MECHANICAL PROPERTIES OF THE HEART I &

II
Recommended Reading:

Guyton, A. Textbook of Medical Physiology, 10th Edition. Chapters 9, 14, 20.

Berne & Levy. Principles of Physiology. 4th Edition. Chapter 23.

Learning Objectives:

1. To understand the hemodynamic events occurring during the different

phases of the cardiac cycle and to be able to explain these both on the
pressure-volume diagram and on curves of pressure and volume versus
time.

2. To understand how the end-diastolic pressure volume relationship

(EDPVR) and the end-systolic pressure-volume relationship (ESPVR)
characterize ventricular diastolic and systolic properties, respectively.

3. To understand the concepts of contractility, preload, afterload,

compliance.

4. To understand what Frank-Starling Curves are, and how they are

influenced by ventricular afterload and contractility.

5. To understand how afterload resistance can be represented on the PV

diagram using the Ea concept and to understand how Ea can be used in
concert with the ESPVR to predict how cardiac performance varies
with contractility, preload and afterload.

6. To understand the determinants of myocardial oxygen demand and

regulation of myocardial blood flow.

Glossary

Afterload - The mechanical "load" on the ventricle during ejection. Under

normal physiological conditions, this is determined by the arterial system.
Indices of afterload include, aortic pressure, ejection wall stress, total
peripheral resistance (TPR) and arterial impedance.
Compliance - A term used in describing diastolic properties ("stiffness") of
the ventricle. Technically, it is defined as the reciprocal of the slope of the
EDPVR ([dP/dV]-1). Colloquially, it is frequently used in describing the
elevation of the EDPVR.
Contractility - An ill-defined concept, referring the intrinsic "strength" of the
ventricle or cardiac muscle. This notion is classically considered to be
independent of the phenomenon whereby changes in loading conditions
(preload or afterload) result in changes in pressure (or force) generation.
Diastole - (Greek, "dilate"). The phase of the cardiac cycle during which
contractile properties return to their resting state.
EDPVR - end-diastolic pressure-volume relationship - The relationship
between pressure and volume in the ventricle at the instant of complete
relaxation (end-diastole).
Ees - end-systolic Elastance - the slope of the ESPVR; has units of mmHg/ml,
and is considered to be an index of "contractility".
EF - ejection fraction - the ratio between SV and EDV. It is the most
commonly used index of contractility, mostly because it is relatively easy to
measure in the clinical setting. Its major limitation is that it is influenced by
afterload conditions.
Elastance - The change in pressure for a given change in volume within a
chamber and is an indication of the "stiffness" of the chamber. It has units of
mmHg/ml. The higher the elastance the stiffer the wall of the chamber.
ESPVR - end-systolic pressure-volume relationship - The relationship
between ventricular pressure and volume at the instant of maximal activation
(end-systole) during the cardiac cycle. This relationship is reasonably linear,
and reasonably independent of the loading conditions: Pes = Ees [ESV-Vo].
Preload - The "load" imposed on the ventricle at the end of diastole. Measures
of preload include end-diastolic volume, end-diastolic pressure and end-
diastolic wall stress.
Systole - The first phase of the cardiac cycle which includes the period of time
during which the electrical events responsible for initiating contraction and the
mechanical events responsible for contraction occur. It ends when the muscles
are in the greatest state of activation during the contraction.
SV - stroke volume - the amount of blood expelled during each cardiac cycle.
SV = EDV - ESV.

I. INTRODUCTION
The heart is functionally divided into a right side and a left side. Each side
may be further subdivided into a ventricle and an atrium. The primary role of
each atrium is to act as a reservoir and booster pump for venous return to the
heart. With the discovery of atrial naturetic peptides, other homeostatic roles
of the atrium have been proposed. The primary physiologic function of each
ventricle is to maintain circulation of blood to the organs of the body. The left
heart receives oxygenated blood from the pulmonary circulation and
contraction of the muscles of the left ventricle provide energy to propel that
blood through the systemic arterial network. The right ventricle receives blood
from the systemic venous system and propels it through the lungs and onward
to the left ventricle. The reason that blood flows through the system is because
of the pressure gradients set up by the ventricles between the various parts of
the circulatory system.
In order to understand how the heart performs its task, one must have an
appreciation of the force-generating properties of cardiac muscle (excitation-
contraction coupling), the factors which regulate the transformation of muscle
force into intraventricular pressure, the functioning of the cardiac valves, and
something about the load against which the ventricles contract (i.e., the
properties of the systemic and pulmonic vascular systems). This syllabus
section will focus on a description of the pump function of the ventricles with
particular attention to a description of those properties as represented on the
pressure-volume diagram. Emphasis will be given to the clinically relevant
concepts of contractility, afterload and preload. In addition, we will review
how the ventricle and the arterial system interact to determine cardiovascular
performance (cardiac output and blood pressure). Exercises have been created
for a web-based cardiovascular simulator in order to help you learn about
these fundamental properties as well as the complex and dynamic physiology.
http://www.columbia.edu……

II. EXCITATION-CONTRACTION COUPLING.

The sequence of events that lead to myocardial contraction is triggered by
electrical depolarization of the cell; electrical depolarization increases the
probability of sarcolemmal calcium channel opening, which in turn results in
calcium influx into the cell. A rise in calcium concentration then occurs in the
subsarcolemmal space near the lateral cisternae of the sarcoplasmic reticulum.
This rise in local calcium concentration causes the release of a larger pool of
calcium stored in the sarcoplasmic reticulum through calcium release channels
called ryanodine receptors, which are found in high concentration near the
lateral cisternae. The mechanisms by which the subsarcolemmal rise in
calcium concentration results in calcium release from the sarcoplasmic
reticulum, a process referred to as calcium-induced calcium release, are not
fully elucidated; a tight anatomic coupling between the sarcolemmal calcium
channels and ryanodine receptors has suggested that conformational changes
of calcium channel proteins can directly influence the properties of the
ryanodine receptor. The calcium released from the sarcoplasmic reticulum
diffuses through the myofilament lattice and is available for binding to
troponin, which disinhibits actin and myosin interactions and results in force
production.

