Pathophysiology of heart failure: Left ventricular pressure-volume relationships

Author
Wilson S Colucci, MD
Section Editor
Stephen S Gottlieb, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2013. | This topic last updated: Nov 1, 2012.
INTRODUCTION Heart failure may be due to either systolic or diastolic dysfunction of the left ventricle. While
both are characterized by elevated left ventricular filling pressures, the underlying hemodynamic processes differ
considerably. These differences can be best understood when described in terms of the left ventricular pressurevolume relationship. Understanding these principles has practical implications for the treatment of patients with
heart failure. (See "Overview of the therapy of heart failure due to systolic dysfunction" .)
NORMAL LEFT VENTRICULAR PRESSURE-VOLUME RELATIONSHIP As a pump, the ventricle generates
pressure (to eject blood) and displaces a volume of blood. The normal relationship between left ventricular (LV)
pressure generation and ejection can be expressed as a plot of LV pressure versus LV volume ( figure 1 ). At end
diastole, the fibers have a particular stretch or length, which is determined by the resting force, myocardial
compliance, and the degree of filling from the left atrium. This distending force is the preload of the muscle.
After depolarization, the ventricle generates pressure isovolumically (without any change in volume), which leads
to the opening of the aortic valve and the ejection of blood. Up to this point, the course of systolic pressure is related
to the force created by the myocardium. The magnitude of this force is a function of both chamber pressure and
volume. During ejection, the myocardium must also sustain a particular force, which is a function of the resistance
and capacitance of the circulatory vasculature and is called the afterload.
The volume of ejected blood represents the forward effective stroke volume of systolic contraction. At endejection,
the aortic valve closes followed by isovolumic relaxation, as left ventricular pressure falls while volume remains
constant. When pressure falls sufficiently, the mitral valve opens and left ventricular diastolic filling begins ( figure
1 ).
Thus, the three major determinants of the left ventricular forward stroke volume/performance are the preload
(venous return and enddiastolic volume), myocardial contractility (the force generated at any given enddiastolic
volume) and the afterload (aortic impedance and wall stress) [ 1 ].
Preload Landmark studies by Frank and Starling established the relationship between ventricular enddiastolic
volume (preload) and ventricular performance (stroke volume, cardiac output, and/or stroke work). Subsequent
studies have shown that the isovolumetric force at any given contractile state is a function of the degree of end
diastolic fiber stretch. These mechanical characteristics of contraction are based upon the ultrastructure of cardiac
muscle. Increasing sarcomere length up to a point increases the area of overlap between actin filaments and
portions of the myosin filaments containing forcegenerating crossbridges, thereby allowing increased tension
development ( figure 2 ) [ 2 ]. Thus, there is an augmentation of developed force as enddiastolic volume and fiber
length increase. The left ventricle normally functions on the ascending limb of this forcelength relationship.
Contractility The stroke volume at any given fiber length is also a function of contractility, as variations in
contractility create nonparallel shifts in the developed forcelength relation. Each myocardial cell is capable of
varying the amount of tension generated during contraction. This tension is a function of the amount of calcium
bound to a regulatory site on the troponin complex of the myofilaments. The amount of calcium available is in turn a
function of intracellular calcium delivery.
Drug therapy can alter the developed force-length relation. For example, the administration of norepinephrine
stimulates cardiac adrenergic receptors which increase myocardial cell cAMP levels, thereby raising the

