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From: Essential Cardiology: Principles and Practice, 2nd Ed.
Edited by: C. Rosendorff © Humana Press Inc., Totowa, NJ
During the initial phase of contraction, the LV pressure builds up until it exceeds that in the left atrium (normally 10 to 15 mmHg), whereupon the mitral valve closes. With the aortic and mitral valves both shut, the LV volume cannot change and contraction must be isovolumic (iso = the same) until the aortic valve is forced open as the LV pressure exceeds that in the aorta. Once the aortic valve is open, blood is vigorously ejected from the LV into the aorta, which is the phase of maximal or rapid ejection. The speed of ejection of blood is determined both by the pressure gradient across the aortic valve and by the elastic properties of the aorta, which undergoes systolic expansion.
Ventricular Relaxation
After the LV pressure rises to a peak, it starts to fall. As the cytosolic calcium is taken up into the sarcoplasmic reticulum under the influence of active phospholamban, more and more myo- fibers enter the state of relaxation. As a result, the rate of ejection of blood from the aorta falls (phase of reduced ejection). Although the LV pressure is falling, blood flow is maintained by aortic recoil.
Next, the aortic valve closes as the pressure in the aorta exceeds the falling pressure in the LV. Now the ventricular volume is sealed, because both aortic and mitral valves are closed. The left ventri- cle therefore relaxes without changing its volume (isovolumic relaxation). Next, the filling phase of the cardiac cycle restarts as the LV pressure falls to below that in the left atrium, which causes the mitral valve to open and the filling phase to start.
Ventricular Filling Phases
The first phase of rapid or early filling accounts for most of ventricular filling. It starts very soon after mitral valve opening, as the LV pressure drops below that in the left atrium. In addition, some evidence shows that there is also active diastolic relaxation of the ventricle (ventricular suc- tion) that also contributes to early filling. In the next phase, diastasis (i.e., separation), LV filling tem- porarily stops as pressures in the atrium and ventricle equalize. Thereafter atrial contraction (atrial systole), also called the left atrial booster, renews ventricular filling by increasing the pressure gradient across the open mitral valve.
Definitions of Systole and Diastole
In Greek, systole means “contraction” and diastole means “to send apart.” For the physiologist, systole starts at the beginning of isovolumic contraction when LV pressure exceeds the atrial pressure. The start of cardiological systole, defined as mitral valve closure, corresponds reasonably well with the start of physiological systole, because mitral valve closure (M1) actually occurs only
about 20 ms after the onset of physiological systole at the crossover point of pressures. Thus in practice the term isovolumic contraction often also includes this brief period of early systolic con- traction before the mitral valve shuts, when the heart volume does not change substantially.
Cardiological systole is demarcated by the interval between the first and second heart sounds (Fig. 1), lasting from the first heart sound (M1) to A2, the point of closure of the aortic valve (1).
The remainder of the cardiac cycle automatically becomes cardiological diastole. Thus cardiolog- ical systole starts fractionally later than physiological systole but ends significantly later. By con- trast, from the physiological point of view, end-systole is just before the ventricle starts to relax, a concept that fits well with the standard pressure-volume curve. Thus, diastole commences as cal- cium ions are taken up into the sarcoplasmic reticulum, so that myocyte relaxation dominates over contraction, and the LV pressure starts to fall as shown on the pressure volume curve (Fig. 2).
In contrast stands another concept, argued by Brutsaert and colleagues (2), namely that diastole starts much later than the moment at which relaxation starts or at which the aortic valve closes, and only when the whole of the contraction-relaxation cycle is over. According to this view, diastole would occupy only a small portion of the pressure volume cycle (Fig. 1). This definition of diastole, although not often used in cardiological practice, does help to remind us that abnormalities of left ventricular contraction often underlie defective relaxation.
