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Pressure–volume relationships in pediatric systolic and diastolic heart failure
Progress in Pediatric Cardiology 11 Ž2000. 211᎐218
Pressure᎐volume relationships in pediatric systolic and diastolic heart failure Steven C. Cassidy U Department of Pediatrics, The Ohio State Uni¨ ersity and Children’s Hospital, Columbus, OH, USA
Abstract The left ventricular pressure᎐volume relationship has been used to examine ventricular systolic and diastolic function as well as to evaluate myocardial energetics and ventricular᎐vascular coupling. Preload, afterload and contractility can be separately examined using indices derived from simultaneous pressure and volume measurement. Due to the development of new instrumentation and diagnostic tools, these techniques now can be more readily applied to the evaluation of patients in heart failure. Indices of function can be examined on-line during diagnostic cardiac catheterization. Pharmacologic interventions can be evaluated using these methods, allowing for assessment of therapeutic interventions. Medical therapy can be optimized during these studies, allowing more effective and individualized treatment. 䊚 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Pressure ᎐volume relationship; Contractility; Diastole; Ventricular᎐vascular coupling; Myocardial energetics
1. Introduction The left ventricular pressure volume relationship has been extensively used for examination of ventricular function in a variety of research and clinical settings. Many aspects of ventricular function can be examined in the pressure᎐volume plane, including contractile function, diastolic relaxation, passive filling, myocardial energetics and ventricular᎐vascular coupling. Newer methods that allow on-line examination of left ventricular volume have facilitated the use of indices of function derived from the pressure᎐volume relationship, making it possible for these techniques to be clinically useful in diagnosis and treatment of heart failure and congenital heart disease.
This paper will explore the use of the left ventricular pressure᎐volume relationship and its applications for diagnosing and treating heart failure in children. First, a brief historical perspective on the derivation of this method of examination of ventricular function will be presented. Next, the various indices of function that are derived from the pressure᎐volume relationship will be discussed. These will be followed by a discussion of the techniques that may be used to implement pressure᎐volume analysis of ventricular function in clinical practice. Finally, a discussion of different types of heart failure, and how they may be recognized using the pressure᎐volume relationship will be presented.
2. History U
Section of Cardiology, ED627 Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA. Tel.: q1-614-722-2530; fax: q1-614-722-2549. E-mail address: [email protected] ŽS.C. Cassidy..
The first descriptions of heart function based upon left ventricular pressure᎐volume relationship came
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from the work of Otto Frank, who studied the function of frog ventricles, and found that systolic performance is a function of end-diastolic volume, or preload w1x. Starling advanced these theories in studies of function in dog hearts, finding that stroke volume and external work performed by the left ventricle were a function of filling pressure, given constant afterload. In the 1960s, Sarnoff et al. developed the concept of a family of parallel ventricular function curves of cardiac output vs. filling pressure. Shifts to higher curves were associated with increased inotropic state w2x. In the 1970s Suga and Sagawa began pioneering work in left ventricular pressure᎐volume relationships in isolated perfused dog hearts using an ingenious cardiometer system comprised of an intraventricular balloon connected to a pump w3x. From this and their subsequent work, and with the evolution of their instrumentation, the majority of our understanding of time-varying pressure᎐volume relationships, endsystolic elastance, and ventricular᎐vascular coupling has come. Using more modern and clinically applicable techniques such as the conductance catheter, developed by Baan et al. w4x, Kass et al. have brought the use of pressure᎐volume relationships to the bedside w5,6x. Using these techniques, the principles that have been developed in the laboratory using animal models and isolated hearts have become a reality for functional assessment of the intact circulation in patients with heart disease undergoing diagnostic cardiac catheterization.
sarcomeres prior to activation of the contractile apparatus. Historically, this has most often been clinically represented by filling pressure, either ventricular end-diastolic pressure or atrial pressure. At best, pressure measurement is a very crude measure of preload and sarcomere length. Although still an inexact estimate, a better index of preload is left ventricular end-diastolic volume. End-diastolic volume does not take into account the mass of the myocardium and does not precisely measure sarcomere stretch, but it is generally accepted to be a more reliable measure of preload than other indices, such as enddiastolic pressure. 3.2. Afterload Afterload consists of the forces that oppose contraction once fiber shortening has begun. Most commonly, left ventricular afterload is considered to be equivalent to systemic arterial pressure, or systemic vascular resistance. However, there is more to afterload than simply pressure or resistance. Afterload also includes arterial compliance and the characteristic impedance of the arterial circuit. From pressure᎐volume analysis, an accepted index of afterload is known as arterial elastance. Arterial elastance is an index of afterload that combines compliance, resistance and characteristic impedance of the arterial system w7,8x. Arterial elastance is calculated as the ratio of end-systolic pressure to stroke volume, measured during normal loading conditions. 3.3. Contractile function
3. Indices of function from the pressure–volume relationship Cardiac output and cardiovascular function are determined by a number of separate but related factors, including heart rate, preload, afterload, intrinsic contractile function of the myocardium, and diastolic function. To understand the contribution of each of these parameters to cardiac function and cardiac output, separate measurement of each is desirable. Except for heart rate, which is readily measured, indices of each of these parameters have been developed that are relatively independent of one another, allowing for separate measurement of each using pressure᎐ volume relationships. In addition, other methods of determination of the performance of the cardiovascular system, such as the interaction of contractile function and afterload and ventricular energetics can be examined using analysis in the pressure᎐volume plane. 3.1. Preload Preload is best thought of as the stretch of the
Examination of contractile function is often complicated by the interaction of preload, afterload, and the intrinsic contractility of the myocardium. Using simultaneous measurement of left ventricular pressure and volume, the effects of preload and afterload can be separated from contractility, so that each can be separately examined. Indices of contractility that are relatively independent of loading conditions can be measured, allowing for more accurate estimation of intrinsic contractility. Several relatively load-independent indices of left ventricular contractile function can be derived from the pressure᎐volume relationship. These include end-systolic elastance, preload-recruitable stroke work, and the d Prdtmax ᎐end-diastolic volume relationship. End-systolic elastance is graphically represented as the slope of end-systolic left ventricular pressure᎐volume points acquired during alteration of preload or afterload ŽFig. 1.. This slope becomes steeper under conditions of increased inotropy. Endsystolic elastance is thought to be relatively independent of loading conditions in the physiologic range w9x,
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Fig. 1. Graphical representation of end-systolic elastance Ž Ees .. These pressure᎐volume loops were acquired during transient occlusion of the inferior vena cava using inflation of a balloon catheter. Every other loop has been deleted for clarity. The loops get progressively smaller Žshift to the left. with reduction in preload. Linear regression of the end-systolic pressure᎐volume points yields end-systolic elastance, represented by the slope of the regression line shown. An increase in this slope represents an increase in contractile function of the ventricle. V0 represents the unstressed volume of the heart.
although some curvilinearity has been shown at higher afterload w10x. Despite its load independence, endsystolic elastance is somewhat less sensitive than other indices to alterations in contractile state w9x. Another relatively load-independent index of left ventricular contractile function that can be derived from the pressure᎐volume relationship is preloadrecruitable stroke work. The relationship between work performed by the heart and preload as an index of contractile function is derived from concepts first introduced by Starling, and refined in its usage by Glower et al. w11x. In their work, they demonstrated the linearity of the relationship between stoke work and end-diastolic volume. In addition, the slope of this relationship increases in the presence of inotropic stimulation, is insensitive to alterations in preload and afterload, and is only minimally dependent on heart rate. This index is calculated by performing linear regression of the area within pressure᎐volume loops Žexternal or stroke work. vs. end-diastolic volume for each loop, acquired during manipulation of preload Žvena caval occlusion, for example.. A third relatively load-independent index of contractile function that can be derived from the left ventricular pressure᎐volume relationship is the d Prdt max ᎐end-diastolic volume index proposed by Little w12x. This index is the regression of the first derivative of the left ventricular pressure tracing vs. end-diastolic volume, acquired during a reduction of preload, such as vena caval occlusion. The d Prdt max ᎐end-diastolic volume index has been also been shown to be independent of loading conditions and sensitive to alterations in contractile function, although its use is limited by its variability or noise w6x.