intracellular calcium concentration and contractility. As a result, the ventricle is able to develop a greater force from
any given fiber length. Administration of a beta-blocker, on the other hand, attenuates the slope of the forcelength
relation.
Afterload A third element determining ventricular performance is the impedance during ejection, the afterload.
The afterload on the shortening fibers is defined as the force per unit area acting in the direction in which these
fibers are arranged in the ventricular wall. This constitutes the wall stress and can be estimated by applying
Laplace's Law [ 3 ]. Changes in ventricular volume and wall thickness as well as aortic pressure or aortic impedance
determine the afterload. As an example, elevations in systolic pressure act to reduce the ejected fraction of stroke
volume from any particular diastolic volume.
This relationship can be viewed as a type of feedback control of myocardial contraction. A primary increment in
stroke volume, for example, leads to an increase in aortic impedance. As a result of this rise in afterload, subsequent
contractions have an attenuated stroke volume. If, on the other hand, an increment in aortic impedance is the initial
event, the accompanying reduction in stroke volume should lead to a greater endejection and enddiastolic
chamber volume. The ensuing prolongation of fiber length should restore stroke volume to the baseline level.
Stroke volume is only minimally altered by changes in afterload in the normal heart. In comparison, the failing heart
is progressively more afterload-dependent and small changes in afterload can produce large changes in stroke
volume ( figure 3 ). Reducing afterload in patients with heart failure, via the administration of angiotensin
converting enzyme inhibitors, angiotensin receptor blockers, or direct vasodilators (eg, hydralazine ), has the dual
advantage of increasing cardiac output and, over the long-term, slowing the rate of loss of myocardial function.
(See "Overview of the therapy of heart failure due to systolic dysfunction" .)
PRESSURE-VOLUME RELATIONSHIPS IN HEART FAILURE Systolic and diastolic dysfunction of the left
ventricle can be understood by analysis of the relationships between left ventricular developed pressure and
volume [ 4-6 ].
Systolic dysfunction The term systolic dysfunction refers to a decrease in myocardial contractility. As a result,
the slope of the relationship between initial length and developed force is reduced (as in the beta-blocker example
above) and the curve is shifted to the right. This shift is associated with a reduction in stroke volume, and
consequently, cardiac output. The fall in cardiac output leads to increased sympathetic activity, which helps to
restore cardiac output by increasing both contractility and heart rate. The fall in cardiac output also promotes renal
salt and water retention leading to expansion of the blood volume, thereby raising enddiastolic pressure and
volume which, via the Frank-Starling relationship, enhances ventricular performance and tends to restore the
stroke volume ( figure 4 ). Left ventricular hypertrophy is also part of the adaptive response to systolic dysfunction,
since it unloads individual muscle fibers and thereby decreases wall stress and afterload.
As systolic heart failure progresses, a series of Frank-Starling curves may be seen due to the progressive decline in
the maximal cardiac output generated for any given cardiac filling pressure. Flattening of the Frank-Starling curve in
advanced disease means that changes in venous return and/or left ventricular end-diastolic pressure (LVEDP) now
fail to increase stroke volume ( figure 4 ). Two factors may contribute to a plateau in the pressure-volume curve:

The heart may simply have reached its maximum capacity to increase contractility in response to increasing
stretch. In vitro studies suggest that this abnormality may result from decreased calcium affinity for and
therefore binding to troponin C and from decreased calcium availability within the myocardial cells [ 7 ]. These
abnormalities may result in part from lengthening of the sarcomeres to a point which exceeds the optimal
degree of overlap of thick and thin myofilaments, thereby preventing developed force from increasing in
response to increasing load.

The Frank-Starling relationship actually applies to left ventricular end-diastolic volume, since it is the stretching
of cardiac muscle that is responsible for the enhanced contractility. The more easily measured LVEDP is used
clinically since, in relatively normal hearts, pressure and volume vary in parallel. However, cardiac compliance
may be reduced with heart disease. As a result, a small increase in volume may produce a large elevation in
LVEDP, but no substantial stretching of the cardiac muscle and therefore little change in cardiac output [ 8 ].

The plateau in the Frank-Starling curve also represents a reduction in the heart's systolic reserve. As a result, the
ability of positive inotropic agents to shift this relation to the left and permit greater shortening becomes impaired.
In terms of the pressurevolume plot, the systolic pressurevolume loop is "rightshifted" with a reduced slope
representing the decreased contractility. In contrast, the diastolic pressurevolume loop is normal initially,
although the patient with systolic dysfunction begins at a point farther right on the curve because of the increase in
left ventricular volume produced by cardiac dilatation ( figure 5 ).
However, decreased compliance due to hypertrophy and fibrosis may eventually produce disturbed diastolic
function in many patients with advanced heart failure [ 6 ]. In this setting, there is also an upwardshift in the end
diastolic pressurevolume relationship as a higher pressure is required to achieve the same volume.
Diastolic dysfunction With pure diastolic heart failure, left ventricular endsystolic volume and stroke volume
are preserved. There is, however, an abnormal increase in left ventricular diastolic pressure at any given volume.
This reflects a decrease in left ventricular diastolic dispensability (or compliance) such that a higher diastolic
pressure is required to achieve the same diastolic volume or contractility. In a pressurevolume plot, diastolic
dysfunction would therefore be characterized by a normal systolic pressure volume loop and an "upwardshift" of
the diastolic pressurevolume loop without a change in end-diastolic volume ( figure 5 ). (See "Clinical
manifestations and diagnosis of diastolic heart failure" .)
SUMMARY

The normal relationship between left ventricular (LV) pressure generation and ejection can be expressed as a
plot of LV pressure versus LV volume (Frank Starling curve) ( figure 1 ). (See 'Normal left ventricular pressurevolume relationship' above.)

