum during excitation-contraction coupling. The amount of Ca2+ released from the sarcoplasmic reticulum depends on the
size of the inward Ca2+ current during the plateau phase of the action potential and the amount of Ca2+ already stored in the sarcoplasmic reticulum
before its release. The latter mechanism explains the increase in contractility with an increased heart rate, which is called the positive staircase, the
Bowditch staircase, or the Treppe e ect.

E ect of the Sympathetic and Parasympathetic Nervous Systems on Contractility

Sympathetic stimulation to the heart results in increased contractility of the heart, which is called the positive inotropic e ect. This occurs via the
stimulation of norepinephrine on the myocyte β1-adrenergic receptors. The β1-adrenergic receptors activate the cell membrane Gs protein that in turn
stimulates the membrane-bound adenylyl cyclase to produce cAMP (cyclic AMP) from the ATP. The cAMP activates protein kinases inside the cell that
phosphorylate several cellular proteins which increase contractility. One of these proteins is the L-type Ca2+ channel, which increases Ca2+ influx and
triggers Ca2+ release from the sarcoplasmic reticulum (SR) and the cytosolic Ca2+, which increases the force of a contraction. Other cellular proteins
include phospholamban, which when phosphorylated, increase Ca2+ uptake in the SR and enhance relaxation and a subsequent contraction.

Conversely, parasympathetic stimulation of the heart leads to a decrease in the contractility of the heart, also called the negative inotropic e ect. ACh
releases from the parasympathetic nerve endings mainly in both atria and binds to muscarinic M2 receptors, activating Gi proteins. As a result, adenylate
cyclase is inhibited and the amount of intracellular cAMP decreases. Ultimately, this cholinergic e ect decreases the heart rate at the sinus level and
decreases the force of a contraction by counteracting sympathetic activation, especially in the atria.

Length-Tension Relationship

The level of tension developed in the cardiac muscle fibers depends on the resting length just prior to its stimulation, similar to skeletal muscle fibers.
The physiological basis of this relationship is the degree of overlap between the thin and thick filaments that determine the possible number of cross-
bridge formations in the muscle fibers. The concentration of intracellular Ca2+ then activates the cross-bridge cycling to develop the active tension. The
maximum tension is developed at the optimum length of the cardiac muscle fiber that is approximately 2.2 μm as shown in Fig. 5.5. The same concept
occurs in the whole ventricle and the length in the ventricle before a contraction corresponds to the preload that is best measured as end-diastolic
volume. However, the cardiac muscle normally works only within the ascending limb of the curve because of the sti er nature of the cardiac muscle.
Therefore, the working length of the cardiac muscle is always less than the optimum length of the muscle. This relationship is the basis of the Frank-
Starling relationship, which maintains the equality of the cardiac output and the venous return.

Figure 5.5
The length-tension relationship.

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Frank-Starling Relationship

The Frank-Starling relationship is the relationship between the stroke volume or cardiac output and preload, which corresponds to the ventricular end-
diastolic volume or right atrial pressure or venous return. This relationship was demonstrated by two scientists, a German named Otto Frank, and his
British counterpart, Ernest Starling, in a series of experiments that showed that the volume of blood ejected by the ventricle depends on the volume of
blood present in the ventricle at the end of diastole. This end-diastolic volume depends on the blood returning to the ventricle, which corresponds to
the venous return. The Frank-Starling relationship (also called the Frank-Starling law of the heart) is the cornerstone of normal ventricular function,
where the heart ejects what it will receive. Thus, because of this intrinsic property of the cardiac muscle, the cardiac output equals the venous return in
the steady state of the heart. Within this physiological condition, the stroke volume and the cardiac output are almost linear with the end-diastolic
volume and the venous return. In a higher level of venous return, the curve starts to plateau, which indicates the limitation of the ventricle to maintain
the increase of cardiac output.

An increase in contractility (ie, positive inotropic) for whatever reason (eg, digitalis, catecholamine) shi s the normal Frank-Starling curve upward and
increases the stroke volume or the cardiac output at any particular point of the preload as shown in Fig. 5.6. Similarly, a decrease in contractility (ie,
negative inotropic) such as in heart failure or from pharmacological drugs such as β-blockers or calcium channel blockers shi s the normal curve
downward and results in a decreasing stroke volume or cardiac output with any particular preload. The opposite will occur in the case of a negative
inotropic e ect and the ejection fraction will decrease.