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Each of these indices of contractile function assesses a different part of systole. The pre-ejection indices d Prdtmax and the d Prdt max ᎐end-diastolic volume index are very sensitive to changes in contractility. Under normal loading conditions, these indices are generally measured prior to ejection. Therefore, they do not assess ejection. Stroke work, preloadrecruitable stroke work and ejection fraction are ejection phase indices, and are therefore sensitive to alterations in afterload. End-systolic elastance, an end-systolic index, is independent of contraction history, and although is less sensitive to loading conditions, is less sensitive to the contractile state of the ventricle. Studies that simultaneously have examined several of these indices have shown that on occasion, one or another of these indices may not show the same changes in contractile state w9,13,14x. To completely assess all aspects of contractile function, it is useful to use several of these indices, addressing each phase of systole. The use of several contractility indices is relatively straightforward using pressure᎐ volume analysis of function, as several indices can be simultaneously calculated from pressure and volume data both at rest and during alteration of loading conditions. In addition to these indices, other standard measures of contractile function, such as ejection fraction, stroke work, and d Prdt max can be derived from simultaneous measurement of left ventricular pressure and volume. Evaluation of contractile function cannot just be thought of as a simple single value measurement. In many circumstances, the failing heart functions at or near the maximum of its intrinsic contractile function. This may be due to chronically high levels of circulating catecholamines, downregulation of -adrenergic receptor numbers, altered calcium handling by the diseased myocytes, or replacement of contractile myocardial cells by fibrous tissue. In this circumstance, the cardiac output cannot be further increased by an increase in ventricular contractility. Contractile reserve is a measure of the ability of the cardiovascular system to increase contractile function to adapt to additional stressors, exercise, etc. In order to measure the contractile reserve of the left ventricle, it is necessary to measure contractile function at baseline as well as after inotropic stimulation using one or more inotropic agents. In this way, the ability of the cardiovascular system to provide additional output in response to additional stress can be assessed. Using pressure᎐volume analysis, left ventricular contractility and contractile reserve has been shown to change during early postnatal maturation w13, 15᎐17x. Early in the postnatal period, the left ventricle functions at close to the maximum systolic function that can be elicited by -adrenergic stimulation.
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During early postnatal development, resting contractility falls relative to maximum, allowing for this contractile reserve. 3.4. Diastolic function The period of ventricular diastole can be broken down into relaxation, rapid filling, and passive filling. Each of these phases requires separate indices of function for adequate description. Several different indices of diastolic function can be derived from left ventricular pressure, volume, and simultaneously measured pressure and volume. Relaxation is best examined by examination of left ventricular pressure alone. A widely-used index of relaxation is tau Ž ., a relaxation time constant w18,19x. Tau can be calculated from the formula: Ps P0 eyt r where P is the pressure immediately before ventricular filling begins, P0 is the pressure at which minimum end-systolic volume is reached, and t is the time interval between these pressures. The more rapid relaxation takes place, the smaller the value of . Another commonly-used relaxation index is the maximum negative first derivative of the ventricular pressure tracing Žd Prdtmin .. Rapid filling occurs at the end of relaxation as the mitral valve opens, and is dependent upon relaxation, mitral valve characteristics, atrial pressure and the viscoelastic properties of the myocardium. It is a complex period not well described by any single index. In fact, it is particularly difficult to examine the viscoelastic properties of the myocardium in the intact heart. An index that is commonly used for this period is the peak filling rate, dVrdt max , which can be derived from the diastolic volume tracing. This index is, however, limited in its use by its dependence on loading conditions. Simultaneous measurement of left ventricular pressure and volume allows for calculation of indices of diastolic stiffness, including end-diastolic elastance and kappa, a stiffness constant. A widely-used index of left ventricular stiffness is the end-diastolic elastance, or the slope of the end-diastolic pressure᎐ volume points, plotted during variation of preload. Under normal loading conditions, this relationship is relatively linear ŽFig. 2.. However, when heart failure exists and filling pressures increase, this relationship becomes exponential as represented by the dashed line in Fig. 2. If the end-diastolic pressure᎐volume curve is not linear, it may be more appropriate to use kappa Ž ., a stiffness constant derived from the exponential end-diastolic pressure᎐volume relationship. can be calculated using the formula:
Fig. 2. Graphical representation of end-diastolic elastance Ž ⌬ Pr⌬V .. As in Fig. 1, these pressure᎐volume loops were acquired during transient occlusion of the inferior vena cava using a balloon catheter. The end-diastolic points for these loops fall on a segment of the diastolic pressure᎐volume relationship that is relatively linear. Once again, elastance is represented as the slope of the regression line connecting these points. At higher filling pressures, the end-diastolic pressure᎐volume relationship becomes more exponential Žbroken line.. If the end-diastolic pressure᎐volume points were to fall on this portion of the line, it may be more representative to use an exponential index of diastolic stiffness, such as Kappa.
s Ž d PrdV . rP where d PrdV is the first derivative of the diastolic pressure᎐volume curve, and P is instantaneous pressure. For an exponential diastolic pressure᎐volume relationship, this constant should be independent of the portion of the curve from which it is derived w20x. 3.5. Ventricular᎐¨ ascular coupling Matching ventricular contractile state to the afterload conditions faced by the ventricle during ejection can be accomplished using pressure᎐volume data using end-systolic elastance as an index of contractile function and arterial elastance as an index of afterload. Arterial elastance can be calculated from measured left ventricular pressure and volume, and is defined as the ratio of end-systolic pressure to stroke volume, acquired under normal loading conditions. The arterial elastance to end-systolic elastance ratio Ž EA rEes . reflects the efficiency of energy transfer from the ventricle to the vascular system. Mechanical energy transfer from the ventricle to the arterial system is maximal when arterial elastance equals end-systolic elastance w21x. The EA rEes ratio has been shown to change as part of normal development. In the young piglet, the EArEes ratio was found to change during the first weeks of postnatal life w13x. In this study, 1-week-old pigs were found to have a resting EArEes ratio of close to 1, while by 6 weeks of age, the resting EArEes ratio was closer to 2.5. This change was due to a fall in resting end-systolic elastance; arterial elastance increased a small but insignificant amount between 1
S.C. Cassidy r Progress in Pediatric Cardiology 11 (2000) 211᎐218
and 6 weeks of age. In older age groups, isoproterenol infusion caused EA rEes to fall to approximately 1, maximizing energy transfer from ventricular elastance to arterial elastance. 3.6. Ventricular energetics Use of the left ventricular pressure᎐volume relationship allows for examination of myocardial energetics through use of the pressure᎐volume area. The pressure᎐volume area is defined as the area bounded by the end-diastolic and systolic pressure᎐volume curves, the end-systolic pressure᎐volume relationship from the end-systolic pressure᎐volume point to the volume axis intercept, and the volume axis to the end-systolic volume w22x ŽFig. 3.. The pressure᎐volume area is linearly related to myocardial oxygen consumption. The area bounded by the pressure᎐volume loop is known as stroke work, or external work performed by the heart during ejection. The area bounded by the end-systolic pressure᎐volume trajectory, the end-systolic volume, and the volume axis is the potential energy of the ventricle that remains at the end of contraction. One way of thinking of this area is as a reservoir of energy that can be tapped to improve cardiac performance in the face of stress, heart failure, etc. An index of contractile efficiency can be calculated as the ratio of external work Žstroke work. to myocardial oxygen consumption, w23x or the ratio of stroke work to pressure᎐volume area. In this way, the amount of myocardial oxygen consumption used to perform ejection work can be determined.
4. Clinical use of pressure–volume analysis Until recently, the use of pressure᎐volume relationships for clinical evaluation of left ventricular
Fig. 3. Stroke work, potential energy, and pressure᎐volume area. Stroke work ŽSW., or the external work performed by the ventricle during ejection is represented by the area bounded by the pressure᎐volume loop. Potential energy ŽPE. or the energy remaining in the ventricle after ejection is represented by the shaded area, bounded by the end-systolic pressure᎐volume trajectory, the volume axis and the isovolumic relaxation portion of the pressure᎐volume loop. The sum of SW and PE is the pressure᎐volume area, which is an index of myocardial oxygen consumption.