The three major determinants of the left ventricular forward stroke volume/performance are the preload
(venous return and enddiastolic volume), myocardial contractility (the force generated at any given end
diastolic volume), and the afterload (aortic impedance and wall stress). (See 'Normal left ventricular pressurevolume relationship' above.)

With depressed myocardial contractility, the slope of the relationship between myocardial fiber length and
developed force is reduced and the Frank Starling curve is shifted to the right ( figure 4 ). (See 'Systolic
dysfunction' above.)

With isolated diastolic dysfunction there is a normal systolic pressure volume loop and an "upwardshift" of the
diastolic pressurevolume loop without a change in end-diastolic volume ( figure 5 ). (See 'Diastolic
dysfunction' above.)

There are many different ways to categorize heart failure, including:

the side of the heart involved (left heart failure versus right heart failure). Right heart failure compromises
pulmonary flow to the lungs. Left heart failure compromises aortic flow to the body and brain. Mixed presentations
are common; left heart failure often leads to right heart failure in the longer term.

whether the abnormality is due to insufficient contraction (systolic dysfunction), or due to insufficient relaxation of
the heart (diastolic dysfunction), or to both.

whether the problem is primarily increased venous back pressure (preload), or failure to supply adequate arterial
perfusion (afterload).

whether the abnormality is due to low cardiac output with high systemic vascular resistance or high cardiac output
with low vascular resistance (low-output heart failure vs. high-output heart failure).

the degree of functional impairment conferred by the abnormality (as reflected in the New York Heart Association
Functional Classification[39])

the degree of coexisting illness: i.e. heart failure/systemic hypertension, heart failure/pulmonary hypertension,
heart failure/diabetes, heart failure/kidney failure, etc.

Functional classification generally relies on the New York Heart Association functional classification. The classes (I-IV)
are:

Class I: no limitation is experienced in any activities; there are no symptoms from ordinary activities.

Class II: slight, mild limitation of activity; the patient is comfortable at rest or with mild exertion.

Class III: marked limitation of any activity; the patient is comfortable only at rest.

Class IV: any physical activity brings on discomfort and symptoms occur at rest.

This score documents severity of symptoms, and can be used to assess response to treatment. While its use is widespread,
the NYHA score is not very reproducible and does not reliably predict the walking distance or exercise tolerance on
formal testing.[40]
In its 2001 guidelines the American College of Cardiology/American Heart Association working group introduced four
stages of heart failure:[41]

Stage A: Patients at high risk for developing HF in the future but no functional or structural heart disorder.

Stage B: a structural heart disorder but no symptoms at any stage.

Stage C: previous or current symptoms of heart failure in the context of an underlying structural heart problem, but
managed with medical treatment.

Stage D: advanced disease requiring hospital-based support, a heart transplant or palliative care.

The ACC staging system is useful in that Stage A encompasses "pre-heart failure" a stage where intervention with
treatment can presumably prevent progression to overt symptoms. ACC Stage A does not have a corresponding NYHA
class. ACC Stage B would correspond to NYHA Class I. ACC Stage C corresponds to NYHA Class II and III, while ACC Stage D
overlaps with NYHA Class IV.

Patients with heart failure are classically divided into two groups: those with HF with preserved ejection fraction
(HFpEF), also called diastolic HF (DHF) and those with HF and reduced ejection fraction (HFrEF), better known as systolic
HF (SHF)1.

Pathophysiology of Heart Failure Four Basic Mechanisms

1. Increased Blood Volume (Excessive Preload)

2. Increased Resistant to Blood Flow (Excessive Afterload)
3. Decreased contractility
4. Decreased Filling

Pathophysiology of Heart Failure

The pathophysiology of heart failure involves changes in :

cardiac function

neurohumoral status

systemic vascular function

blood volume

integration of cardiac and vascular changes

Cardiac dysfunction precipitates changes in vascular function, blood volume, and neurohumoral status. These changes
serve as compensatory mechanisms to help maintain cardiac output (primarily by the Frank-Starling mechanism) and
arterial blood pressure (by systemic vasoconstriction). However, these compensatory changes over months and years can
worsen cardiac function. Therefore, some of the most effective treatments for chronic heart failure involve modulating
non-cardiac factors such as arterial and venous pressures by administering vasodilator and diuretic drugs.
Cardiac Function
Cardiac and Vascular Changes
Accompanying Heart Failure
Cardiac

