pathophysiology of heart failure - left ventricular pressure-volume relationships.pdf

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ophysiology of heart failure: Left ventricular pressure-volume relati... http://www.uptodate.com/online/content/topic.do?topicKey=hrt

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Pathophysiology of heart failure: Left ventricular

pressure-volume relationships

AuthorWilson S Colucci, MD

Section EditorStephen S Gottlieb, MD

Deputy EditorSusan B Yeon, MD, JD, FACC

Last literature review for version 16.1:January 31, 2008 | This topic last updated:February

13, 2008

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 (show figure 1). At enddiastole, 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 ( show 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 enddiastolic 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 ( show 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.


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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. For example, the

administration of norepinephrinestimulates 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, anincrement 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 (show 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 (show 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 ( show figure 4). Two factors may

contribute to a plateau in the pressure-volume curve:


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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 itis 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

(show figure 5).

However, decreased compliance due to hypertrophy and fibrosis may eventually produces disturbed

diastolic function in many patients with advanced heart failure [ 6] . In this setting, there is also an

upwardshift in the enddiastolic 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 orcontractility. 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 ( show figure 5). (See "Clinical manifestations and diagnosis of

diastolic heart failure").

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REFERENCES

Ross, J Jr, Braunwald, E. Control of cardiac performance. In: Handbook of Physiology, vol 1,The Heart, Williams & Wilkins, Baltimore 1980. p.533.

1.

Braunwald, E. Pathophysiology of heart failure. In: Heart Disease, 4th ed, Braunwald, E (Ed),Saunders, Philadelphia 1992. p.393.

2.

BADEER, HS. CONTRACTILE TENSION IN THE MYOCARDIUM. Am Heart J 1963; 66:432.3.

Grossman, W. Evaluation of systolic and diastolic function of the myocardium. In: CardiacCatheterization and Angiography, 3d ed, Grossman, W (Ed), Lea and Febiger, Philadelphia1986. p.301.

4.

Litwin, SE, Grossman, W. Diastolic dysfunction as a cause of heart failure. J Am Coll Cardiol1993; 22:49A.

5.


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Holubarsch, C, Ruf, T, Goldstein, DJ, et al. Existence of the Frank-Starling mechanism in thefailing human heart: Investigations on the organ, tissue, and sarcomere levels. Circulation1996; 94:683.

6.

Schwinger, RH, Bohm, M, Koch, A, et al. The failing human heart is unable to use theFrank-Starling mechanism. Circ Res 1994; 74:959.

7.

Komamura, K, Shannon, RP, Ihara, T, et al. Exhaustion of Frank-Starling mechanism inconscious dogs with heart failure. Am J Physiol 1993; 265:H1119.

8.

GRAPHICS

Left ventricular pressure versus volume relationship

The normally contracting left ventricle ejects blood under pressure andthe relationship between left ventricular pressure generation and ejectioncan be expressed in a plot of developed pressure versus volume. In theidealized pressure-volume loop, the left ventricular end-diastolic pressureis represented by point A. Isovolumic contraction at the beginning ofsystole is represented by line AB. As the developed left ventricularpressure exceeds that of the aorta, the aortic valve opens at point B. Thisleads to left ventricular ejection of blood (line BC). The volume of bloodejected (point B minus point C) represents the forward effective strokevolume of this contraction. At end-ejection, the aortic valve closes atpoint C followed by isovolumic relaxation (line CD). The mitral valve thenopens at point D with left ventricular diastolic fill ing represented by line

DA. The shaded area enclosed by the PV loop (ABCD) represents theexternal left ventricular stroke work, which can be represented

mathematically as PdV.

Relationship between myocardial sarcomere length and tension

Top panel (A) is a schematic of a sarcomere. The thin filaments (actin, shown in dark red) areattached at the Z band. The length of two actin filaments as they extend from the Z band isindicated by "b". The length of a thick filament (myosin, shown in pink) is denoted by "a".


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Panels B and C show the correlation between sarcomere stretch and tension. Position number1 shows extreme sarcomere stretch (as occurs in the volume-overloaded ventricle) whereneither actin filament can interact with the myosin filament; as a result, tension developmentis zero. Points 2 and 3 demonstrate situations of maximum actin myosin overlap withmaximal tension production. Reproduced with permission from: Braunwald, E, Ross, J Jr,Sonnenblick, EH, Mechanisms of Contraction of the Normal and Failing Heart, 2d ed, Little, Brown,Boston, 1972; p. 77. Copyright 1972 Lippincott Williams & Wilkins.

Effect of increasing afterload on cardiac function

Curves relating stroke volume or cardiac to afterload or systemic vascularresistance (SVR) in normal subjects and those with heart failure andincreasing degrees of ventricular dysfunction. Increasing afterload haslittle acute effect in normal subjects but becomes progressively morelimiting on cardiac output in CHF. Even though the effect is small withmild CHF, lowering afterload is still important over the long-term becauseit slows the rate of loss of myocardial function.

Frank-Starling curves in CHF

Idealized family of Frank-Starling curves produced by worseningventricular function in heart failure. In ventricles with normal cardiacperformance, there is a steep and positive relationship between increasedcardiac filling pressures (as estimated from the left ventricular end-diastolic or pulmonary capillary wedge pressure) and increased strokevolume or cardiac output (top curve). In comparison, during progressionfrom mild to severe myocardial dysfunction, this relationship isright-shifted (ie, a higher filling pressure is required to achieve the samecardiac output) and flattened so that continued increases in left heartfilling pressures lead to minimal increases in cardiac output at thepossible expense of pulmonary edema. The onset of mild heart failureresults in an initial reduction in cardiac function (point B), a change that


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can be normalized, at least at rest, by raising the LVEDP via fluidretention (point C). In comparison, normalization of stroke volume is notattainable in severe heart failure (bottom curve).

Systolic versus diastolic dysfunction in CHF

Pressure-volume loops in normal subjects (in blue) and those with congestiveheart failure due to systolic (left panel) or diastolic (right panel) dysfunction.The pressure-volume loop is shifted to the right with systolic dysfunction.The end-diastolic pressure is increased compared to normal (25 versus 10mmHg in this example), but at a higher ventricular volume and lower

ejection fraction. In contrast, the pressure-volume loop is shifted to the leftwith isolated diastolic dysfunction. Contractility is normal in this setting, butthe increase in ventricular stiffness results in an elevated end-diastolicpresure at a lower left ventricular volume. Data from Zile, MR, ConceptsCardiovasc Dis 1990; 59:1.

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pathophysiology of heart failure - left ventricular pressure-volume relationships.pdf

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