Calcium release is rapid and does not require energy because of the large
calcium concentration gradient between the sarcoplasmic reticulum and the
cytosol during diastole. In contrast, removal of calcium from the cytosol and
from troponin occurs up a concentration gradient and is an energy-requiring
process. Calcium sequestration is primarily accomplished by pumps on the
sarcoplasmic reticulum membrane that consume ATP (sarcoplasmic reticulum
Ca2+-ATPase pumps); these pumps are located in the central portions of the
sarcoplasmic reticulum and are in close proximity to the myofilaments.
Sarcoplasmic reticulum Ca2+-ATPase activity is regulated by the
phosphorylation status of another sarcoplasmic reticulum protein,
phospholamban. To maintain calcium homeostasis, an amount of calcium
equal to what entered the cell through the sarcolemmal calcium channels must
also exit with each beat. This equilibrium is accomplished primarily by the
sarcolemmal sodium-calcium exchanger, a transmembrane protein that
translocates calcium across the membrane down its concentration gradient in
exchange for sodium ions moved in the opposite direction. Sodium
homeostasis is in turn regulated largely by the ATP-requiring sodium-
potassium pump on the sarcolemma.

As suggested above, the amount of calcium release and the rate of calcium
uptake are under regulation of the -adrenergic pathway which provides a
ready means of enhancing contractile force under settings of stress. -

agonist (e.g., epinephrine or norepinephrine) binding to the -receptor

activates membrane bound adenylyl cyclase which results in the generation of
cAMP and thence to phosphokinase A (PKA) activation. PKA activation
results in phosphorylation of phospholamban, the calcium channel, the
ryanodine receptor and sarcomeric regulatory proteins. The modification of
protein function caused by such phosphorylations results in a coordinated
increase in calcium entry, uptake and release with associated increase in
contractile strength.

III. FORCE-LENGTH RELATIONS.

In addition to calcium, cardiac muscle length exerts a major influence on force
production. Because each muscle is composed of a linear array of sarcomere
bundles from one end of the muscle to the other, muscle length is directly
proportional to the average sarcomere length. Changes in sarcomere length
alter the geometric relationship between thick and thin filaments. For
myofilaments in general, optimal force is achieved when sarcomere length is
about 2.2 to 2.3 m, the length that provides optimal overlap of thick and thin
filaments. As sarcomere length is decreased below about 2.0 m, the tips of
apposing thin filaments hit each other, the thick filaments approach the Z
lines, and the lateral distance between thick and thin filaments increases. Each
of these factors contributes to a reduction in force with decreasing sarcomere
length. In skeletal muscle, when sarcomeres are stretched beyond 2.3 m,
force decreases because fewer myosin heads can reach and bind with actin;
skeletal muscle can typically operate in this so-called descending limb of the
sarcomere force-length relationship. In cardiac muscle, however, constraints
imposed by the sarcolemma prevent myocardial sarcomeres from being
stretched beyond 2.3 m, even under conditions of severe heart failure when
very high stretching pressures are imposed on the heart.

Force-length relationships are conveniently used to characterize systolic and

diastolic contractile properties of cardiac muscle. These relationships are
measured by holding the ends of an isolated muscle strip and measuring the
force developed at different muscle lengths while preventing the muscle from
shortening (isometric contractions). As the muscle is stretched from its slack
length (the length at which no force is generated), both the resting (end-
diastolic) tension and the peak (end-systolic) tension increase. The end-
diastolic force-length relationship is non-linear and exhibits a shallow slope at
small lengths and a steeper slope at larger lengths, which is a reflection of the
non-linear mechanical restraints imposed by the sarcolemma and extracellular
matrix to prevent overstretch of the sarcomeres. End-systolic force increases
with increasing muscle length to a much greater degree than does end-
diastolic force. The difference in force at end-diastole as compared with end-
systole increases as muscle length increases and indicates a greater amount of
developed force as the muscle is stretched. This fundamental property of
cardiac muscle is called the Frank-Starling law of the heart in recognition of
its two discoverers. If a drug increases the amount of calcium released to the
myofilaments (for example, epinephrine, which belongs to a class of drugs
referred to as inotropic agents), the end-systolic force-length relationship will
be shifted upward and at any given length the muscle can generate more force.
Inotropic agents typically do not affect the end-diastolic force-length
relationship. In view of the prominent effect of muscle length on force
generation, the intrinsic strength of cardiac muscle, commonly referred to as
muscle contractility, should be indexed by the end-systolic force-length
relationship and not simply by peak force generation.

IV. MYOCARDIAL OXYGEN CONSUPTION.

The heart relies almost exclusively on oxidation of fatty acids and glucose as
an immediate source of energy. The heart normally extracts free fatty acids
preferentially from the coronary perfusion for oxidative energy production.
Under conditions of limited oxygen supply, this preference is changed to
glucose. Greater energy is consumed in metabolizing free fatty acids than in
metabolizing glucose. Under most conditions, anaerobic metabolism provides
very limited energy. Severe hypoxia with high coronary flow produces lactate
and anaerobic ATP. The much more common condition of ischemia with
acidosis results in little anaerobic energy. Under most steady-state
circumstances, the heart is dependent on the availability of oxygen to continue
its function.

The oxygen and energy consumption of the heart is determined principally by

its contractile activity. Three major independent hemodynamic or mechanical
factors contribute to myocardial oxygen consumption by the heart: heart rate,
the tension developed by the heart during systole, and the contractile state
(contractility) of the heart. If the heart rate rises from 60 to 180 beats per
minute during exercise or stress, oxygen consumption will increase
approximately three-fold over the basal value. Only 10% or less of the total
oxygen consumption of the heart is used to maintain functions other than
contraction; if the heart ceases to beat but is kept alive, it will consume
approximately 10% of the normal amount of oxygen. With an increase in the
contractile state, an additional obligatory increase in oxygen consumption is
produced due to the increased sarcoplasmic reticular ATPase activity required
to sequester the increased amount of cycling calcium that underlies the
increase in contractility.