Figure 5.6
The Frank-Starling relationship.

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Relations and Regulation of Cardiac Output and Venous Return

The Frank-Starling relationship has shown that the cardiac output depends on the end-diastolic volume of the ventricle, which in turns depends on the
venous return. The venous return depends on the right atrial pressure and the cardiac output. To examine the e ect of the various variables on the
cardiac output and the venous return, their function with the right atrial pressure has been plotted in Fig. 5.7.

Figure 5.7
Cardiac output and the venous pressure curves.

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The cardiac output and the venous return are plotted separately, and both curves are also combined for further illustration. The relationship between
the cardiac output and the right atrial pressure is called the cardiac function curve, and the relationship between the venous return and the right atrial
pressure is called the vascular function curve. Each curve and their combinations plus the e ect of the various conditions are discussed in more detail
below.

Cardiac and Vascular Function Curves Coupling

As shown in Fig. 5.7A, there is a direct relationship between the cardiac output in the le ventricle and the right atrial pressure and the venous return
based on the Frank-Starling relationship. Thus, the cardiac output increases with increasing right atrial pressure, up to about 4 mmHg, a er which the
curve starts to bend and the le ventricle cannot keep up with the venous return. The level of the cardiac output ejected by the ventricle can reach
around 9 L/min in normal conditions.

In the vascular function curve, there is an inverse relationship between the venous return and the right atrial pressure. The venous return increases
when the right atrial pressure decreases. This inverse relationship is due to the pressure gradient between the right atrium and the systemic pressure
that drives the venous return. The vascular function curve intercepts with the x-axis, which represents the mean circulatory pressure and is the pressure
of the circulatory system when the heart stops pumping. Mean circulatory pressure is determined and regulated by the vascular capacitance and the
total blood volume. The plateau part of the vascular function curve that intercepts with the y-axis is a negative value because the veins are collapsed and
block the venous return back to the heart. This represents the maximum cardiac output as the venous pressure is reduced, which is the operating
venous pressure in a normal heart.

The intersection between the cardiac and vascular function curves represents a steady state operating point. At this equilibrium point, the cardiac
output is equal to the venous return in normal steady state conditions with normal values of the right atrial pressure and the mean systemic pressure, as
shown in Fig. 5.7A. The combined curves are a useful tool for predicting the cardiac output with changing various parameters with each curve. The
cardiac function changes with a positive or a negative inotropic e ect. The vascular function curve is altered by changing the blood volume or the
venous constriction. Both curves are also changed by total peripheral resistance changes.

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Changes in the Equilibrium Point

A positive inotropic e ect (eg, digoxin) shi s the cardiac function curve upward that results in an equilibrium point with a higher cardiac output and
lower right atrial pressure. A negative inotropic e ect will have the opposite e ect, with a new equilibrium point characterized by lower cardiac output
and increased right atrial pressure, as shown in Fig. 5.7B.

Increased blood volume and venoconstriction shi the vascular function curve to the right and lead to an equilibrium point with higher cardiac output
and mean circulatory pressure. Decreasing blood volume, or venodilation, such as a case of severe hemorrhage, has the opposite e ect, in which the
vascular function curve will shi to the le and create a new equilibrium point characterized by lower cardiac output and mean circulatory pressure, as
shown in Fig. 5.7C.

Changes in the total peripheral resistance (TPR) alter both curves, and thus, its e ect is more complicated. Increased TPR (eg, constriction in arterioles)
increases the a erload on the heart and, as a result, decreases the cardiac output. Graphically, as shown in Fig. 5.7D, the cardiac function curve shi s
downward, while the vascular function curve rotates downward as a result of less venous return to the heart at a given right atrial pressure.
Consequently, the equilibrium point will be lower than normal, which means both the cardiac output and the venous return are decreased. Increased
TPR has opposite e ect on the right atrial pressure through decreased cardiac output that backs up the blood and increases the right atrial pressure; it
also decreases the venous return, which decreases the right atrial pressure. The actual right atrial pressure is a compromise between both the opposing
e ects. Decreased TPR has an e ect in the opposite direction, thus increasing TPR with a higher equilibrium point than normal, and a ecting the rest of
the parameters.

Pressure-Volume Loops
Another way of representing the relationship between the ventricular pressure and the blood volume during the cardiac cycle is the ventricular
pressure-volume loop. As shown in Fig. 5.8, the x-axis represents the volume in the right or le ventricle and the y-axis represents the pressure in the
right or le ventricle through 1 cycle of the heart.