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function has been limited because of inadequate means to rapidly and accurately measure ventricular volume in the intact closed-chest patient. Advances in cardiac catheterization equipment and techniques, ultrasound equipment and in radiologic techniques have allowed fast and accurate measurement of ventricular dimensions or volume. The ability to rapidly measure ventricular pressure and volume simultaneously allows for analysis of ventricular function using pressure᎐volume relationships. 4.1. Conductance catheter The use of the conductance catheter allows for real-time on-line measurement of ventricular volume and simultaneous measurement of pressure w6,24,25x. This multielectrode catheter measures ventricular volume by electrical conductivity within the ventricle. The most proximal and distal electrode on the catheter are used to set up a harmless alternating current field within the ventricle; electrodes between the current electrodes measure segmental electrical conductivity within the ventricle. Ventricular volume is directly proportional to conductivity, so real-time volumes can be measured using this technique. Modern conductance catheters additionally have a manometer mounted on the catheter, so that pressure and volume can be measured using only one catheter. These catheters have been miniaturized and are commercially available in sizes as small as 5F, allowing use of this technique in even relatively small infants. The use of the conductance catheter for measurement of left ventricular pressure and volume allows readily available, simultaneously obtained pressure and volume signals for digital recording and analysis. This technique can be performed during routine cardiac catheterization w6x, in the operating room before and after cardiopulmonary bypass for heart surgery w26x, and, potentially, in the intensive care unit setting. In order to transiently alter loading conditions, a balloon catheter has been used to transiently occlude the inferior vena cava, so that measures of contractile function including end-systolic elastance, preload-recruitable stroke work, and the d Prd t max ᎐enddiastolic volume relationship and end-diastolic ventricular stiffness can be obtained w5,6x. Use of these techniques allows assessment of interventions for improvement in cardiovascular function, from improvement of contractile function and diastolic function to maximizing ventricular-arterial interaction. 4.2. Angiocardiography Left ventricular angiocardiography has traditionally been used for accurate measurement of left ventricular volume, and allows simultaneous measurement of
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pressure. It is, however, labor-intensive, as measurement left ventricular volume for use in pressure᎐ volume analysis requires frame-by-frame determination of volume, which is time consuming, even with the use of a computer. High-pressure injection of radio-opaque contrast has been shown to affect ventricular contractile function, so the measurement technique itself may alter contractile and diastolic function. In addition, it is difficult to simultaneously alter loading conditions, limiting the utility of this modality for pressure᎐volume analysis of ventricular function using load-independent indices of contractile function. 4.3. Non-in¨ asi¨ e methods of ¨ olume estimation Some newer cardiac ultrasound packages contain sophisticated edge-detection routines that allow realtime measurement of ventricular area, an index of volume. Fast computed tomography and magnetic resonance imaging may also be used for accurate measurement of ventricular volume. These methods, along with simultaneous measurement of ventricular pressure allow for calculation of some indices of function using pressure᎐volume relationships. Since it is difficult to non-invasively alter loading conditions acutely without changing contractile state, the usefulness of these non-invasive means of calculating some of the indices of contractile function using pressure᎐volume analysis is somewhat limited.
5. Heart failure and the pressure–volume relationship There are several ways in which heart failure can be demonstrated by use of the left ventricular pressure᎐volume relationship and ventricular᎐vascular coupling. Due to the altered neurohormonal environment in heart failure, including chronically elevated levels of circulating catecholamines, and activation of the renin᎐angiotensin᎐aldosterone system, the function of the heart and circulation can be potentially altered in several ways. These functional alterations include altered left ventricular diastolic filling, depressed contractile function, inadequate contractile reserve, and inefficient ventricular vascular coupling. Using analysis of left ventricular function and ventricular᎐vascular coupling in the pressure᎐volume plane, each part of ventricular and circulatory function can be examined and optimized individually for patients in heart failure. Several different abnormalities in diastolic function in the failing circulation can be identified from left ventricular pressure and volume. The most common diastolic filling abnormality that accompanies or
causes heart failure in the pediatric population is increased ventricular elastance or stiffness. This may result from severe dilation or hypertrophy of the ventricle, from a primary myocardial abnormality in patients with either hypertrophic or restrictive cardiomyopathy, or from chronically increased preload. In these patients, filling pressures are high, and small increases in ventricular volume can lead to large increases in end-diastolic pressure. In these patients, the end-diastolic pressure᎐volume points would likely fall on the exponential portion of the diastolic pressure᎐volume relationship, represented by the broken line in Fig. 2. These patients often have symptoms of congestive heart failure because of elevation of left atrial and pulmonary venous pressures. In patients without primary myocardial abnormalities or in those with chronically increased preload, diuretics are often used to reduce filling pressures and along with efforts to increase forward output of the heart through manipulation of inotropy or afterload, can relieve symptoms in these patients. In patients who have hypertrophic or restrictive cardiomyopathies, calcium channel blockers or -adrenergic blockers have been used to improve diastolic filling. Diastolic relaxation abnormalities are occasionally found in patients with heart failure. Relaxation abnormalities are very unusual causes of heart failure in the pediatric population, and are unlikely to be of significance in filling abnormalities. Although it would seem that abnormalities in systolic function would be easily identified in the failing circulatory system, one must use caution in interpretation of indices of systolic function derived from the pressure᎐volume relationship. The indices of systolic function that are commonly calculated from left ventricular pressure and volume do not take into account the myocardial mass or patient size, making absolute use of the numerical indices or between patient comparisons difficult. Unless indices of systolic function are corrected for individual heart size w27x, one must examine indices of systolic function in light of abnormalities in contractile reserve or in the context of ventricular᎐vascular coupling for proper assessment of abnormalities in systolic function, as outlined below. Heart failure may be accompanied by a lack of contractile reserve. In most normal circumstances, ventricular contractile function is less than its maximum state, allowing for an increase in contractility to augment cardiac output in response to stress, exercise, or whatever increased demands may be faced. In the failing circulation this may not be so. Due to immaturity of the myocardium in the very young or due to chronically elevated levels of endogenous catecholamines, damage to or fibrous replacement of myocytes, contractile reserve may be limited. This would
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be evident during examination of the pressure᎐volume relationship by an inability to increase indices of contractile function by administration of inotropic agents, like -adrenergic drugs such as dobutamine or isoproterenol, or phosphodiesterase inhibitors such as amrinone or milrinone. In this circumstance, little can be done pharmacologically to improve contractile function. -Adrenergic blockade may be useful to diminish the effects of elevated levels of circulating catecholamines, and may improve contractile function of the myocardium w28᎐30x. Treatment efforts must also concentrate on maximizing efficiency and optimal matching of afterload to maximize cardiac output. Ventricular᎐vascular coupling can be examined and improved in the failing circulation. High resting afterload may result from neurohormonal activation, leading to inefficient energy transfer from the ventricle to the arterial system. This principle is demonstrated in Fig. 4. In panel Ža., afterload, as represented by arterial elastance, is graphically demonstrated as the negative slope of the line marked yEA ; end-systolic elastance is also shown, along with a normally loaded pressure᎐volume loop. In this example, arterial elastance exceeds end-systolic elastance, leading to inefficient energy transfer from the ventricle to the aorta. Graphically, one can see that the stroke work, or the area bounded by the pressure᎐volume loop, is a small proportion of the pressure᎐volume area, and the stroke volume is limited by afterload. By administration of medications, optimization of the EArEes ratio can improve the energy transfer from ventricle to the arterial system by lowering arterial elastance, increasing end-systolic elastance, or both. In Fig. 4b, infusion of a drug such as dobutamine has increased endsystolic elastance slightly, decreased arterial elastance, resulting in optimization of stroke work. The resultant increase in stroke volume from the same end-diastolic volume can be graphically seen. Further reduction in afterload may further increase efficiency of energy transfer from the ventricle to the arterial system w31x Another way of thinking about mismatched ventricular᎐vascular coupling is in terms of ventricular energetics. In the failing circulation, energy transfer from the ventricle to the arterial system is inefficient. Work efficiency can be studied and improved using pressure᎐volume analysis. In Fig. 4a, the stroke work, represented by the area within the pressure volume loop, is a smaller proportion of the pressure᎐volume area than in panel Žb.. Improvement of ventricular᎐ vascular coupling can lead to more efficient use of contractile energy, with less potential energy left at the end of contraction. Further reduction in afterload may allow for even greater stroke volume at the same level of contractile function.
