Pathophysiology of heart failure: Left ventricular pressure-volume relati...

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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

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 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 (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 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 (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 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 ( show figure 5). (See "Clinical manifestations and diagnosis of diastolic heart failure").

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REFERENCES
1. 2. 3. 4. Ross, J Jr, Braunwald, E. Control of cardiac performance. In: Handbook of Physiology, vol 1, The Heart, Williams & Wilkins, Baltimore 1980. p.533. Braunwald, E. Pathophysiology of heart failure. In: Heart Disease, 4th ed, Braunwald, E (Ed), Saunders, Philadelphia 1992. p.393. BADEER, HS. CONTRACTILE TENSION IN THE MYOCARDIUM. Am Heart J 1963; 66:432. Grossman, W. Evaluation of systolic and diastolic function of the myocardium. In: Cardiac Catheterization and Angiography, 3d ed, Grossman, W (Ed), Lea and Febiger, Philadelphia 1986. p.301. Litwin, SE, Grossman, W. Diastolic dysfunction as a cause of heart failure. J Am Coll Cardiol 1993; 22:49A.

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Holubarsch, C, Ruf, T, Goldstein, DJ, et al. Existence of the Frank-Starling mechanism in the failing human heart: Investigations on the organ, tissue, and sarcomere levels. Circulation 1996; 94:683. Schwinger, RH, Bohm, M, Koch, A, et al. The failing human heart is unable to use the Frank-Starling mechanism. Circ Res 1994; 74:959. Komamura, K, Shannon, RP, Ihara, T, et al. Exhaustion of Frank-Starling mechanism in conscious dogs with heart failure. Am J Physiol 1993; 265:H1119.

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GRAPHICS
Left ventricular pressure versus volume relationship

The normally contracting left ventricle ejects blood under pressure and the relationship between left ventricular pressure generation and ejection can be expressed in a plot of developed pressure versus volume. In the idealized pressure-volume loop, the left ventricular end-diastolic pressure is represented by point A. Isovolumic contraction at the beginning of systole is represented by line AB. As the developed left ventricular pressure exceeds that of the aorta, the aortic valve opens at point B. This leads to left ventricular ejection of blood (line BC). The volume of blood ejected (point B minus point C) represents the forward effective stroke volume of this contraction. At end-ejection, the aortic valve closes at point C followed by isovolumic relaxation (line CD). The mitral valve then opens at point D with left ventricular diastolic filling represented by line DA. The shaded area enclosed by the PV loop (ABCD) represents the external 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) are attached at the Z band. The length of two actin filaments as they extend from the Z band is indicated 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 number 1 shows extreme sarcomere stretch (as occurs in the volume-overloaded ventricle) where neither actin filament can interact with the myosin filament; as a result, tension development is zero. Points 2 and 3 demonstrate situations of maximum actin myosin overlap with maximal 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 vascular resistance (SVR) in normal subjects and those with heart failure and increasing degrees of ventricular dysfunction. Increasing afterload has little acute effect in normal subjects but becomes progressively more limiting on cardiac output in CHF. Even though the effect is small with mild CHF, lowering afterload is still important over the long-term because it slows the rate of loss of myocardial function.

Frank-Starling curves in CHF

Idealized family of Frank-Starling curves produced by worsening ventricular function in heart failure. In ventricles with normal cardiac performance, there is a steep and positive relationship between increased cardiac filling pressures (as estimated from the left ventricular enddiastolic or pulmonary capillary wedge pressure) and increased stroke volume or cardiac output (top curve). In comparison, during progression from mild to severe myocardial dysfunction, this relationship is right-shifted (ie, a higher filling pressure is required to achieve the same cardiac output) and flattened so that continued increases in left heart filling pressures lead to minimal increases in cardiac output at the possible expense of pulmonary edema. The onset of mild heart failure results 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 fluid retention (point C). In comparison, normalization of stroke volume is not attainable in severe heart failure (bottom curve).

Systolic versus diastolic dysfunction in CHF

Pressure-volume loops in normal subjects (in blue) and those with congestive heart 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 10 mmHg in this example), but at a higher ventricular volume and lower ejection fraction. In contrast, the pressure-volume loop is shifted to the left with isolated diastolic dysfunction. Contractility is normal in this setting, but the increase in ventricular stiffness results in an elevated end-diastolic presure at a lower left ventricular volume. Data from Zile, MR, Concepts
Cardiovasc Dis 1990; 59:1.

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