Figure 5.8
A normal pressure-volume loop. (Reproduced, with permission, from Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical
Physiology. 24th ed. New York, NY: McGraw-Hill; 2012.)

Image not available.

At point A, the mitral valve opens, and filling of the le ventricle with blood from the le atrium begins. This phase is called ventricular filling and
corresponds to the diastolic phase of the cardiac cycle. During this phase, the ventricular pressure increases slightly as the volume increases, which
creates a passive tension of the cardiac muscle. When the pressure of the le ventricle exceeds the pressure of the le atrium, the mitral valve closes,
which marks the end of ventricular filling (point B). At this point, the volume of the ventricle has reached the maximum value known as the end-diastolic
volume (EDV).

At point B, where the le ventricle is filled, the systolic phase begins. With both the aortic and mitral valve closed, the ventricle begins to contract against
a fixed volume; this phase is called an isovolumetric contraction. This causes the pressure to increase in the le ventricle, and when the pressure in the
le ventricle becomes greater than the aortic diastolic pressure, the aortic valve opens (point C) and the blood is ejected into the aorta. In this phase,
also called ventricular ejection, the blood in the ventricle decreases, but the pressure continues to increase until it reaches a peak and then starts to
decrease until the pressure in the ventricle is lower than the aortic pressure. At this point, the aortic valve closes; which is represented as point D. The
volume of the le ventricle is at the lowest value at this point and is known as the end-systolic volume (ESV). At this point, both the aortic valve and
mitral valve are closed as the ventricle relaxes with a fixed volume; this phase is called isovolumetric relaxation. The diastolic phase of the cardiac cycle
also starts at this point. When the pressure of the ventricle is lower than that of the le atrium, the mitral valve reopens (point A) and the cycle starts
over again.

The di erence between the EDV and the ESV marks the stroke volume, which is the amount of blood ejected in each systolic contraction, or 1 heartbeat.
The volume of blood in the heart a er diastole and systole is influenced by numerous factors, including preload, a erload, and contractility.

E ect of Preload on the Pressure-Volume Loop

Increased end-diastolic volume, or preload, such as in the case of excessive IV fluid, results in an increased stroke volume, assuming that the a erload
and contractility are constant, as shown in Fig. 5.9A. Also note that the end-systolic volume remains constant. This adjustment of the stroke volume with
the diastolic filling volume in a normal ventricle is based on the Frank-Starling mechanism. The preload and its e ects are compromised in the case of
severe ventricular hypertrophy, or sti ness, of the ventricle where compliance is reduced.

Figure 5.9
The e ects of preload, a erload, and contractility on the pressure-volume loop. (Reproduced, with permission, from Mohrman DE, Heller LJ.
Cardiovascular Physiology. 8th ed. New York, NY: McGraw-Hill; 2014.)

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E ect of the A erload on the Pressure-Volume Loop

Assuming the preload and contractility are constant, an increase in the a erload, such as in the case of hypertension or aortic stenosis, increases the
ventricular systolic pressure to overcome the high resistance. Furthermore, the stroke volume is reduced, with more blood being retained in the
ventricle at the end of systole (ie, higher LV-ESV), as shown in Fig. 5.9B. The relationship between the a erload and the ESV is linear; thus, the more the
a erload, the higher the ESV.

E ect of Contractility on the Pressure-Volume Loop

When preload and a erload are constant, increased contractility, as in the case of an injection of epinephrine, increases the stroke volume, with less
blood remaining in the ventricle (ie, smaller ESV), as shown in Fig. 5.9C. Thus, ESV depends on the a erload and the contractility of the ventricle but not
on the preload.

Key Points
Cardiac output is determined by the heart rate and the stroke volume.

Various factors regulate the cardiac output, the heart rate, and the stroke volume.

Sympathetic stimulation is mediated by norepinephrine binding to β1 receptors and results in a positive inotropic e ect.

Parasympathetic stimulation is mediated by ACh binding to M2 receptors and results in a negative inotropic e ect.

When an action potential is initiated, an influx of Ca2+ ions intracellularly allows actin to bind to myosin. Generation of a power stroke then leads to the
physical shortening of the muscle cell.

Inotropy can be positively or negatively influenced by drugs (ie, norepinephrine or β-blockers) or a cardiac state (ie, heart failure).