The volume of coronary or myocardial blood flow under normal conditions is

largely regulated by myocardial oxygen demands. Because the heart extracts
75% or more of the oxygen present in the coronary blood, the striking
increases in oxygen consumption that occur with high tension development,
higher heart rates, and/or high contractility are met almost entirely by
increases in coronary blood flow.

The most important regulators of coronary vascular tone are adenosine and
nitric oxide. Adenosine is the byproduct of the breakdown of ATP to
adenosine monophosphate and then to adenosine. Nitric oxide is produced by
coronary vascular endothelial cells and has a direct local vasodilating effect on
coronary arteries and the more distal bed. In addition to adenosine and nitric
oxide, other longer-acting coronary vasodilators such as bradykinin,
prostaglandins, and CO2 may have a direct effect in maintaining coronary
artery blood flow.

Given that the coronary vessels are surround a pressurized chamber, it should
not be surprising that mechanical factors also influence coronary blood flow.
The head of pressure at the origin of the coronary artery and the pressure
within the large epicardial coronary arteries directly reflect the central aortic
pressure. During diastole, the resistance to blood flow from the coronary
arteries is largely from the tone of resistance vessels. However, during systole,
left ventricular intracavitary pressure will compress conornary vessels; due to
their proximaity, endocardial coronary arteries are remarkably compressed,
while epicaridal vessels are much less compressed. Therefore, under normal
conditions, coronary blood flow occurs both during systole and diastole in
epicardial vessels, but is essentially exclusively limited to diastole in the
subendocardium. Under some pathologic conditions However, if left
ventricular diastolic pressure significantly increases for whatever reason,
subendocardial blood flow may be reduced during this critical period of
diastole. Additionally, tachycardia can profoundly reduce subendocardial
blood flow given that the time period of diastole decreases with increased
heart rate. In fact, administration of drugs to slow the heart rate is one of the
main treatment strategies in the setting of coronary artery disease and
myocardial ischemia (while a reduction in heart rate reduces myocardial
oxygen demand, it also very importantly increases the diastolic time period for
oxygen delivery).

V. THE CARDIAC CYCLE AND PRESSURE-VOLUME LOOPS

The cardiac cycle (the period of time required for one heart beat) is divided
into two major phases: systole and diastole. Systole (from Greek, meaning
"contracting") is the period of time during which the muscle transforms from
its totally relaxed state (with crossbridges uncoupled) to the instant of
maximal mechanical activation (point of maximal crossbridge coupling). The
onset of systole occurs when the cell membrane depolarizes and calcium
enters the cell to initiate a sequence of events which results in cross-bridge
interactions (excitation-contraction coupling). Diastole (from Greek, meaning
"dilation") is the period of time during which the muscle relaxes from the end-
systolic (maximally activated) state back towards its resting state. Systole is
considered to start at the onset of electrical activation of the myocardium
(onset of the ECG); systole ends and diastole begins as the activation process
of the myofilaments passes through a maximum. In the discussion to follow,
we will review the hemodynamic events occurring during the cardiac cycle in
the left ventricle. The events in the right ventricle are similar, though
occurring at slightly different times and at different levels of pressure than in
the left ventricle.

The mechanical events occurring during the cardiac cycle consist of changes
in pressure in the ventricular chamber which cause blood to move in and out
of the ventricle. Thus, we can characterize the cardiac cycle by tracking
changes in pressures and volumes in the ventricle as shown in the Figure 1
where ventricular volume (LVV), ventricular pressure (LVP), left atrial
pressure (LAP) and aortic pressure (AoP) are plotted as a function of time.
Shortly prior to time "A" LVP and LVV are relatively constant and AoP is
gradually declining. During this time the heart is in its relaxed (diastolic)
state; AoP falls as the blood ejected into the arterial system on the previous
beat gradually moves from the large arteries to the capillary bed. At time A
there is electrical activation of the heart, contraction begins, and pressure rises
inside the chamber. Early after contraction begins, LVP rises to be greater than
left atrial pressure and the mitral valve closes. Since LVP is less than AoP, the
aortic valve is closed as well. Since both valves are closed, no blood can enter
or leave the ventricle during this time, and therefore the ventricle is
contracting isovolumically (i.e., at a constant volume). This period is called
isovolumic contraction. Eventually (at time B), LVP slightly exceeds AoP and
the aortic valve opens. During the time when the aortic valve is open there is
very little difference between LVP and AoP, provided that AoP is measured
just on the distal side of the aortic valve. During this time, blood is ejected
from the ventricle into the aorta and LV volume decreases. The exact shapes
of the aortic pressure and LV volume waves during this ejection phase are
determined by the complex interaction between the ongoing contraction
process of the cardiac muscles and the properties of the arterial system and is
beyond the scope of this lecture. As the contraction process of the cardiac
muscle reaches its maximal effort, ejection slows down and ultimately, as the
muscles begin to relax, LVP falls below AoP (time C) and the aortic valve
closes. At this point ejection has ended and the ventricle is at its lowest
volume. The relaxation process continues as indicated by the continued
decline of LVP, but LVV is constant at its low level. This is because, once
again, both mitral and aortic valves are closed; this phase is called isovolumic
relaxation. Eventually, LVP falls below the pressure existing in the left atrium
and the mitral valve opens (at time D). At this point, blood flows from the left
atrium into the LV as indicated by the rise of LVV; also note the slight rise in
LVP as filling proceeds. This phase is called filling. In general terms, systole
includes isovolumic contraction and ejection; diastole includes isovolumic
relaxation and filling.