Decreased stroke volume & cardiac output

Increased end-diastolic pressure

Ventricular dilation or hypertrophy

Impaired filling (diastolic dysfunction)

Reduced ejection fraction (systolic dysfunction)

Increased systemic vascular resistance

Decresed aterial pressure

Impaired arterial pressure

Impaired organ perfusion

Decreased venous compliance

Increased venous pressure

Increased blood volume

Vascular

Overall, the changes in cardiac function associated with heart failure result in a decrease in cardiac output. This results
from a decline in stroke volume that is due to systolic dysfunction, diastolic dysfunction, or a combination of the two.
Briefly,systolic dysfunction results from a loss of intrinsic inotropy(contractility), which can be caused by alterations
in signal transduction mechanisms responsible for regulating inotropy. Systolic dysfunction can also result from the loss
of viable, contracting muscle as occurs following acute myocardial infarction. Diastolic dysfunction refers to the diastolic
properties of the ventricle and occurs when the ventricle becomes less compliant (i.e., "stiffer"), which impairs ventricular
filling. Reduced filling of the ventricle results in less ejection of blood. Both systolic and diastolic dysfunction result in a
higherventricular end-diastolic pressure, which serves as a compensatory mechanism by utilizing the Frank-Starling
mechanism to augment stroke volume. In some types of heart failure (e.g., dilated cardiomyopathy), the ventricle dilates
anatomically, which helps to normalize the preload pressures by accomodating the increase in filled volume.
Therapeutic interventions to improve cardiac function in heart failure include the use of cardiostimulatory
drugs (e.g., beta-agonists and digitalis) that stimulate heart rate and contractility, and vasodilator drugs that
reduce ventricular afterload and thereby enhance stroke volume.
Neurohumoral Status
Compensatory Mechanisms During
Heart Failure
Cardiac

Frank-Starling mechanism

Chronic ventricular dilation or hypertrophy

Tachycardia

Autonomic Nerves

Increased sympathetic adrenergic activity

Reduced vagal activity to heart

Renin-angiotensin-aldosterone system

Vasopressin (antidiuretic hormone)

Circulating catecholamines

Natriuretic peptides

Hormones

Neurohumoral responses occur during heart failure. These include activation of sympathetic nerves and the reninangiotensin system, and increased release of antidiuretic hormone (vasopressin) andatrial natriuretic peptide. The net
effect of these neurohumoral responses is to produce arterial vasoconstriction (to help maintain arterial pressure),
venous constriction (to increase venous pressure), and increased blood volume to increase ventricular filling. In general,
these neurohumoral responses can be viewed as compensatory mechanisms, but they can also aggravate heart failure by
increasing ventricular afterload (which depresses stroke volume) and increasing preload to the point where pulmonary
or systemic congestion and edema occur. Therefore, it is important to understand the pathophysiology of heart failure
because it serves as the rationale for therapeutic intervention.
There is also evidence that other factors such as nitric oxide andendothelin (both of which are increased in heart failure)
may play a role in the pathogenesis of heart failure.

Some drug treatments for heart failure involve attenuating the neurohumoral changes. For example, certain betablockers have been shown to provide significant long-term benefit, quite likely because they block the effects of excessive
sympathetic activation on the heart. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers,
and aldosterone receptor antagonists are commonly used to treat heart failure by inhibiting the actions of the reninangiotensin-aldosterone system.
Systemic Vascular Function
In order to compensate for reduced cardiac output during heart failure, feedback mechanisms within the body try to
maintain normal arterial pressure by constricting arterial resistance vessels through activation of the sympathetic
adrenergic nervous system, thereby increasing systemic vascular resistance. Veins are also constricted to elevatevenous
pressure. Arterial baroreceptors are important components of this feedback system, especially in acute heart
failure. Humoral activation, particularly the renin-angiotensin system and antidiuretic hormone (vasopressin) also
contribute to systemic vasoconstriction.
Heightened sympathetic activity, and increased circulating angiotensin II and increased vasopressin contribute to an
increase in systemic vascular resistance. Drugs that block some of these mechanisms, such angiotensin-converting
enzyme inhibitors, angiotensin receptor blockers, improve ventricular stroke volume by reducing afterload on the
ventricle. Vasodilator drugs such as hydralazine and sodium nitroprusside are also used to reduce afterload on the
ventricle and thereby enhance cardiac output.
Blood Volume
In heart failure, there is a compensatory increase in blood volume that serves to increase ventricular preload and thereby
enhance stroke volume by the Frank-Starling mechanism. Blood volume is augmented by a number of factors. Reduced
renal perfusion results in decreased urine output and retention of fluid. Furthermore, a combination of reduced renal
perfusion and sympathetic activation of the kidneys stimulates the release of renin, thereby activating the reninangiotensin system. This, in turn, enhances aldosterone secretion. There is also an increase in circulating arginine
vasopressin (antidiuretic hormone) that contributes to renal retention of water. The final outcome of humoral activation
is an increase in renal reabsorption of sodium and water. The resultant increase in blood volume helps to
maintain cardiac output; however, the increased volume can be deleterious because it raises venous pressures, which can
lead to pulmonary and systemic edema. When edema occurs in the lungs, this can result in exertional dyspnea (shortness
of breath during exertion). Therefore, most patients in heart failure are treated with diuretic drugs to reduce blood
volume and venous pressures in order to reduce edema.
Integration of Cardiac and Vascular Changes