Preload is determined by the amount of venous return to the heart and can be influenced by drugs and the volume status of the body.

Pressure-volume loops describe the relationship between the pressure and the volume in the le ventricle through 1 cardiac cycle.

Preload, a erload, and contractility have a significant impact on the pressure-volume loop, which are manifested in various clinical conditions.

CLINICAL CORRELATION 5.1

During exercise, the heart needs to modify output so that the blood can adequately supply the active muscles. During strenuous exercise, muscles take
up to 85% of total cardiac output due to the e ects of the local vasodilators. The sympathetic nervous system plays a role in increasing total cardiac
output and contracting blood vessels to increase the blood volume and preload so that more blood is returned to the heart with each stroke. The overall
e ect of exercise is an increased heart rate, increased stroke volume due to an increased preload and increased contractility, and decreased a erload.
The total peripheral resistance is decreased and blood perfusion to the muscles is increased.

CLINICAL CORRELATION 5.2

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Digitalis is a plant species also known as foxglove. It has been used for centuries to control the rhythm of the heart, though it was not approved by the
Food and Drug Administration (FDA) until 1998. Its mechanism of action is to block sodium potassium ATPase, which renders the pump inactive. The
increased sodium decreases the concentration gradient across the cell membrane, making the sodium calcium pump more unfavorable. As a result,
calcium is stored in the sarcoplasmic reticulum of the cell, so more is released during contraction, resulting in positive inotropy.

CLINICAL CORRELATION 5.3

Digitalis is a positive inotropic agent which has been studied for many years in the treatment of systolic heart failure. Due to a relative decrease in the
number of functional myocytes in these patients, optimal function of each viable one is crucial. Digitalis can help optimize the contractility of those
which remain by increasing the intracellular Ca2+ when an action potential is initiated. Digitalis has been shown to improve exercise tolerance but has
not been shown to have any mortality benefit.

Case Studies
CASE 5.1 Use the following diagram, which demonstrates the relationship between the le ventricular volume and the le ventricular pressure in 1
cardiac cycle, to answer Questions 1 and 2.

1. Which of the following values (in mL) represents the stroke volume?

a. 50

b. 75

c. 100

d. 125

e. 150

The correct answer is b.

Based on the normal pressure-volume loop, the stroke volume is the di erence between the end-diastolic volume and the end-systolic volume. The
second heart sound is due to the closing of the aortic and pulmonic valves that occurs in the beginning of the isovolumetric relaxation and filling phases.

2 Which of the points in the figure represents the second heart sound?

a. A

b. B

c. C

d. D

e. E

The correct answer is e.

Based on the normal pressure-volume loop, the stroke volume is the di erence between the end-diastolic volume and the end-systolic volume. The
second heart sound is due to the closing of the aortic and pulmonic valves that occurs in the beginning of the isovolumetric relaxation and filling phases.

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CASE 5.2 The following Frank-Starling diagram belongs to a 36-year-old patient who has come to the emergency department a er he was involved in a
major accident. Point X is considered the equilibrium point for a healthy individual. Which point is best applied to this patient who lost a large volume of
blood and is in a coma with no neural or hormonal adaptation?

a. A

b. B

c. C

d. D

e. E

The correct answer is c.

Point C is the correct answer because severe bleeding results in a lower venous return, which leads to a decrease in the end-diastolic volume and
pressure. The patient also lost his adaptation mechanisms, therefore his stroke volume and cardiac output will be reduced and his tissue perfusion is
compromised especially to the vital organs such as the brain, heart, and kidneys.

Suggested Readings

Fuster  V, Walsh  RA, Harrington  RA. Hurst’s the Heart, Part 2. 13th ed. New York, NY: McGraw-Hill; 2011.

Hall  JE. The pioneering use of systems analysis to study cardiac output regulation. Am J Physiol Regul Integr Comp Physiol. 2004;287(5):R1009–R1011. 
[PubMed: 15475497]

Mathews  L, Singh  RK. Cardiac output monitoring. Ann Card Anaesth. 2008;11(1):56–68.  [PubMed: 18182765]

Triposkiadis  F, Karayannis  G, Giamouzis  G, Skoularigis  J, Louridas  G, Butler  J. The sympathetic nervous system in heart failure physiology,
pathophysiology, and clinical implications. J Am Coll Cardiol. 2009;54(19):1747–1762.  [PubMed: 19874988]

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