Whereas the four phases of the cardiac cycle are clearly illustrated on the plots
of LVV, LVP, LAP and AoP as a function of time, it turns out that there are
many advantages to displaying LVP as a function of LVV on a "pressure-
volume diagram" (these advantages will be made clear by the end of this
syallbus entry). This is accomplished simply by plotting the simultaneously
measured LVV and LVP on appropriately scaled axes; the resulting pressure-
volume diagram corresponding to the curves of Figure 1 is shown in Figure 2,
with volume on the x-axis and pressure on the y-axis. As shown, the plot of
pressure versus volume for one cardiac cycle forms a loop. This loop is called
the pressure-volume loop (abbreviated PV loop). As time proceeds, the PV
points go around the loop in a counter clockwise direction. The point of
maximal volume and minimal pressure (i.e., the bottom right corner of the
loop) corresponds to time A on Fig. 1, the onset of systole. During the first
part of the cycle, pressure rises but volume stays the same (isovolumic
contraction). Ultimately LVP rises above AoP, the aortic valve opens (B),
ejection begins and volume starts to go down. With this representation, AoP is
not explicitly plotted; however as will be reviewed below, several features of
AoP are readily obtained from the PV loop. After the ventricle reaches its
maximum activated state (C, upper left corner of PV loop), LVP falls below
AoP, the aortic valve closes and isovolumic relaxation commences. Finally,
filling begins with mitral valve opening (D, bottom left corner).
VI. PHYSIOLOGIC MEASUREMENTS RETRIEVABLE FROM THE
PRESSURE-VOLUME LOOP.
As reviewed above, the ventricular pressure-volume loop displays the
instantaneous relationship between intraventricular pressure and volume
throughout the cardiac cycle. It turns out that with this representation it is easy
to ascertain values of several parameters and variables of physiologic
importance.

Consider first the volume axis (Figure 3). It is appreciated that we can readily
pick out the maximum volume of the cardiac cycle. This volume is called the
end-diastolic volume (EDV) because this is the ventricular volume at the end
of a cardiac cycle. Also, the minimum volume the heart attains is also
retrieved; this volume is known as the end-systolic volume (ESV) and is the
ventricular volume at the end of the ejection phase. The difference between
EDV and ESV represents the amount of blood ejected during the cardiac cycle
and is called the stroke volume (SV).
Now consider the pressure axis (Figure 4). Near the top of the loop we can
identify the point at which the ventricle begins to eject (that is, the point at
which volume starts to decrease) is the point at which ventricular pressure just
exceeds aortic pressure; this pressure therefore reflects the pressure existing in
the aorta at the onset of ejection and is called the diastolic blood pressure
(DBP). During the ejection phase, aortic and ventricular pressures are
essentially equal; therefore, the point of greatest pressure on the loop also
represents the greatest pressure in the aorta, and this is called the systolic
blood pressure (SBP). One additional pressure, the end-systolic pressure (Pes)
is identified as the pressure of the left upper corner of the loop; the
significance of this pressure will be discussed in detail below. Moving to the
bottom of the loop, we can reason that the pressure of the left lower corner
(the point at which the mitral valve opens and ejection begins) is roughly
equal to the pressure existing in the left atrium (LAP) at that instant in time
(recall that atrial pressure is not a constant, but varies with atrial contraction
and instantaneous atrial volume). The pressure of the point at the bottom right
corner of the loop is the pressure in the ventricle at the end of the cardiac
cycle and is called the end-diastolic pressure (EDP).
VII. PRESSURE-VOLUME RELATIONSHIPS
It is readily appreciated that with each cardiac cycle, the muscles in the
ventricular wall contract and relax causing the chamber to stiffen (reaching a
maximal stiffness at the end of systole) and then to become less stiff during
the relaxation phase (reaching its minimal stiffness at end-diastole). Thus, the
mechanical properties of the ventricle are time-varying, they vary in a cyclic
manner, and the period of the cardiac cycle is the interval between beats. In
the following discussion we will explore one way to represent the time-
varying mechanical properties of the heart using the pressure-volume diagram.
We will start with a consideration of ventricular properties at the extreme
states of stiffness -- end systole and end diastole -- and then explore the
mechanical properties throughout the cardiac cycle.

End-diastolic pressure-volume relationship (EDPVR).

Let us first examine the properties of the ventricle at end-diastole. Imagine the
ventricle frozen in time in a state of complete relaxation. We can think of the
properties of this ventricle with weak, relaxed muscles, as being similar to
those of a floppy balloon. What would happen to pressure inside a floppy
balloon if we were to vary its volume. Let's start with no volume inside the
balloon; naturally there would be no pressure. As we start blowing air into the
balloon there is initially little resistance to our efforts as the balloon wall
expands to a certain point. Up to that point, the volume increases but pressure
does not change. We will refer to this volume as Vo, or the maximal volume at
which pressure is still zero mmHg; this volume is also frequently referred to
as the unstressed volume. As the volume increases we meet with increasing
resistance to or efforts to expand the balloon, indicating that the pressure
inside the balloon is becoming higher and higher. The ventricle, frozen in its
diastolic state, is much like this balloon. A typical relationship between
pressure and volume in the ventricle at end-diastole is shown in Figure 5. As
volume is increased initially, there is little increase in pressure until a certain
point, designated "Vo". After this point, pressure increases with further
increases in volume. This curve is called the "end-diastolic pressure-volume
relationship" (EDPVR).

Under normal conditions, the heart would never exist in such a frozen state as
proposed above. However, during each contraction there is a period of time
during which the mechanical properties of the heart are characterized by the
EDPVR; knowledge of the EDPVR allows one to specify, for the end of
diastole, EDP if EDV is known, or visa versa. Furthermore, since the EDPVR
provides the pressure-volume relation with the heart in its most relaxed state,
the EDPVR provides a boundary on which the PV loop falls at the end of the
cardiac cycle as shown in Figure 6.
Under certain circumstances, the EDPVR may change. Physiologically, the
EDPVR changes as the heart grows during childhood. Most other changes in
the EDPVR accompany pathologic situations. Examples include the changes
which occur with hypertrophy, the healing of an infarct, and the evolution of a
dilated cardiomyopathy, to name a few.