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Fig. 4. Ventricular vascular coupling and efficiency of energy transfer from ventricle to the arterial system. A normally-loaded pressure᎐volume loop is shown in each panel, along with the end-systolic pressure᎐volume line, the slope of which is end-systolic elastance Ž Ees ., and the line representing arterial elastance Ž EA ., the slope of which is shown as yEA . Two different states of inotropy and afterload are shown. Ža. Under resting conditions, arterial elastance exceeds end-systolic elastance, causing a mismatch in loading conditions for inotropic state, and inefficient energy transfer from the ventricle to the arterial system. Žb. A drug such as dobutamine has been given, leading to a relatively small increase in end-systolic elastance, along with a reduction of arterial elastance. In this state, end-systolic elastance is approximately equal to arterial elastance, allowing for stroke work to be maximized. For the starting end-diastolic ventricular volume, stroke volume has been increased. Note also that the area within the pressure᎐volume loop Žstroke work. is a higher proportion of the pressure᎐volume area in Žb., indicating higher relative efficiency of energy transfer in this state.
6. Summary The use of pressure᎐volume relationships for evaluation of ventricular and circulatory function allows for examination of each of the circulatory conditions that may be associated with heart failure. Preload, afterload, diastolic and contractile function, ventricular᎐vascular coupling, and ventricular energetics can be separated from one another and examined during diagnostic evaluation of the heart. Newer techniques and equipment have facilitated the simultaneous measurement of left ventricular pressure and volume, mainly by allowing more rapid determination of accurate ventricular volumes. Analysis of function in the pressure᎐volume plane allows for measurement of indices of contractile function that are relatively independent of loading conditions. Furthermore, the use of these methods allows for pharmacologic manipula-
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tion and optimization of these different factors during functional evaluation of the heart and circulation to maximize effective cardiac output, and relieve patient symptoms.
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References
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Frank O. Zur Dynamik des Herzmuskels. Z Biol 1895;32:370᎐447. Cited in: Sagawa K, Maughan L, Suga H, Sunagawa K. Introduction. Cardiac contraction and the pressure᎐volume relationship. New York: Oxford University Press, 1988:3᎐41.. Sarnoff SJ, Mitchell JH. The controls of the function of the heart. In: Hamilton WF, editor. Handbook of physiology. Washington, DC: American Physiological Society, 1962: 489᎐532. Suga H, Sagawa K. Instantaneous pressure᎐volume relationships and their ratio in the excised, supported canine left ventricle. Circ Res 1974;35:117᎐126. Baan J, Jong TT, Kerkhof PL et al. Continuous stroke volume and cardiac output from intra-ventricular dimensions obtained with impedance catheter. Cardiovasc Res 1981; 15:328᎐334. Kass DA, Midei M, Graves W, Brinker JA, Maughan WL. Use of a conductance Žvolume. catheter and inferior vena caval occlusion for rapid determination of pressure᎐volume relationships in man. Cathet Cardiovasc Diagn 1988;15: 192᎐202. Kass DA. Clinical evaluation of left heart function by conductance catheter technique. Eur Heart J 1992;13:57᎐64. Sunagawa K, Maughan WL, Burkoff D, Sagawa K. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983;245:H773᎐H780. Kass DA, Grayson R, Marino P. Pressure᎐volume analysis as a method for quantifying simultaneous drug Žamrinone. effects on arterial load and contractile state in vivo. J Am Coll Cardiol 1990;16:726᎐732. Kass DA, Maughan WL, Guo ZM, Kono A, Sunagawa K, Sagawa K. Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure᎐volume relationships. Circulation 1987;76:1422᎐1436. van der Velde ET, Burkhoff D, Steendijk P, Karsdon J, Sagawa K, Baan J. Nonlinearity and load sensitivity of endsystolic pressure᎐volume relation of canine left ventricle in vivo. Circulation 1991;83:315᎐327. Glower DD, Spratt JA, Snow ND et al. Linearity of the Frank᎐Starling relationship in the intact heart: the concept of preload recruitable stroke work. Circulation 1985;71: 994᎐1009. Little WC. The left ventricular dPrdtmax-end-diastolic volume relation in closed-chest dogs. Circ Res 1985;56: 808᎐815. Cassidy SC, Chan DP, Allen HD. Left ventricular systolic function, arterial elastance, and ventricular᎐vascular cou-
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pling: a developmental study in piglets. Pediatr Res 1997; 42:273᎐281. Cassidy SC, McGovern JJ, Chan DP, Allen HD. Effects of commonly used adrenergic agonists on left ventricular function and systemic vascular resistance in young piglets. Am Heart J 1997;133:174᎐183. Romero TE, Friedman WF. Limited left ventricular response to volume overload in the neonatal period: a comparative study with the adult animal. Pediatr Res 1979;13:910᎐915. Anderson PA, Glick KL, Manring A, Crenshaw Jr C. Developmental changes in cardiac contractility in fetal and postnatal sheep: in vitro and in vivo. Am J Physiol 1984;247: H371᎐H379. Teitel DF, Sidi D, Chin T, Brett C, Heymenn MA, Rudolph AM. Developmental changes in myocardial contractile reserve in the lamb. Pediatr Res 1985;19:948᎐955. Gaasch WH, Carroll JD, Blaustein AS, Bing OH. Myocardial relaxation: effects of preload on the time course of isovolumetric relaxation. Circulation 1986;73:1037᎐1041. Starling MR, Montgomery DG, Mancini GBJ, Walsh RA. Load independence of the rate of isovolumic relaxation in man. Circulation 1987;76:1274᎐1281. Grossman W, McLaurin LP, Stefadouros MA. Left ventricular stiffness associated with chronic pressure and volume overloads in man. Circ Res 1974;35:783᎐800. Sagawa K, Maughan L, Suga HKS. Cardiovascular interaction. Cardiac contraction and the pressure᎐volume relationship. New York: Oxford University Press, 1988:232᎐298. Sagawa K, Maughan L, Suga H, Sunagawa K. Energetics of the heart. Cardiac contraction and the pressure᎐volume relationship. New York: Oxford University Press, 1988:171᎐231. Suga H, Goto Y, Kawaguchi O et al. Ventricular perspective on efficiency. Basic Res Cardiol 1993;88:43᎐65. Baan J, van der Velde ET, de Bruin HG et al. Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 1984;70:812᎐823. Teitel DF, Klautz RJ, Cassidy SC et al. The end-systolic pressure᎐volume relationship in young animals using the conductance technique. Eur Heart J 1992;13:40᎐46. White P, Chaturvedi R, Shore D et al. Left ventricular parallel conductance during cardiac cycle in children with congenital heart disease. Am J Physiol 1997;273:H295᎐H302. Suga H, Hisano R, Goto YOY. Normalization of end-systolic pressure᎐volume relation and Emax of different sized hearts. Jpn Circ J 1984;48:136᎐143. van Campen L, Visser F, Visser C. Ejection fraction improvement by beta-blocker treatment in patients with heart failure: an analysis of studies published in the literature. J Cardiovasc Pharm 1998;32ŽSuppl 1.:S31᎐S35. Sharpe N. Beta-blockers in heart failure. Future directions. Eur Heart J 1996;17ŽSuppl B.:39᎐42. Eichhorn E. Restoring function in failing hearts: the effects of beta blockers. Am J Med 1998;104:163᎐169. Ishizaka S, Asanoi H, Kameyama T, Sasayama S. Ventricular-load optimization by inotropic stimulation in patients with heart failure. Int J Cardiol 1991;31:51᎐58.