Contractility versus Load
Contractility is the inherent capacity of the myocardium to contract independently of changes in the preload or afterload. Increased contractility means a greater rate of contraction, to reach a
Fig. 1. The cardiac cycle, first assembled by Lewis in 1920, although conceived by Wiggers (19). Systole and diastole relate to cardiological, not physiological, phases: (1) mitral valve closure that occurs shortly after the crossover point of atrial and ventricular pressures at the start of systole; (2) aortic valve opening; (3) aortic valve closure; and (4) mitral valve opening. Note the four phases of diastole: isovolumic relaxation and three filling phases.
greater peak force. Often an increased contractility is associated with enhanced rates of relaxation, called the lusitropic effect. Alternate names for contractility are the inotropic state (ino, fiber;
tropos, to move) or the contractile state. Contractility is an important regulator of the myocardial oxygen uptake. Factors that increase contractility include adrenergic stimulation, digitalis, and other inotropic agents. At a molecular level, an increased inotropic state is enhanced interaction between calcium ions and the contractile proteins. Such an interaction could result either from increased calcium transients or from sensitization of the contractile proteins to a given level of cyto- solic calcium. Calcium-sensitizing drugs act by the latter mechanism, and conventional inotropes such as digitalis through an increase of internal calcium.
Preload and Afterload
Contractility is therefore a common part of the essential cardiological language. It is important to stress that any change in the contractile state must occur independently of the loading conditions.
The two types of load are the preload and the afterload. The preload is the load present before contraction has started, at the end of diastole. The preload reflects the venous filling pressure that fills the atrium and hence the left ventricle during diastole. The afterload is the systolic load on the left ventricle after it has started to contract. When the preload increases, the left ventricle dis- tends during diastole, and the stroke volume rises according to Starling’s law (see next section). The heart rate also increases by stimulation of the atrial mechanoreceptors that enhance the rate of discharge of the sinoatrial node. Thus, the cardiac output (stroke volume times heart rate) rises.
Venous Return and Heart Volume: Starling’s Law of the Heart
Starling (3) related the venous pressure in the right atrium to the heart volume in the dog heart- lung preparation (Fig. 3). He concluded that “[w]ithin physiological limits, the larger the volume of the heart, the greater the energy of its contraction and the amount of chemical change at each contraction.”
Thus, assuming that an increased diastolic heart volume means that the end-diastolic fiber length increases, Starling’s law is often paraphrased to mean that (1) an increased right atrial venous filling pressure translates into an increased left ventricular end diastolic fiber length, and (2) this
Fig. 2. Pressure-volume loop. Normal left ventricular pressure-volume relationship. The aortic valve opens at b and closes at c. The mitral valve opens at d and closes at a. External work is defined by a, b, c, d while potential energy (less accurately called internal work) is given by the triangle e, d, c. The pressure-volume area is the sum of external work and potential energy.
increase in length increases the force of contraction and hence the stroke volume. Because the heart volume is difficult to determine even with modern echocardiographic techniques, the left ventricular diastolic filling pressure (the difference between the left atrial pressure and the left ventricular diastolic pressure) is often taken as a surrogate for heart volume. This is important because the venous filling pressure can be measured in humans, albeit indirectly, by the technique of Swan-Ganz catheterization (Fig. 4), as can the stroke volume. Nonetheless, there is a defect in this reasoning. The left ventricular pressure and volume are not linearly related because the myo- cardium cannot continue to stretch indefinitely. Rather, as the left ventricular end-diastolic pressure increases, so does the cardiac output reach a plateau. The LV volume can now be directly measured with two-dimensional echocardiography. Yet the value found depends on a number of simplifying assumptions such as a spherical LV shape and neglects the confounding influence of the complex anatomy of the left ventricle. In practice, the LV volume is not often measured. Therefore, although the Starling concept is valuable and underlies the hemodynamic management of those critically ill and receiving a Swan-Ganz catheter, several approximations are required to make these concepts clinically applicable.