Compliance is a term which is frequently used in discussions of the end-

diastolic ventricular. Technically, compliance is the change in volume for a
given change in pressure or, expressed in mathematical terms, it is the
reciprocal of the derivative of the EDPVR ( [dP/dV] -1 ). Since the EDPVR is
nonlinear, the compliance varies with volume; compliance is greatest at low
volume and smallest at high volumes (Figure 7). In the clinical arena,
however, compliance is used in two different ways. First, it is used to express
the idea that the diastolic properties are, in a general way, altered compared to
normal; that is, that the EDPVR is either elevated or depressed compared to
normal. Second, it is used to express the idea that the heart is working at a
point on the EDPVR where its slope is either high or low (this usage is
technically more correct). Undoubtedly you will hear this word used in the
clinical setting, usually in a casual manner: "The patients heart is
noncompliant". Such a statement relays no specific information about what is
going on with the diastolic properties of the heart. Statements specifying
changes in the EDPVR or changes in the working volume range relay much
more information. Understanding of these concepts has been highlighted
recently with growing appreciation for the fact that some patients can
experience heart failure when the EDPVR becomes elevated (as in
hypertrophy) despite that fact that the strength of the heart during contraction
is normal. This clinical phenomenon has been referred to as diastolic
dysfunction.
End-systolic pressure-volume relationship (ESPVR)
Let us move now to the opposite extreme in the cardiac cycle: end-systole. At
that instant of the cardiac cycle, the muscles are in their maximally activated
state and it is easy to imagine the heart as a much stiffer chamber. As for end
diastole, we can construct a pressure-volume relationship at end systole if we
imagine the heart frozen in this state of maximal activation. An example is
shown in Figure 8. As for the EDPVR, the end-systolic pressure volume
relationship (ESPVR) intersects the volume axis at a slightly positive value
(Vo), indicating that a finite amount of volume must fill the ventricle before it
can generate any pressure. For our purposes, we can assume that the Vo of the
ESPVR and the Vo of the EDPVR are the same (this is not exactly true, but
little error is made in assuming this and it simplifies further discussions). In
contrast to the nonlinear EDPVR, the ESPVR has been shown to be
reasonably linear over a wide range of conditions, and can therefore be
expressed by a simple equation:

Pes = Ees (V-Vo)

where Pes is the end-systolic pressure, Vo is as defined above, V is the volume

of interest and Ees is the slope of the linear relation. There is no a priori
reason to expect that this relationship should be linear, it is simply an
experimental observation. Ees stands for end systolic elastance. Elastance
means essentially the same thing as stiffness and is defined as the change in
pressure for a given change in volume within a chamber; the higher the
elastance, the stiffer the wall of the chamber.
As discussed above for the EDPVR, the heart would never exist
in a frozen state of maximal activation. However, it does pass
through this state during each cardiac cycle. The ESPVR
provides a line which the PV loop will hit at end-systole, thus
providing a second boundary for the upper left hand corner of the
PV loop (Figure 9). Examples of different PV loops bounded by
the ESPVR and EDPVR are shown in Figure 10. In the panel on
the left, there are three PV loops, which have the same EDV but
have different aortic pressures; in obtaining these loops the
properties of the arterial system were changed (specifically, the
total peripheral resistance was modified) without modifying
anything about the way the ventricle works. The upper left hand
corner of each loop falls on the ESPVR, while the bottom right
part of the loop falls on the EDPVR. In the panel on the right,
three different loops are shown which have different EDVs and
different aortic pressures. Here, the loops were obtained by
modifying only the EDV without modifying anything about the
heart or the arterial system. The upper left hand corner of each
loop falls on the ESPVR, while the bottom right part of the loop
falls on the EDPVR.

Time varying elastance: E(t)

In the above discussion we have described the pressure-volume relationships
at two instances in the cardiac cycle: end diastole and end systole. The idea of
considering the pressure-volume relation with the heart frozen in a given state
can be generalized to any point during the cardiac cycle. That is, at each
instant of time during the cardiac cycle there exists a pressure-volume
relationship. Such relations have been determined in the physiology
laboratory. These experiments show, basically, that there is a relatively smooth
transition from the EDPVR to the ESPVR and back. For most parts of the
cardiac cycle these relations can be considered 1) to be linear and 2) to
intersect at a common point, namely Vo. This idea is schematized in Figure
11. In the left panel the transition from the EDPVR towards the ESPVR
during the contraction phase is illustrated, and the relaxation phase is depicted
in the right panel. Since the instantaneous pressure-volume relations (PVR)
are reasonably linear and intersect at a common point, it is possible to
characterize the time course of change in ventricular mechanical properties by
plotting the time course of change in the slope of the instantaneous PVR.
Above, we referred to the slope of the ESPVR as an elastance. Similarly, we
can refer to the slopes of the instantaneous PVRs as elastances. A rough
approximation of the instantaneous elastance throughout a cardiac cycle is
shown in Figure 12. Note that the maximal value, Ees, is the slope of the
ESPVR. The minimum slope, Emin, is the slope of the EDPVR in the low
volume range. We refer to the function depicted in Fig. 11 as the time varying
elastance and it is referred to as E(t). With this function it is possible to relate
the instantaneous pressure (P) and volume (V) throughout the cardiac cycle:
P(V,t) = E(t) [V(t) - Vo], where Vo and E(t) are as defined above and V(t) is
the time varying volume. This relationship breaks down near end-diastole and
early systole when there are significant nonlinearities in the pressure-volume
relations at higher volumes. More detailed mathematical representations,
beyond the scope of these lectures, are now available to describe the time-
varying contractile properties of the ventricle which account for the nonlinear
EDPVR. Nevertheless, the implication of this equation is that if one knows the
E(t) function and if one knows the time course of volume changes during the
cycle, one can predict the time course of pressure changes throughout the
cycle.
VIII. CONTRACTILITY
Contractility is an ill-defined concept used when referring to the intrinsic
strength of the ventricle or cardiac muscle. By intrinsic strength we mean
those features of the cardiac contraction process that are intrinsic to the
ventricle (and cardiac muscle) and are independent of external conditions
imposed by either the preload or afterload (i.e., the venous, atrial or arterial)
systems. For example consider, once again, the PV loops in Fig. 10. We see
that in the panel on the left that the actual amount of pressure generated by the
ventricle and the stroke volume are different in the three cases, although we
stated that these loops were obtained by modifying the arterial system an not
changing anything about the ventricle. Thus, the changes in pressure
generation in that figure do not represent changes in contractility. Similarly,
the changes in pressure generation and stroke volume shown in the panel on
the right side of the figure were brought about simply by changing the EDV of
the ventricle and do not represent changes in ventricular contractility.