Pressure᎐volume relationships in pediatric systolic and diastolic heart failure Steven C. Cassidy U Department of Pediatrics, The Ohio State Uni¨ ersity and Children’s Hospital, Columbus, OH, USA
Abstract The left ventricular pressure᎐volume relationship has been used to examine ventricular systolic and diastolic function as well as to evaluate myocardial energetics and ventricular᎐vascular coupling. Preload, afterload and contractility can be separately examined using indices derived from simultaneous pressure and volume measurement. Due to the development of new instrumentation and diagnostic tools, these techniques now can be more readily applied to the evaluation of patients in heart failure. Indices of function can be examined on-line during diagnostic cardiac catheterization. Pharmacologic interventions can be evaluated using these methods, allowing for assessment of therapeutic interventions. Medical therapy can be optimized during these studies, allowing more effective and individualized treatment. 䊚 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Pressure ᎐volume relationship; Contractility; Diastole; Ventricular᎐vascular coupling; Myocardial energetics
1. Introduction The left ventricular pressure volume relationship has been extensively used for examination of ventricular function in a variety of research and clinical settings. Many aspects of ventricular function can be examined in the pressure᎐volume plane, including contractile function, diastolic relaxation, passive filling, myocardial energetics and ventricular᎐vascular coupling. Newer methods that allow on-line examination of left ventricular volume have facilitated the use of indices of function derived from the pressure᎐volume relationship, making it possible for these techniques to be clinically useful in diagnosis and treatment of heart failure and congenital heart disease.
This paper will explore the use of the left ventricular pressure᎐volume relationship and its applications for diagnosing and treating heart failure in children. First, a brief historical perspective on the derivation of this method of examination of ventricular function will be presented. Next, the various indices of function that are derived from the pressure᎐volume relationship will be discussed. These will be followed by a discussion of the techniques that may be used to implement pressure᎐volume analysis of ventricular function in clinical practice. Finally, a discussion of different types of heart failure, and how they may be recognized using the pressure᎐volume relationship will be presented.
2. History U
Section of Cardiology, ED627 Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA. Tel.: q1-614-722-2530; fax: q1-614-722-2549. E-mail address: [email protected] ŽS.C. Cassidy..
The first descriptions of heart function based upon left ventricular pressure᎐volume relationship came
1058-9813r00r$ - see front matter 䊚 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 5 8 - 9 8 1 3 Ž 0 0 . 0 0 0 5 2 - 7
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from the work of Otto Frank, who studied the function of frog ventricles, and found that systolic performance is a function of end-diastolic volume, or preload w1x. Starling advanced these theories in studies of function in dog hearts, finding that stroke volume and external work performed by the left ventricle were a function of filling pressure, given constant afterload. In the 1960s, Sarnoff et al. developed the concept of a family of parallel ventricular function curves of cardiac output vs. filling pressure. Shifts to higher curves were associated with increased inotropic state w2x. In the 1970s Suga and Sagawa began pioneering work in left ventricular pressure᎐volume relationships in isolated perfused dog hearts using an ingenious cardiometer system comprised of an intraventricular balloon connected to a pump w3x. From this and their subsequent work, and with the evolution of their instrumentation, the majority of our understanding of time-varying pressure᎐volume relationships, endsystolic elastance, and ventricular᎐vascular coupling has come. Using more modern and clinically applicable techniques such as the conductance catheter, developed by Baan et al. w4x, Kass et al. have brought the use of pressure᎐volume relationships to the bedside w5,6x. Using these techniques, the principles that have been developed in the laboratory using animal models and isolated hearts have become a reality for functional assessment of the intact circulation in patients with heart disease undergoing diagnostic cardiac catheterization.
sarcomeres prior to activation of the contractile apparatus. Historically, this has most often been clinically represented by filling pressure, either ventricular end-diastolic pressure or atrial pressure. At best, pressure measurement is a very crude measure of preload and sarcomere length. Although still an inexact estimate, a better index of preload is left ventricular end-diastolic volume. End-diastolic volume does not take into account the mass of the myocardium and does not precisely measure sarcomere stretch, but it is generally accepted to be a more reliable measure of preload than other indices, such as enddiastolic pressure. 3.2. Afterload Afterload consists of the forces that oppose contraction once fiber shortening has begun. Most commonly, left ventricular afterload is considered to be equivalent to systemic arterial pressure, or systemic vascular resistance. However, there is more to afterload than simply pressure or resistance. Afterload also includes arterial compliance and the characteristic impedance of the arterial circuit. From pressure᎐volume analysis, an accepted index of afterload is known as arterial elastance. Arterial elastance is an index of afterload that combines compliance, resistance and characteristic impedance of the arterial system w7,8x. Arterial elastance is calculated as the ratio of end-systolic pressure to stroke volume, measured during normal loading conditions. 3.3. Contractile function
3. Indices of function from the pressure–volume relationship Cardiac output and cardiovascular function are determined by a number of separate but related factors, including heart rate, preload, afterload, intrinsic contractile function of the myocardium, and diastolic function. To understand the contribution of each of these parameters to cardiac function and cardiac output, separate measurement of each is desirable. Except for heart rate, which is readily measured, indices of each of these parameters have been developed that are relatively independent of one another, allowing for separate measurement of each using pressure᎐ volume relationships. In addition, other methods of determination of the performance of the cardiovascular system, such as the interaction of contractile function and afterload and ventricular energetics can be examined using analysis in the pressure᎐volume plane. 3.1. Preload Preload is best thought of as the stretch of the
Examination of contractile function is often complicated by the interaction of preload, afterload, and the intrinsic contractility of the myocardium. Using simultaneous measurement of left ventricular pressure and volume, the effects of preload and afterload can be separated from contractility, so that each can be separately examined. Indices of contractility that are relatively independent of loading conditions can be measured, allowing for more accurate estimation of intrinsic contractility. Several relatively load-independent indices of left ventricular contractile function can be derived from the pressure᎐volume relationship. These include end-systolic elastance, preload-recruitable stroke work, and the d Prdtmax ᎐end-diastolic volume relationship. End-systolic elastance is graphically represented as the slope of end-systolic left ventricular pressure᎐volume points acquired during alteration of preload or afterload ŽFig. 1.. This slope becomes steeper under conditions of increased inotropy. Endsystolic elastance is thought to be relatively independent of loading conditions in the physiologic range w9x,
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Fig. 1. Graphical representation of end-systolic elastance Ž Ees .. These pressure᎐volume loops were acquired during transient occlusion of the inferior vena cava using inflation of a balloon catheter. Every other loop has been deleted for clarity. The loops get progressively smaller Žshift to the left. with reduction in preload. Linear regression of the end-systolic pressure᎐volume points yields end-systolic elastance, represented by the slope of the regression line shown. An increase in this slope represents an increase in contractile function of the ventricle. V0 represents the unstressed volume of the heart.
although some curvilinearity has been shown at higher afterload w10x. Despite its load independence, endsystolic elastance is somewhat less sensitive than other indices to alterations in contractile state w9x. Another relatively load-independent index of left ventricular contractile function that can be derived from the pressure᎐volume relationship is preloadrecruitable stroke work. The relationship between work performed by the heart and preload as an index of contractile function is derived from concepts first introduced by Starling, and refined in its usage by Glower et al. w11x. In their work, they demonstrated the linearity of the relationship between stoke work and end-diastolic volume. In addition, the slope of this relationship increases in the presence of inotropic stimulation, is insensitive to alterations in preload and afterload, and is only minimally dependent on heart rate. This index is calculated by performing linear regression of the area within pressure᎐volume loops Žexternal or stroke work. vs. end-diastolic volume for each loop, acquired during manipulation of preload Žvena caval occlusion, for example.. A third relatively load-independent index of contractile function that can be derived from the left ventricular pressure᎐volume relationship is the d Prdt max ᎐end-diastolic volume index proposed by Little w12x. This index is the regression of the first derivative of the left ventricular pressure tracing vs. end-diastolic volume, acquired during a reduction of preload, such as vena caval occlusion. The d Prdt max ᎐end-diastolic volume index has been also been shown to be independent of loading conditions and sensitive to alterations in contractile function, although its use is limited by its variability or noise w6x.