Frank and Isovolumic Contraction
Starling emphasized that increasing the heart volume increased the initial length of the muscle fiber and thereby increased the stroke volume and cardiac output, which suggested but did not prove that diastolic stretch of the LV increased the force of contraction. In fact, his German predecessor, Frank, had already in 1895 (4) studied the relation between filling pressure and the force of con- traction in an isolated heart (Fig. 5). He found that the greater the initial volume, the more rapid the rate of rise, the greater the peak pressure reached, the faster the rate of relaxation. Frank was there- fore able to show that an increasing diastolic heart volume stimulated the ventricle to contract more rapidly and more forcefully, which is a positive inotropic effect. Thus the earlier observations of Frank could explain the contractile behavior of the heart during the operation of Starling’s law. These findings of Frank and Starling are so complementary that they often referred to as the Frank-Starling Law. The beauty of the dual name is that between the two they described what accounts for the increased stroke volume of exercise, namely both the increased inotropic state (4) and the increased diastolic filling (3).
Fig. 3. Starling’s law of the heart as applied to the preload (venous filling pressure). As the preload increases (bottom in both figures), the heart volume increases (left top), as does the cardiac output (right top). Starling’s explanation was: “The output of the heart is a function of its filling; the energy of contraction depends on the state of dilatation of the heart’s cavities” (3).
Fig. 4. A family of Starling curves with relevance to Swan-Ganz catheterization. Each curve relates the filling pressure (pulmonary capillary wedge pressure, PCWP) to the left ventricular (LV) stroke output and to the cardiac output. Note that the depressed inotropic state of the myocardium causes an abnormally low curve and that the downward limb can be related to an increased afterload. Clinically the measurements relating fill- ing pressure to cardiac output are obtained by Swan-Ganz catheterization (a procedure presently undertaken less frequently than previously). Note the close association between LV diastolic dysfunction and pulmonary congestion. LA, left atrium; CHF, congestive heart failure (Copyright © L.H. Opie, 2004.)
Fig. 5. Frank’s family of isometric (isovolumic) curves. Frank related heart volume to what would now be recognized as an index of contractility, a term not known then, as can be seen if two tangential lines are added to the curves of the original figure. In modern terms, these lines give the maximal rate of change of the intra- ventricular pressure (dP/dt max). Each curve was obtained at a greater initial filling of the left ventricle by an increased left atrial filling pressure. Then valves were shut to produce isovolumic conditions. Curve 6 has a greater velocity of shortening. Hence, the initial fiber length (volume of ventricle) can influence contrac- tility. The line on curve 6 has the much steeper slope and, therefore, indicates a greater rate of contraction or a greater, in contrast to the line drawn on curve 1, which ascends more slowly and indicates a lower contractile state. (Figure based on author’s interpretation of ref. 4.)
Afterload
Starling and his colleagues gave a simple picture of the how an acute change in the afterload could influence an isolated muscle: (3): “The extent to which it will contract depends on... the amount of the weight which it has to overcome” and “the tension aroused in it.”
In clinical practice, arterial blood pressure is one of three important measures of the afterload, the others being any aortic stenosis and aortic compliance—the extent to which the aorta can “yield”
during systole. Aortic impedance is an index of the afterload and is the aortic pressure divided by the aortic flow of that incidence, so that the afterload varies during each phase of the contraction cycle.
Preload and Afterload Are Interlinked
In practice, it is often difficult to separate preload from afterload. During the start of exercise, the venous return and the preload increase. When the left ventricle then starts to contract, the tension in the left ventricular wall will be higher because of greater distention of the left ventricle by the greater pressure. The load during systole also will rise, and the afterload will increase. Nonetheless, in general, the preload is related to the degree to which the myocardial fibers are stretched at the end of diastole, and the afterload is related to the wall stress generated by those fibers during systole.
