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 pressure-

volume 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 end–ejection,

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 end–diastolic volume), myocardial contractility (the force generated at any given end–diastolic

volume) and the afterload (aortic impedance and wall stress) [ 1 ].

Preload — Landmark studies by Frank and Starling established the relationship between ventricular end–diastolic

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 force–generating cross–bridges, thereby allowing increased tension

development ( figure 2 ) [ 2 ]. Thus, there is an augmentation of developed force as end–diastolic volume and fiber

length increase. The left ventricle normally functions on the ascending limb of this force–length 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 force–length 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 force–length

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 end–ejection and end–diastolic

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 ß 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 end–diastolic 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 pressure–volume plot, the systolic pressure–volume loop is "right–shifted" with a reduced slope

representing the decreased contractility. In contrast, the diastolic pressure–volume 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 upward–shift in the end–

diastolic pressure–volume relationship as a higher pressure is required to achieve the same volume.

Diastolic dysfunction — With pure diastolic heart failure, left ventricular end–systolic 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 pressure–volume plot, diastolic

dysfunction would therefore be characterized by a normal systolic pressure volume loop and an "upward–shift" of

the diastolic pressure–volume 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 pressure-

volume relationship' above.)

The three major determinants of the left ventricular forward stroke volume/performance are the preload

(venous return and end–diastolic volume), myocardial contractility (the force generated at any given end–

diastolic volume), and the afterload (aortic impedance and wall stress). (See 'Normal left ventricular pressure-

volume 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 "upward–shift" of the

diastolic pressure–volume 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)

Vascular

Increased systemic vascular resistance

Decresed aterial pressure

Impaired arterial pressure

Impaired organ perfusion

Decreased venous compliance

Increased venous pressure

Increased blood volume

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

Hormones

Renin-angiotensin-aldosterone system

Vasopressin (antidiuretic hormone)

Circulating catecholamines

Natriuretic peptides

Neurohumoral responses occur during heart failure. These include activation of sympathetic nerves and the renin-

angiotensin 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 beta-

blockers 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 renin-

angiotensin-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 renin-

angiotensin 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, β-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).