Now that we have demonstrated changes in ventricular performance (i.e.,

pressure generation and SV), which do not represent changes in contractility,
let's explore some changes that do result from changes in contractility. First,
how can contractility be changed? Basically, we consider ventricular
contractility to be altered when any one or combination of the following
events occurs:

1. the amount of calcium released to the myofilaments is changed

2. the affinity of the myofilaments for calcium is changed

 3. there is an alteration in the number of myofilaments available to
participate in the contraction process.

You will recall that calcium interacts with troponin to trigger a sequence of
events that allows actin and myosin to interact and generate force. The more
calcium available for this process, the greater the number of actin-myosin
interactions. Similarly, the greater troponin's affinity for calcium the greater
the amount of calcium bound and the greater the number of actin-myosin
interactions. Here we are linking contractility to cellular mechanisms that
underlie excitation-contraction coupling and thus, changes in ventricular
contractility would be the global expression of changes in contractility of the
cells that make up the heart. Stated another way, ventricular contractility
reflects myocardial contractility (the contractility of individual cardiac cells).

Through the third mechanism, changes in the number of muscle cells, as

apposed to the functioning of any given muscle cell, cause changes in the
performance of the ventricle as an organ. In acknowledging this as a
mechanism through which ventricular contractility can be modified we
recognize that ventricular contractility and myocardial contractility are not
always linked to each other.

Humoral and pharmacologic agents can modify ventricular contractility by the

first two mechanisms. -adrenergic agonists (e.g. norepinephrine) increase the
amount of calcium released to the myofilaments and cause an increase in
contractility. In contrast, -adrenergic antagonists (e.g., propranolol) blocks
the effects of circulating epinephrine and norepinephrine and reduce
contractility. Nifedipine is a drug that blocks entry of calcium into the cell and
therefore reduces contractility when given at high doses. One example of how
ventricular contractility can be modified by the third mechanism mentioned
above is the reduction in ventricular contractility following a myocardial
infarction where there is loss of myocardial tissue, but the unaffected regions
of the ventricle function normally.
While it is true that when contractility is changed there are
generally changes in ventricular pressure generation and stroke
volume, we have seen above that both of these can occur as a
result of changes in EDV or arterial properties alone. Thus,
measures like stroke volume and pressure would not be
reliable indices of contractility. It turns out that we can look
towards changes in the ESPVR to indicate changes in
contractility, as shown in Figure 13. When agents known to
increase ventricular contractility are administered to the heart
there is an increase in Ees, the slope of the ESPVR. Such
agents are known as positive "inotropic" agents. (Inotropic:
from Greek meaning influencing the contractility of muscular
tissue). Conversely, agents that are negatively inotropic reduce
Ees. It is significant that neither Vo (the volume-axis intercept
of the ESPVR) nor the EDPVR are affected significantly by
these acute changes in contractility. Thus, because Ees varies
with ventricular contractility but is not affected by changes in
the arterial system properties nor changes in EDV, Ees is
considered to be an index of contractility.

The major draw back to the use of Ees in the clinical setting is that it is very
difficult to measure ventricular volume. Clearly, it is required that volume be
measured in the assessment of Ees. Currently, the most commonly employed
index of contractility in the clinical arena is ejection fraction (EF). EF is
defined as the ratio between EDV and SV:

EF = SV/EDV * 100. [4]

This number ranges from 0% to 100% and represents the percentage of the
volume present at the start of the contraction that is ejected during the
contraction. The normal value of EF ranges between 55% and 65%. EF can be
estimated by a number of techniques, including echocardiography and nuclear
imagining techniques. The main disadvantage of this index is that it is a
function of the properties of the arterial system. This can be appreciated by
examination of the PV loops in the panel on the left of Figure 10, were
ventricular contractility is constant yet EF is changing as a result of modified
arterial properties. Nevertheless, because of its ease of measurement, and the
fact that it does vary with contractility, EF remains and will most likely
continue to be the preferred index of contractility in clinical practice for the
foreseeable future.

IX. PRELOAD
Preload is the hemodynamic load or stretch on the myocardial wall at the end
of diastole just before contraction begins. The term was originally coined in
studies of isolated strips of cardiac muscle where a weight was hung from the
muscle to prestretch it to the specified load before (pre-) contraction. For the
ventricle, there are several possible measures of preload: 1) EDP, 2) EDV, 3)
wall stress at end-diastole and 4) end-diastolic sarcomere length. Sarcomere
length probably provides the most meaningful measure of muscle preload, but
this is not possible to measure in the intact heart. In the clinical setting, EDP
probably provides the most meaningful measure of preload in the ventricle.
EDP can be assessed clinically by measuring the pulmonary capillary wedge
pressure (PCWP) using a Swan-Ganz catheter that is placed through the right
ventricle into the pulmonary artery.

X. AFTERLOAD
Afterload is the hydraulic load imposed on the ventricle during ejection. This
load is usually imposed on the heart by the arterial system, but under
pathologic conditions when either the mitral valve is incompetent (i.e., leaky)
or the aortic valve is stenotic (i.e., constricted) afterload is determined by
factors other than the properties of the arterial system (we won't go into this
further in this entry). There are several measures of afterload that are used in
different settings (clinical versus basic science settings). We will briefly
mention four different measures of afterload.