CELLULAR BASIS OF CONTRACTILITY AND STARLING’S LAW Length-Dependent Activation
How could an increased end-diastolic muscle length increase the force and rate of muscular contraction? Previously this effect of increased muscle length was ascribed to a more “optimal”
overlap between actin and myosin. Intuitively, however, if actin and myosin are stretched further apart, there would be less rather than more overlap. Another earlier proposal—that troponin C, one of the contractile proteins, is the length sensor—is currently less favored. A more current view is that there is a complex interplay between anatomic and regulatory factors (5), including the concept that an increased sarcomere length leads to greater sensitivity of the contractile apparatus to the prevailing cytosolic calcium. The major mechanism for this regulatory change, although not yet clarified, may reside in the interfilament spacing (6). At short sarcomere lengths, as the lattice spacing increases, the number of strong cross bridges decreases (7). Conversely, as the heart mus- cle is stretched, the interfilament distance decreases (Fig. 6), and, hypothetically, there is an increased rate of transition from the weak to the strong binding state.
bbbbb-Adrenergic Stimulation, Contractility, and Calcium (Fig. 7)
b-Adrenergic stimulation mediates the major component of its inotropic effect through increas- ing the cytosolic calcium transient and the factors controlling it. The following are all enhanced:
the rate of entry of calcium ions through the sarcolemmal L-type channels, the rate of calcium uptake under the influence of phospholamban into the sarcoplasmic reticulum (SR), and the rate of calcium release from the ryanodine receptor on the SR in response to calcium entry, which in turn follows depolarization. Of all these factors, phosphorylation of phospholamban may be most important (8), acting on the calcium uptake pump of the SR to increase the rate of uptake of calcium during diastole. Thereby the SR is preloaded with increased Ca so that more can be liberated during ensuing depolarizations.
Conversely, contractility is decreased whenever calcium transients are depressed, as when b- adrenergic blockade decreases calcium entry through the L-type calcium channel. Alternatively, there may be faulty control of the uptake and release of calcium ions by the SR, as when the SR is damaged in congestive heart failure. Anoxia or ischemia deplete the calcium uptake pump of the SR of the ATP required for calcium uptake, so that the contraction-relaxation cycle is inhibited.
Problems With the Contractility Concept
The concept of contractility has at least two serious defects, including first the absence of any potential index that can be measured in situ and is free of significant criticism, especially the absence
Fig. 6. Length-dependent activation. A volume load extends the anterior segment length, which corresponds to the diastolic volume in Starling’s observations. The result is that the resting PV loop (loop 1) increases in area and in peak left ventricular systolic pressure (see loops 2 and 3). This is the Starling effect (also see legend to Fig. 9). After a few minutes (broken lines and shaded area) contractility increases modestly, pushing the length-pressure slope upwards and to the left, an example of length-dependent activation. (Figure based on data extracted from ref. 23 with permission of Lippincott Williams & Wilkins.)
of any acceptable noninvasive index; and second, the impossibility of separating the cellular mech- anisms of contractility changes from those of load or heart rate. Thus, an increased heart rate acts by the sodium pump lag mechanism to give rise to an increased cytosolic calcium, giving the in- creased force of contraction of the Bowditch or treppe phenomenon. An increased preload involves increased fiber stretch, which in turn causes length activation, thought to be explicable in part by sen- sitization of the contractile proteins to the prevailing cytosolic calcium concentration. An increased afterload may indirectly, through stimulation of stretch-sensitive channels, increase cytosolic cal- cium. Thus, in relation to the underlying cellular mechanisms, there is a clear overlap between con- tractility (which should be independent of load or heart rate) and the effects of myocyte stretch and heart rate, which have some effects that could be called an increase in contractility.
In clinical terms, it nonetheless remains important to separate the effects of a primary increase of load or heart rate, on the one hand, from a primary increase in contractility, on the other. This distinction is especially relevant in congestive heart failure, where a decreased contractility could indirectly or directly result in increased afterload, preload, and heart rate, all of which could then predispose to a further decrease in myocardial performance. Because muscle length can influence contractility, the traditional separation of length and inotropic state into two independent regulators of cardiac muscle performance is no longer true if the end result is considered. However, it remains true that b-adrenergic stimulation has a calcium-dependent positive inotropic effect independent of loading conditions, which is therefore a true positive inotropic effect.