As described above, both systolic and diastolic heart failure lead to changes in systemic vascular resistance, blood volume,
and venous pressures. These changes can be examined graphically by using cardiac and vascular function curves as
shown to the right. The decrease in cardiac performance causes a downward shift in the slope of the cardiac function
curve. This alone would lead to an increase in right atrial or central venous pressure (point B) as well as a large decrease
in cardiac output. The increase in blood volume and venoconstriction (decreased venous compliance) causes a parallel
shift to the right of the systemic vascular function curve (point C). Because systemic vascular resistance also increases, the
slope of the vascular function curve shifts downward (point D). These changes in vascular function, coupled with the
downward shift in the cardiac function curve, result in a large increase in right atrial or central venous pressure (point D),
which helps to partially offset the large decline in cardiac output that would occur in the absence of the systemic vascular
responses (point B). Therefore, the systemic responses (vascular constriction and increased blood volume) help to
compensate for the loss of cardiac performance; however, these compensatory responses cause a large increase in venous
pressure that can lead to edema. Furthermore, the increase in systemic vascular resistance increases the afterload on the
left ventricle, which can further depress its output.
General mechanism of action of antiarrhythmic drugs Drugs slow automaticity (Fig-7): Automaticity is reduced by: 1.
Elevation of threshold potential- Quinidine, propranolol, verapamil (less negative) diltiazem, potassium 2. Reducing RMP
(More negative)- Adenosine, lidocaine, phenytoin 3. Prolonging APD (ERP) - Quinidine, amiodarone (Class Ia & III) 4.
Reducing slope of phase-4. - Class IV drugs, propranolol Drugs reduce afterdepolarizations: EADs and DADs are inhibited
by: 1. Inhibiting upstroke of AP (Na+ or Ca++ currents in fast and slow fibers respectively)-Verapamil and phenytoin
inhibit DADs. 2. Shortening of APD-Isoprenaline inhibits EADs -Magnesium acts by blocking triggered beats and reduce
EADs induced heterogeneity in ventricular cells.
Drugs affect conduction and reentry by: 1. Slowing anterograde (upside down) conduction in AV node: Digoxin,
propranolol and verapamil. Paroxysmal supraventricular tachycardia (PSVT) is terminated in this way. Rate reduction in
atrial fibrillation also occurs by this mechanism. 2. Prolongation of refractoriness (& thus retrograde or downside-up
conduction) in accessory pathways by Na+ channel block. Example is use of Class-Ia drugs to terminate PSVT in WPW
syndrome. 3. Converting unidirectional block into bi-directional block by facilitating conduction in slow conducting
pathway. Lidocaine blocks extrasystoles in myocardial infarction by this mechanism (Fig-5 C). Facilitated conduction
through AV node by phenytoin makes it a useful drug in digoxin induced atrial tachycardia with varying AV nodal block. 4.
Reduction in the dispersion (variablility) of refractoriness by lengethening of ERP also blocks reentry by quinidine.
A. Resting membrane potential more negative. The maximum diastolic potential needs to increase for generation of AP.
Examples : Acetylcholine, adenosine, Lidocaine, potassium.
B. Reduced slope of Phase-4. Examples: Adenosine, amiodarone, -blockers.

C. Elevation of threshold potential. Examples: Class-I drugs, lidocaine, verapamil.

D. Prolongation of ERP (APD). Examples: Class-Ia, Class-III drugs. E. Shortening of atrial ERP. Examples: Adenosine and
lidocaine (blue dashed line).