1) Aortic Pressure. This provides a measure of the pressure that the ventricle
must overcome to eject blood. It is simple to measure, but has several
shortcomings. First, aortic pressure is not a constant during ejection. Thus,
many people use the mean value when considering this as the measure of
afterload. Second, as will become clear below, aortic pressure is determined
by properties of both the arterial system and of the ventricle. Thus, mean
aortic pressure is not a measure, which uniquely indexes arterial system
properties.

2) Total Peripheral Resistance. The total peripheral resistance (TPR) is the

ratio between the mean pressure drop across the arterial system [which is
equal to the mean aortic pressure (MAP) minus the central venous pressure
(CVP)] and mean flow into the arterial system [which is equal to the cardiac
output (CO)]. Unlike aortic pressure by itself, this measure is independent of
the functioning of the ventricle. Therefore, it is an index which describes
arterial properties. According to its mathematical definition, it can only be
used to relate mean flows and pressures through the arterial system.

3) Arterial Impedance. This is an analysis of the relationship between

pulsatile flow and pressure waves in the arterial system. It is based on the
theories of Fourier analysis in which flow and pressure waves are decomposed
into their harmonic components and the ratio between the magnitudes of
pressure and flow waves are determined on a harmonic-by-harmonic basis.
Thus, in simplistic terms, impedance provides a measure of resistance at
different driving frequencies. Unlike TPR, impedance allows one to relate
instantaneous pressure and flow. It is more difficult to understand, most
difficult to measure, but the most comprehensive description of the intrinsic
properties of the arterial system as they pertain to understanding the influence
of afterload on ventricular performance.

4) Myocardial Peak Wall Stress. During systole, the muscle contracts and
generates force, which is transduced into intraventricular pressure, the amount
of pressure being dependent upon the amount of muscle and the geometry of
the chamber. By definition, wall stress ( ) is the force per unit cross sectional
area of muscle and is simplistically interrelated to intraventricular pressure
(LVP) using Laplace's law: =LVP*r/h, where r is the internal radius of
curvature of the chamber and h is the wall thickness. In terms of the muscle
performance, the peak wall stress relates to the amount of force and work the
muscle does during a contraction. Therefore, peak wall stress is sometimes
used as an index of afterload. While this is a valid approach when trying to
explain forces experienced by muscles within the wall of the ventricular
chamber, wall stress is mathematically linked to aortic pressure which, as
discussed above, does not provide a measure of the arterial properties and
therefore is not useful within the context of indexing the afterload of the
ventricular chamber.

XI. UNDERSTANDING THE DETERMINANTS OF VENTRICULAR

PERFORMANCE
Two primary measures of overall cardiovascular performance are the arterial
blood pressure and the cardiac output. These parameters are also of primary
concern in the clinical setting since both an adequate blood pressure and an
adequate cardiac output are necessary to maintain life. It is important to
appreciate, however, that both cardiac output and blood pressure are
determined by the interaction between the heart, the arterial system (afterload)
and the venous system (preload); this is a fundamental concept. Furthermore,
it is important to develop an appreciation for how the heart and vasculature
interact to determine these indices of performance. This is highlighted by the
fact that one major facet of intensive care medicine deals with maintaining
adequate blood pressure and cardiac output by manipulating ventricular
contractility, heart rate, arterial resistance and ventricular preload. Two
approaches to understanding how these parameters regulate cardiovascular
performance will be reviewed: a classical approach, commonly referred to as
Frank-Starling Curves, and a more modern approach based upon pressure-
volume analyses.

Frank-Starling Curves
Otto Frank (1899) is credited with the seminal observation that peak
ventricular pressure increases as the end-diastolic volume is increased (as in
Fig. 8). This observation was made in an isolated frog heart preparation in
which ventricular volume could be measured with relative ease. Though of
primary importance, the significance may not have been appreciated to the
degree it could have been because it was (and remains) difficult to measure
ventricular volume in more intact settings (e.g., experimental animals or
patients). Thus it was difficult for other investigators to study the relationship
between pressure and volume in these more relevant settings.

Around the mid 1910's, Starling and coworkers observed a related

phenomenon, which they presented in a manner that was much more useful to
physiologists and ultimately to clinicians. They measured the relationship
between ventricular filling pressure (related to end-diastolic volume) and
cardiac output (CO=SVxHR). They showed that there was a nonlinear
relationship between end-diastolic pressure (EDP, also referred to as
ventricular filling pressure) and CO as shown in Fig. 14; as filling pressure
was increased in the low range there is a marked increase in CO, whereas the
slope of this relationship becomes less steep at higher filling pressures.

The observations of Frank and of Starling form one of the basic concepts of
cardiovascular physiology that is referred to as the Frank-Starling Law of the
Heart: cardiac performance (its ability to generate pressure or to pump blood)
increases as preload is increased. There are a few caveats, however. Recall
from the anatomy of the cardiovascular system that left ventricular filling
pressure is approximately equal to pulmonary venous pressure. As pulmonary
venous pressure rises there is an increased tendency (Starling Forces) for fluid
to leak out of the capillaries and into the interstitial space and alveoli. When
this happens, there is impairment of gas exchange across the alveoli and
hemoglobin oxygen saturation can be markedly diminished. This phenomenon
typically comes into play when pulmonary venous pressure rises above
-20mmHg and becomes increasingly prominent with further increases. When
pulmonary venous pressures increases above 25-30 mmHg, there can be
profound transudation of fluid into the alveoli and pulmonary edema is
usually prominent. Therefore, factors extrinsic to the heart dictate a practical
limit to how high filling pressure can be increased.

As noted above, factors other than preload are important for determining
cardiac performance: ventricular contractility and afterload properties. Both of
these factors can influence the Frank-Starling Curves. When ventricular
contractile state is increased, CO for a given EDP will increase and when
contractile state is depressed, CO will decrease (Fig. 15). When arterial
resistance is increased, CO will decrease for a given EDP while CO will
increase when arterial resistance is decreased (Fig. 16). Thus, shifts of the
Frank-Starling curve are nonspecific in that they may signify either a change
in contractility or a change in afterload. It is for this reason that Starling-
Curves are not used as a means of indexing ventricular contractile strength.