CARDIAC OUTPUT
The definition of cardiac output is the product of the stroke volume (SV) and the heart rate (HR):
Cardiac output = SV ´ HR (units = liters per minute)
The normal value is about 6–8 L/min, doubling or sometimes even trebling during peak aerobic exercise. The stroke volume is determined by the preload, the afterload, and the contractile state.
Heart rate is also one of the major determinants of myocardial oxygen uptake. The heart rate responds to a large variety of stimuli, each of which thereby indirectly alters myocardial oxygen
uptake. The three physiological factors most consistently increasing heart rate are exercise, waking up in the morning, and emotional stress.
Heart Rate
Each cycle of contraction and relaxation performs a certain amount of work and takes up a certain amount of oxygen. The faster the heart rate, the higher the cardiac output and the higher the oxygen uptake. Exceptions are: (1) when the heart rate is extremely fast, as may occur during a paroxysmal tachycardia, because an inadequate time for diastolic filling decreases the cardiac output; and (2) in coronary artery disease when lower degrees of tachycardia decrease the stroke volume because of ischemic failure of the left ventricle.
Force-frequency relation. An increased heart rate progressively increases the force of ven- tricular contraction even in an isolated papillary muscle preparation (Bowditch staircase or treppe phenomenon). In isolated human ventricular strips, increasing the stimulation rate from 60 to about 160 per minute stimulates force development. In strips from failing hearts, there is no such increase (9). In the human heart in situ, pacing rates of up to 150 per minute can be tolerated, whereas higher
Fig. 7. b-Adrenergic signal systems, when activated, lead to changes in the cardiac calcium cycle that explain positive inotropic and lusitropic (enhanced relaxation) effects. When the b-adrenergic agonist interacts with the b-receptor, a series of G protein-mediated changes lead to activation of the stimulatory G protein, Gs, that interacts with GTP (guanosine triphosphate) that in turn activates adenylate cyclase (shown as cyclase) to form the adrenergic second messenger, cyclic adenosine monophosphate (cyclic AMP). The latter acts via protein kinase A (PKA) to phosphorylate phospholamban and to increase the activity of the calcium uptake pump on the sarcoplasmic reticulum (SR), hence decreasing cytosolic calcium and explaining the lusitropic (relaxant) effect of adrenergic stimulation. PKA also phosphorylates calcium channel protein. The result is an enhanced opening probability of the calcium channel, thereby increasing the inward movement of Ca2+
ions through the sarcolemma of the T tubule. Additionally, active Gs directly activates the calcium channel opening. More Ca2+ ions enter the cytosol, to release more calcium from the ryanodine release channel of the SR, rapidly to increase cytosolic calcium levels. The result is increased activation of troponin-C, explaining increased peak force development as result of adrenergic stimulation (positive inotropic effect). (Copyright
© L.H. Opie, 2004.)
In these conditions; however, there is also an accompanying tachycardia, as during drug-induced vasodilation. Conversely, when the afterload increases, there is initially a compensatory mecha- nism, possibly acting by increased end-diastolic fiber-stretch, to increase contractility (Fig. 5) and to maintain the stroke volume. If the afterload keeps rising, compensatory mechanisms cannot adapt, and eventually the stroke volume will fall. In exercise, although the peripheral vascular resistance decreases, systolic blood pressure rises, and the afterload increases. Thus, at really high rates of upright exercise, the stroke volume falls even though the cardiac output continues to rise, the latter as a result of heart rate increases (11). In congestive heart failure with a failing left ventri- cle, the stage at which the stroke volume and hence the cardiac output starts to fall in response to the excess “compensatory” peripheral arteriolar constriction is much sooner than with the normal left ventricle.