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Each of these indices of contractile function assesses a different part of systole. The pre-ejection indices d Prdtmax and the d Prdt max ᎐end-diastolic volume index are very sensitive to changes in contractility. Under normal loading conditions, these indices are generally measured prior to ejection. Therefore, they do not assess ejection. Stroke work, preloadrecruitable stroke work and ejection fraction are ejection phase indices, and are therefore sensitive to alterations in afterload. End-systolic elastance, an end-systolic index, is independent of contraction history, and although is less sensitive to loading conditions, is less sensitive to the contractile state of the ventricle. Studies that simultaneously have examined several of these indices have shown that on occasion, one or another of these indices may not show the same changes in contractile state w9,13,14x. To completely assess all aspects of contractile function, it is useful to use several of these indices, addressing each phase of systole. The use of several contractility indices is relatively straightforward using pressure᎐ volume analysis of function, as several indices can be simultaneously calculated from pressure and volume data both at rest and during alteration of loading conditions. In addition to these indices, other standard measures of contractile function, such as ejection fraction, stroke work, and d Prdt max can be derived from simultaneous measurement of left ventricular pressure and volume. Evaluation of contractile function cannot just be thought of as a simple single value measurement. In many circumstances, the failing heart functions at or near the maximum of its intrinsic contractile function. This may be due to chronically high levels of circulating catecholamines, downregulation of -adrenergic receptor numbers, altered calcium handling by the diseased myocytes, or replacement of contractile myocardial cells by fibrous tissue. In this circumstance, the cardiac output cannot be further increased by an increase in ventricular contractility. Contractile reserve is a measure of the ability of the cardiovascular system to increase contractile function to adapt to additional stressors, exercise, etc. In order to measure the contractile reserve of the left ventricle, it is necessary to measure contractile function at baseline as well as after inotropic stimulation using one or more inotropic agents. In this way, the ability of the cardiovascular system to provide additional output in response to additional stress can be assessed. Using pressure᎐volume analysis, left ventricular contractility and contractile reserve has been shown to change during early postnatal maturation w13, 15᎐17x. Early in the postnatal period, the left ventricle functions at close to the maximum systolic function that can be elicited by -adrenergic stimulation.
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During early postnatal development, resting contractility falls relative to maximum, allowing for this contractile reserve. 3.4. Diastolic function The period of ventricular diastole can be broken down into relaxation, rapid filling, and passive filling. Each of these phases requires separate indices of function for adequate description. Several different indices of diastolic function can be derived from left ventricular pressure, volume, and simultaneously measured pressure and volume. Relaxation is best examined by examination of left ventricular pressure alone. A widely-used index of relaxation is tau Ž ., a relaxation time constant w18,19x. Tau can be calculated from the formula: Ps P0 eyt r where P is the pressure immediately before ventricular filling begins, P0 is the pressure at which minimum end-systolic volume is reached, and t is the time interval between these pressures. The more rapid relaxation takes place, the smaller the value of . Another commonly-used relaxation index is the maximum negative first derivative of the ventricular pressure tracing Žd Prdtmin .. Rapid filling occurs at the end of relaxation as the mitral valve opens, and is dependent upon relaxation, mitral valve characteristics, atrial pressure and the viscoelastic properties of the myocardium. It is a complex period not well described by any single index. In fact, it is particularly difficult to examine the viscoelastic properties of the myocardium in the intact heart. An index that is commonly used for this period is the peak filling rate, dVrdt max , which can be derived from the diastolic volume tracing. This index is, however, limited in its use by its dependence on loading conditions. Simultaneous measurement of left ventricular pressure and volume allows for calculation of indices of diastolic stiffness, including end-diastolic elastance and kappa, a stiffness constant. A widely-used index of left ventricular stiffness is the end-diastolic elastance, or the slope of the end-diastolic pressure᎐ volume points, plotted during variation of preload. Under normal loading conditions, this relationship is relatively linear ŽFig. 2.. However, when heart failure exists and filling pressures increase, this relationship becomes exponential as represented by the dashed line in Fig. 2. If the end-diastolic pressure᎐volume curve is not linear, it may be more appropriate to use kappa Ž ., a stiffness constant derived from the exponential end-diastolic pressure᎐volume relationship. can be calculated using the formula:
Fig. 2. Graphical representation of end-diastolic elastance Ž ⌬ Pr⌬V .. As in Fig. 1, these pressure᎐volume loops were acquired during transient occlusion of the inferior vena cava using a balloon catheter. The end-diastolic points for these loops fall on a segment of the diastolic pressure᎐volume relationship that is relatively linear. Once again, elastance is represented as the slope of the regression line connecting these points. At higher filling pressures, the end-diastolic pressure᎐volume relationship becomes more exponential Žbroken line.. If the end-diastolic pressure᎐volume points were to fall on this portion of the line, it may be more representative to use an exponential index of diastolic stiffness, such as Kappa.
s Ž d PrdV . rP where d PrdV is the first derivative of the diastolic pressure᎐volume curve, and P is instantaneous pressure. For an exponential diastolic pressure᎐volume relationship, this constant should be independent of the portion of the curve from which it is derived w20x. 3.5. Ventricular᎐¨ ascular coupling Matching ventricular contractile state to the afterload conditions faced by the ventricle during ejection can be accomplished using pressure᎐volume data using end-systolic elastance as an index of contractile function and arterial elastance as an index of afterload. Arterial elastance can be calculated from measured left ventricular pressure and volume, and is defined as the ratio of end-systolic pressure to stroke volume, acquired under normal loading conditions. The arterial elastance to end-systolic elastance ratio Ž EA rEes . reflects the efficiency of energy transfer from the ventricle to the vascular system. Mechanical energy transfer from the ventricle to the arterial system is maximal when arterial elastance equals end-systolic elastance w21x. The EA rEes ratio has been shown to change as part of normal development. In the young piglet, the EArEes ratio was found to change during the first weeks of postnatal life w13x. In this study, 1-week-old pigs were found to have a resting EArEes ratio of close to 1, while by 6 weeks of age, the resting EArEes ratio was closer to 2.5. This change was due to a fall in resting end-systolic elastance; arterial elastance increased a small but insignificant amount between 1
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and 6 weeks of age. In older age groups, isoproterenol infusion caused EA rEes to fall to approximately 1, maximizing energy transfer from ventricular elastance to arterial elastance. 3.6. Ventricular energetics Use of the left ventricular pressure᎐volume relationship allows for examination of myocardial energetics through use of the pressure᎐volume area. The pressure᎐volume area is defined as the area bounded by the end-diastolic and systolic pressure᎐volume curves, the end-systolic pressure᎐volume relationship from the end-systolic pressure᎐volume point to the volume axis intercept, and the volume axis to the end-systolic volume w22x ŽFig. 3.. The pressure᎐volume area is linearly related to myocardial oxygen consumption. The area bounded by the pressure᎐volume loop is known as stroke work, or external work performed by the heart during ejection. The area bounded by the end-systolic pressure᎐volume trajectory, the end-systolic volume, and the volume axis is the potential energy of the ventricle that remains at the end of contraction. One way of thinking of this area is as a reservoir of energy that can be tapped to improve cardiac performance in the face of stress, heart failure, etc. An index of contractile efficiency can be calculated as the ratio of external work Žstroke work. to myocardial oxygen consumption, w23x or the ratio of stroke work to pressure᎐volume area. In this way, the amount of myocardial oxygen consumption used to perform ejection work can be determined.
4. Clinical use of pressure–volume analysis Until recently, the use of pressure᎐volume relationships for clinical evaluation of left ventricular
Fig. 3. Stroke work, potential energy, and pressure᎐volume area. Stroke work ŽSW., or the external work performed by the ventricle during ejection is represented by the area bounded by the pressure᎐volume loop. Potential energy ŽPE. or the energy remaining in the ventricle after ejection is represented by the shaded area, bounded by the end-systolic pressure᎐volume trajectory, the volume axis and the isovolumic relaxation portion of the pressure᎐volume loop. The sum of SW and PE is the pressure᎐volume area, which is an index of myocardial oxygen consumption.