Ventricular-Vascular Coupling Analyzed on the Pressure-Volume

Diagram
We have already discussed in detail how ventricular properties are represented
on the PV diagram and how they are modified by inotropic agents. We have
seen examples of PV loops obtained with constant ventricular properties at
different EDVs and arterial properties (Figure 10). Therefore, let us now turn
to a discussion of how arterial properties can be represented on the PV
diagram. Specifically, we will explore how TPR can be represented on the PV
diagram an index of afterload, called Ea, which stands for effective arterial
elastance that is closely related to TPR. The ultimate goal of the discussion to
follow is to provide a quantitative method of uniting ventricular afterload,
heart rate, preload and contractility on the PV diagram so that cardiovascular
variables such as cardiac output (stroke volume) and arterial pressure can be
determined from ventricular and vascular properties.

Let us start with the definition of TPR:

TPR = [MAP - CVP] / CO ----- [4]

where CVP is the central venous pressure and MAP is the mean arterial
pressure. Cardiac output (CO) represents the mean flow during the cardiac
cycle and can be expressed as:

CO = SV * HR ----- [5]

where SV is the stroke volume and HR is heart rate. Substituting Eq. [5] into
Eq. [4] we obtain:

TPR = [MAP - CVP] / (SV*HR) . ----- [6]

At this point we make two simplifying assumptions. First, we assume that

CVP is negligible compared to MAP. This is reasonable under normal
conditions, since the CVP is generally around 0-5 mmHg. Second, we will
make the assumption that MAP is approximately equal to the end-systolic
pressure in the ventricle (Pes). Making these assumptions, we can rewrite Eq.
[6] as:

TPR = Pes / (SV*HR) ----- [7]

which can be rearranged to:

TPR * HR = Pes / SV .----- [8]

Note, as shown in Fig. 17, that the quantity Pes/SV can be easily ascertained
from the pressure volume loop by taking the negative value of the slope of the
line connecting the point on the volume-axis equal to the EDV with the end-
systolic pressure-volume point. Let us define the slope of this line as Ea:

Ea = Pes/SV . ----- [9]

This term is designated E for "elastance" because the units of this index are
mmHg/ml (the same as for Ees). The "a" denotes that this term is for the
arterial system. Note that this measure is dependent on the TPR and heart rate.
If the TPR or HR goes up, then Ea goes up, as illustrated in Fig. 18; reduction
in either TPR or HR cause a reduction in Ea. As shown in this Figures 17 and
18, the Ea line is drawn on the pressure-volume diagram (the same set of axes
as the ESPVR and the EDPVR); it starts at EDV and has a slope of -Ea and
intersects with the ESPVR at one point.
Next, we will use these features of the pressure-volume diagram to
demonstrate that it is possible to estimate how the ventricle and arterial system
interact to determine such things as mean arterial pressure (MAP) and SV
when contractility, TPR, EDV or HR are changed. In order to do this, we
reiterate the parameters, which characterize the state of the cardiovascular
system. First, are those parameters necessary to quantify the systolic pump
function of the ventricle; these are Ees and Vo, the parameters which specify
the ESPVR. Second, are the parameters which specify the properties of the
arterial system; we will take Ea as our measure of this, which is dependent on
TPR and heart rate. Finally we must specify a preload; this can be done by
simply specifying EDV or, if the EDPVR is known, we can specify EDP. If
we specify each of these parameters, then we can estimate a value for MAP
and SV (and CO, since CO=SV.HR) as depicted in Fig. 19.
In order to do this, first draw the ESPVR line (panel A). Second (panel B),
mark the EDV on the volume axis and draw a line through this EDV point
with a slope of -Ea. The ESPVR and the Ea line will intersect at one point.
This point is the estimate of the end-systolic pressure-volume point. With that
knowledge you can draw a box which represents an approximation of the PV
loop under the specified conditions, with the bottom of the box determined by
the EDPVR (Panel C). SV and Pes can be measured directly from the
diagram. Recall that Pes is roughly equal to MAP.

Use of this technique is illustrated in Figure. 20 through 23. In each case, the
ESPVR and Ea for the specified conditions are drawn on the pressure-volume
diagram superimposed on actual PV loops. In Fig. 20 we see what happens if
TPR is altered, but EDV is kept constant. As TPR is increased, the slope of the
Ea line increases and intersects the ESPVR at an increasingly higher pressure
and higher volume. Thus, increasing TPR increases MAP but decreases SV
(and CO) when ventricular properties (Ees, Vo and HR) are constant.
The influence of preload (EDV) is shown in the three loops of Fig. 21. Here,
the ESPVR, HR and TPR are constant so that Ea is also constant. The slope of
the Ea line is not altered when preload is increased, the Ea line is simply
shifted in a parallel fashion. With each increase in preload volume, Pes and
SV increase, and clearly it is possible to make a quantitative prediction of
precisely how much.

The influence of contractility is shown in Fig. 22. In this case, nothing is

changed in the arterial system and the EDV is constant; Ees is the only thing
to change. When Ees is increased, the Ea line intersects the ESPVR at a higher
pressure and lower volume. Therefore, despite increased MAP, SV increases
(which contrasts with the decreased SV obtained with increased MAP when
TPR is increased).

Finally, the influence of HR is shown in Fig. 23. The effect of increasing HR

is similar to the effect of increasing TPR as predicted by the fact that both
influence Ea in the same way.

For those of you that are quantitatively inclined, you can derive the following
equations which mathematically predict Pes (.MAP) and SV based on the
graphical techniques described above:

Pes = [EDV - Vo] / [1/Ea + 1/Ees]

SV = [EDV - Vo] / [1 + Ea/Ees]

The technique described above is useful in predicting Pes and SV when the
parameters of the system are known. It is also useful in making qualitative
predictions (e.g., does SV increase or decrease) when only rough estimates of
the parameters are available. Thus, this system provides a simple means of
understanding the determinants of cardiac output and arterial pressure.