Contractility and Cardiac Output
During b-adrenergic stimulation or exercise, the contractile state is enhanced to contribute to the increased cardiac output. Conversely, during congestive heart failure or therapy with b-adrenergic blockade, decreased contractility means a decreased stroke volume.
EFFECTS OF EXERCISE
During dynamic exercise the cardiac output can increase severalfold (Fig. 8). There are three possible explanations: an increased heart rate, increased contractility, and an increased venous return. In humans, an increased heart rate provides most of the increased cardiac output, with the Starling mechanism and increased contractility playing lesser roles (11).
Tachycardia of Exercise
The mechanism of the increase in heart rate during exercise is a combination of withdrawal of inhibitory vagal tone and increased b-adrenergic stimulation. The signals for these changes come from the vasomotor center in the brainstem, which coordinates two types of input: one is from the cerebral cortex (e.g., the runner’s “readiness to go” at the start of exercise), and the second is the Bainbridge reflex. The latter is stimulated by atrial distention, following the increased venous return during exercise. However, this is but a modest effect in humans. A tachycardia, from what- ever cause, can further invoke a positive inotropic effect by the Bowditch (treppe) effect.
Venous Return During Exercise
Starling postulated (but did not measure) events at the start of exercise as follows: “If a man starts to run, his muscular movements pump more blood into the heart, so increasing the venous filling” (3). Because the cardiac output must equal the venous return, the increase in cardiac output during exercise must reflect an equal increase in the venous return. This increase does not, however,
necessarily prove the operation of the Starling mechanism, which requires an increased venous fill- ing pressure. If there were an increased contractility from b-adrenergic stimulation during exer- cise, then the venous filling pressure could actually fall, despite the increase in the venous return.
To be sure of the events at the start of exercise in humans would need simultaneous measurements of venous return, of the venous filling pressure, and of the heart volume. Such data are missing. None- theless, the combination of increased venous return and sympathetic stimulation can give extrapo- lated explanations.
An increased venous return and filling pressure could explain the increased diastolic heart vol- ume during exercise, as found in radionuclide studies (12,13). Cardiac failure can be excluded, because the end-systolic volume decreases and the stroke volume increases. The Starling mecha- nism appears to operate in both supine and upright postures when low-level exercise is compared with rest (12). This sequence is not inviolate, and may be altered by posture (14), by exercise train- ing (15), and by increased contractility. Thus the three major changes during exercise are first, the increase in venous return, which increases the venous filling pressure when comparing the initiation of exercise with rest; second, this increase usually but not invariably evokes a Starling response;
and third, sympathetic stimulation with an increased heart rate and contractility contribute vari- ably but importantly. Once exercise has been initiated, the venous return must stay high and equal the cardiac output. The decrease in the systemic vascular resistance helps to keep the cardiac out- put and venous return high. The end result is that the increased venous return and increased cardiac output will have achieved a new enhanced equilibrium.
Regarding static exercise, the major hemodynamic differences from dynamic exercise are (1) the lesser rise in heart rate; (2) the greater rise in blood pressure; (3) the absence of increases in stroke volume and cardiac output (Fig. 8).
Fig. 8. Static vs dynamic exercise. Static exercise, at 30% of maximum voluntary contraction (MCV), caused a much larger rise in mean blood pressure than did dynamic exercise, first at oxygen consumption values of 28.5 mL/kg/min and then at 43.8 mL/kg/min. Conversely, dynamic exercise increased heart rate much more.
For original data, see ref. 20. Data on stroke volume are extrapolated from ref. 11. Peripheral vascular resis- tance (PVR) for 0–2 min is based on ref. 21 and for 2–4 min on Lind and McNicol, shown above, in which the blood pressure rises markedly at 2–4 min of static exercise even when the rise in heart rate has leveled off; therefore the PVR must have increased. (Figure derived from author’s analysis of conjoint data of above references.)
against the mass of that load. In many cases, it is not possible to define force with such exactitude but, in general, force has the following properties. First, force is always applied by one object (such as muscle) on another object (such as a load). Second, force is characterized both by the direction in which it acts, and its magnitude. Hence, it is a vector, and the effect of a combination of forces can be established by the principle of vectors. Third, each object exerts a force on the other, so that force and counterforce are equal and opposite (Newton’s third law of motion).