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function has been limited because of inadequate means to rapidly and accurately measure ventricular volume in the intact closed-chest patient. Advances in cardiac catheterization equipment and techniques, ultrasound equipment and in radiologic techniques have allowed fast and accurate measurement of ventricular dimensions or volume. The ability to rapidly measure ventricular pressure and volume simultaneously allows for analysis of ventricular function using pressure᎐volume relationships. 4.1. Conductance catheter The use of the conductance catheter allows for real-time on-line measurement of ventricular volume and simultaneous measurement of pressure w6,24,25x. This multielectrode catheter measures ventricular volume by electrical conductivity within the ventricle. The most proximal and distal electrode on the catheter are used to set up a harmless alternating current field within the ventricle; electrodes between the current electrodes measure segmental electrical conductivity within the ventricle. Ventricular volume is directly proportional to conductivity, so real-time volumes can be measured using this technique. Modern conductance catheters additionally have a manometer mounted on the catheter, so that pressure and volume can be measured using only one catheter. These catheters have been miniaturized and are commercially available in sizes as small as 5F, allowing use of this technique in even relatively small infants. The use of the conductance catheter for measurement of left ventricular pressure and volume allows readily available, simultaneously obtained pressure and volume signals for digital recording and analysis. This technique can be performed during routine cardiac catheterization w6x, in the operating room before and after cardiopulmonary bypass for heart surgery w26x, and, potentially, in the intensive care unit setting. In order to transiently alter loading conditions, a balloon catheter has been used to transiently occlude the inferior vena cava, so that measures of contractile function including end-systolic elastance, preload-recruitable stroke work, and the d Prd t max ᎐enddiastolic volume relationship and end-diastolic ventricular stiffness can be obtained w5,6x. Use of these techniques allows assessment of interventions for improvement in cardiovascular function, from improvement of contractile function and diastolic function to maximizing ventricular-arterial interaction. 4.2. Angiocardiography Left ventricular angiocardiography has traditionally been used for accurate measurement of left ventricular volume, and allows simultaneous measurement of
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pressure. It is, however, labor-intensive, as measurement left ventricular volume for use in pressure᎐ volume analysis requires frame-by-frame determination of volume, which is time consuming, even with the use of a computer. High-pressure injection of radio-opaque contrast has been shown to affect ventricular contractile function, so the measurement technique itself may alter contractile and diastolic function. In addition, it is difficult to simultaneously alter loading conditions, limiting the utility of this modality for pressure᎐volume analysis of ventricular function using load-independent indices of contractile function. 4.3. Non-in¨ asi¨ e methods of ¨ olume estimation Some newer cardiac ultrasound packages contain sophisticated edge-detection routines that allow realtime measurement of ventricular area, an index of volume. Fast computed tomography and magnetic resonance imaging may also be used for accurate measurement of ventricular volume. These methods, along with simultaneous measurement of ventricular pressure allow for calculation of some indices of function using pressure᎐volume relationships. Since it is difficult to non-invasively alter loading conditions acutely without changing contractile state, the usefulness of these non-invasive means of calculating some of the indices of contractile function using pressure᎐volume analysis is somewhat limited.
5. Heart failure and the pressure–volume relationship There are several ways in which heart failure can be demonstrated by use of the left ventricular pressure᎐volume relationship and ventricular᎐vascular coupling. Due to the altered neurohormonal environment in heart failure, including chronically elevated levels of circulating catecholamines, and activation of the renin᎐angiotensin᎐aldosterone system, the function of the heart and circulation can be potentially altered in several ways. These functional alterations include altered left ventricular diastolic filling, depressed contractile function, inadequate contractile reserve, and inefficient ventricular vascular coupling. Using analysis of left ventricular function and ventricular᎐vascular coupling in the pressure᎐volume plane, each part of ventricular and circulatory function can be examined and optimized individually for patients in heart failure. Several different abnormalities in diastolic function in the failing circulation can be identified from left ventricular pressure and volume. The most common diastolic filling abnormality that accompanies or
causes heart failure in the pediatric population is increased ventricular elastance or stiffness. This may result from severe dilation or hypertrophy of the ventricle, from a primary myocardial abnormality in patients with either hypertrophic or restrictive cardiomyopathy, or from chronically increased preload. In these patients, filling pressures are high, and small increases in ventricular volume can lead to large increases in end-diastolic pressure. In these patients, the end-diastolic pressure᎐volume points would likely fall on the exponential portion of the diastolic pressure᎐volume relationship, represented by the broken line in Fig. 2. These patients often have symptoms of congestive heart failure because of elevation of left atrial and pulmonary venous pressures. In patients without primary myocardial abnormalities or in those with chronically increased preload, diuretics are often used to reduce filling pressures and along with efforts to increase forward output of the heart through manipulation of inotropy or afterload, can relieve symptoms in these patients. In patients who have hypertrophic or restrictive cardiomyopathies, calcium channel blockers or -adrenergic blockers have been used to improve diastolic filling. Diastolic relaxation abnormalities are occasionally found in patients with heart failure. Relaxation abnormalities are very unusual causes of heart failure in the pediatric population, and are unlikely to be of significance in filling abnormalities. Although it would seem that abnormalities in systolic function would be easily identified in the failing circulatory system, one must use caution in interpretation of indices of systolic function derived from the pressure᎐volume relationship. The indices of systolic function that are commonly calculated from left ventricular pressure and volume do not take into account the myocardial mass or patient size, making absolute use of the numerical indices or between patient comparisons difficult. Unless indices of systolic function are corrected for individual heart size w27x, one must examine indices of systolic function in light of abnormalities in contractile reserve or in the context of ventricular᎐vascular coupling for proper assessment of abnormalities in systolic function, as outlined below. Heart failure may be accompanied by a lack of contractile reserve. In most normal circumstances, ventricular contractile function is less than its maximum state, allowing for an increase in contractility to augment cardiac output in response to stress, exercise, or whatever increased demands may be faced. In the failing circulation this may not be so. Due to immaturity of the myocardium in the very young or due to chronically elevated levels of endogenous catecholamines, damage to or fibrous replacement of myocytes, contractile reserve may be limited. This would
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be evident during examination of the pressure᎐volume relationship by an inability to increase indices of contractile function by administration of inotropic agents, like -adrenergic drugs such as dobutamine or isoproterenol, or phosphodiesterase inhibitors such as amrinone or milrinone. In this circumstance, little can be done pharmacologically to improve contractile function. -Adrenergic blockade may be useful to diminish the effects of elevated levels of circulating catecholamines, and may improve contractile function of the myocardium w28᎐30x. Treatment efforts must also concentrate on maximizing efficiency and optimal matching of afterload to maximize cardiac output. Ventricular᎐vascular coupling can be examined and improved in the failing circulation. High resting afterload may result from neurohormonal activation, leading to inefficient energy transfer from the ventricle to the arterial system. This principle is demonstrated in Fig. 4. In panel Ža., afterload, as represented by arterial elastance, is graphically demonstrated as the negative slope of the line marked yEA ; end-systolic elastance is also shown, along with a normally loaded pressure᎐volume loop. In this example, arterial elastance exceeds end-systolic elastance, leading to inefficient energy transfer from the ventricle to the aorta. Graphically, one can see that the stroke work, or the area bounded by the pressure᎐volume loop, is a small proportion of the pressure᎐volume area, and the stroke volume is limited by afterload. By administration of medications, optimization of the EArEes ratio can improve the energy transfer from ventricle to the arterial system by lowering arterial elastance, increasing end-systolic elastance, or both. In Fig. 4b, infusion of a drug such as dobutamine has increased endsystolic elastance slightly, decreased arterial elastance, resulting in optimization of stroke work. The resultant increase in stroke volume from the same end-diastolic volume can be graphically seen. Further reduction in afterload may further increase efficiency of energy transfer from the ventricle to the arterial system w31x Another way of thinking about mismatched ventricular᎐vascular coupling is in terms of ventricular energetics. In the failing circulation, energy transfer from the ventricle to the arterial system is inefficient. Work efficiency can be studied and improved using pressure᎐volume analysis. In Fig. 4a, the stroke work, represented by the area within the pressure volume loop, is a smaller proportion of the pressure᎐volume area than in panel Žb.. Improvement of ventricular᎐ vascular coupling can lead to more efficient use of contractile energy, with less potential energy left at the end of contraction. Further reduction in afterload may allow for even greater stroke volume at the same level of contractile function.
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Fig. 4. Ventricular vascular coupling and efficiency of energy transfer from ventricle to the arterial system. A normally-loaded pressure᎐volume loop is shown in each panel, along with the end-systolic pressure᎐volume line, the slope of which is end-systolic elastance Ž Ees ., and the line representing arterial elastance Ž EA ., the slope of which is shown as yEA . Two different states of inotropy and afterload are shown. Ža. Under resting conditions, arterial elastance exceeds end-systolic elastance, causing a mismatch in loading conditions for inotropic state, and inefficient energy transfer from the ventricle to the arterial system. Žb. A drug such as dobutamine has been given, leading to a relatively small increase in end-systolic elastance, along with a reduction of arterial elastance. In this state, end-systolic elastance is approximately equal to arterial elastance, allowing for stroke work to be maximized. For the starting end-diastolic ventricular volume, stroke volume has been increased. Note also that the area within the pressure᎐volume loop Žstroke work. is a higher proportion of the pressure᎐volume area in Žb., indicating higher relative efficiency of energy transfer in this state.
6. Summary The use of pressure᎐volume relationships for evaluation of ventricular and circulatory function allows for examination of each of the circulatory conditions that may be associated with heart failure. Preload, afterload, diastolic and contractile function, ventricular᎐vascular coupling, and ventricular energetics can be separated from one another and examined during diagnostic evaluation of the heart. Newer techniques and equipment have facilitated the simultaneous measurement of left ventricular pressure and volume, mainly by allowing more rapid determination of accurate ventricular volumes. Analysis of function in the pressure᎐volume plane allows for measurement of indices of contractile function that are relatively independent of loading conditions. Furthermore, the use of these methods allows for pharmacologic manipula-
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tion and optimization of these different factors during functional evaluation of the heart and circulation to maximize effective cardiac output, and relieve patient symptoms.
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References
w15x
w1 x
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w6x w7x w8x
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w10x
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Frank O. Zur Dynamik des Herzmuskels. Z Biol 1895;32:370᎐447. Cited in: Sagawa K, Maughan L, Suga H, Sunagawa K. Introduction. Cardiac contraction and the pressure᎐volume relationship. New York: Oxford University Press, 1988:3᎐41.. Sarnoff SJ, Mitchell JH. The controls of the function of the heart. In: Hamilton WF, editor. Handbook of physiology. Washington, DC: American Physiological Society, 1962: 489᎐532. Suga H, Sagawa K. Instantaneous pressure᎐volume relationships and their ratio in the excised, supported canine left ventricle. Circ Res 1974;35:117᎐126. Baan J, Jong TT, Kerkhof PL et al. Continuous stroke volume and cardiac output from intra-ventricular dimensions obtained with impedance catheter. Cardiovasc Res 1981; 15:328᎐334. Kass DA, Midei M, Graves W, Brinker JA, Maughan WL. Use of a conductance Žvolume. catheter and inferior vena caval occlusion for rapid determination of pressure᎐volume relationships in man. Cathet Cardiovasc Diagn 1988;15: 192᎐202. Kass DA. Clinical evaluation of left heart function by conductance catheter technique. Eur Heart J 1992;13:57᎐64. Sunagawa K, Maughan WL, Burkoff D, Sagawa K. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983;245:H773᎐H780. Kass DA, Grayson R, Marino P. Pressure᎐volume analysis as a method for quantifying simultaneous drug Žamrinone. effects on arterial load and contractile state in vivo. J Am Coll Cardiol 1990;16:726᎐732. Kass DA, Maughan WL, Guo ZM, Kono A, Sunagawa K, Sagawa K. Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure᎐volume relationships. Circulation 1987;76:1422᎐1436. van der Velde ET, Burkhoff D, Steendijk P, Karsdon J, Sagawa K, Baan J. Nonlinearity and load sensitivity of endsystolic pressure᎐volume relation of canine left ventricle in vivo. Circulation 1991;83:315᎐327. Glower DD, Spratt JA, Snow ND et al. Linearity of the Frank᎐Starling relationship in the intact heart: the concept of preload recruitable stroke work. Circulation 1985;71: 994᎐1009. Little WC. The left ventricular dPrdtmax-end-diastolic volume relation in closed-chest dogs. Circ Res 1985;56: 808᎐815. Cassidy SC, Chan DP, Allen HD. Left ventricular systolic function, arterial elastance, and ventricular᎐vascular cou-
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pling: a developmental study in piglets. Pediatr Res 1997; 42:273᎐281. Cassidy SC, McGovern JJ, Chan DP, Allen HD. Effects of commonly used adrenergic agonists on left ventricular function and systemic vascular resistance in young piglets. Am Heart J 1997;133:174᎐183. Romero TE, Friedman WF. Limited left ventricular response to volume overload in the neonatal period: a comparative study with the adult animal. Pediatr Res 1979;13:910᎐915. Anderson PA, Glick KL, Manring A, Crenshaw Jr C. Developmental changes in cardiac contractility in fetal and postnatal sheep: in vitro and in vivo. Am J Physiol 1984;247: H371᎐H379. Teitel DF, Sidi D, Chin T, Brett C, Heymenn MA, Rudolph AM. Developmental changes in myocardial contractile reserve in the lamb. Pediatr Res 1985;19:948᎐955. Gaasch WH, Carroll JD, Blaustein AS, Bing OH. Myocardial relaxation: effects of preload on the time course of isovolumetric relaxation. Circulation 1986;73:1037᎐1041. Starling MR, Montgomery DG, Mancini GBJ, Walsh RA. Load independence of the rate of isovolumic relaxation in man. Circulation 1987;76:1274᎐1281. Grossman W, McLaurin LP, Stefadouros MA. Left ventricular stiffness associated with chronic pressure and volume overloads in man. Circ Res 1974;35:783᎐800. Sagawa K, Maughan L, Suga HKS. Cardiovascular interaction. Cardiac contraction and the pressure᎐volume relationship. New York: Oxford University Press, 1988:232᎐298. Sagawa K, Maughan L, Suga H, Sunagawa K. Energetics of the heart. Cardiac contraction and the pressure᎐volume relationship. New York: Oxford University Press, 1988:171᎐231. Suga H, Goto Y, Kawaguchi O et al. Ventricular perspective on efficiency. Basic Res Cardiol 1993;88:43᎐65. Baan J, van der Velde ET, de Bruin HG et al. Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 1984;70:812᎐823. Teitel DF, Klautz RJ, Cassidy SC et al. The end-systolic pressure᎐volume relationship in young animals using the conductance technique. Eur Heart J 1992;13:40᎐46. White P, Chaturvedi R, Shore D et al. Left ventricular parallel conductance during cardiac cycle in children with congenital heart disease. Am J Physiol 1997;273:H295᎐H302. Suga H, Hisano R, Goto YOY. Normalization of end-systolic pressure᎐volume relation and Emax of different sized hearts. Jpn Circ J 1984;48:136᎐143. van Campen L, Visser F, Visser C. Ejection fraction improvement by beta-blocker treatment in patients with heart failure: an analysis of studies published in the literature. J Cardiovasc Pharm 1998;32ŽSuppl 1.:S31᎐S35. Sharpe N. Beta-blockers in heart failure. Future directions. Eur Heart J 1996;17ŽSuppl B.:39᎐42. Eichhorn E. Restoring function in failing hearts: the effects of beta blockers. Am J Med 1998;104:163᎐169. Ishizaka S, Asanoi H, Kameyama T, Sasayama S. Ventricular-load optimization by inotropic stimulation in patients with heart failure. Int J Cardiol 1991;31:51᎐58.