Tension exists when the two forces are applied to an object so that the forces tend to pull the object apart. When a spring is pulled by a force, tension is exerted; when more force is applied, the spring stretches, and the tension increases.
Stress develops when tension is applied to a cross-sectional area, and the units are force per unit area. According to the Laplace law:
Wall stress = pressure ´ radius 2 ´ wall thickness
The increased wall thickness due to hypertrophy balances the increased pressure, and the wall stress remains unchanged during the phase of compensatory hypertrophy. In congestive heart failure, the heart dilates to increase the radius factor, thereby elevating wall stress. Furthermore, because ejection of blood is inadequate, the radius stays too large throughout the contractile cycle, and both end-diastolic and end-systolic tensions are higher.
Wall Stress and Myocardial Oxygen Demand
At a fixed heart rate, the myocardial wall stress is the major determinant of the myocardial oxygen uptake. Because myocardial oxygen uptake ultimately reflects the rate of mitochondrial metabolism and ATP production, any increase of ATP requirement will be reflected in an increased oxygen uptake. It is not only external work that determines the requirement for ATP. Rather, ten- sion development (increased wall stress) is oxygen-requiring even without external work being done. The difference between external work and tension developed can be epitomized by a man standing and holding a heavy suitcase, doing no external work yet becoming very tired, compared with the man lifting a much lighter suitcase, doing external work yet not tired. The greater the left ventricular chamber size, the greater the radius, the greater the wall stress. Hence, ejection of the same stroke volume from a large left ventricle against the same blood pressure will produce as much external work as ejection of the same stroke volume by a normal size left ventricle, yet with a much greater wall stress in the case of the larger ventricle. Therefore, more oxygen will be required. In clinical terms, heart size is an important determinant of myocardial oxygen uptake.
In a patient with angina and a large left ventricle the appropriate therapy is to reduce left ventricu- lar size, which will also lessen the myocardial oxygen demand.
The overall concept of wall stress includes afterload because an increased afterload generates an increased systolic wall stress. Wall stress also includes preload, which generates diastolic wall stress. Wall stress increases in proportion to the pressure generated and to the radius of the left ven- tricular cavity, factors that are responsive to increases in afterload and preload respectively. Wall stress allows for energy required for generation of muscular contraction that does not result in exter- nal work. Furthermore, in states of enhanced contractility, wall stress is increased. Thus, thinking in terms of wall stress provides a comprehensive approach to the problem of myocardial oxygen uptake. Apart from a metabolic component that is usually small but may be prominent in certain special circumstances, such as when circulating free fatty acids are abnormally high, changes in heart rate and wall stress account for most of the clinically relevant changes in myocardial oxygen uptake.
External versus Internal Work and Oxygen Demand
Bearing in mind that the major factor in cardiac work is the product of pressure and volume, it follows that external work can be quantified by the integrated pressure-volume area that represents the product of the systolic pressure and the stroke volume. To relate work to oxygen consumption, account must be taken of both the external work (a,b,c,d in Fig. 2) and internal work, which is the volume-pressure triangle joining the end-systolic volume-pressure point to the origin (c,d,e). The latter is more correctly called the potential energy, being the work generated in each contractile cycle that is not converted to external work.
Pressure versus Volume Work and Oxygen Demand
In analyzing the difference between oxygen cost of pressure work and volume work, the estab- lished clinical observation is that the myocardium can tolerate a chronic volume load better than a pressure load. Thus when cardiac work is chronically increased by augmenting the afterload, as during severe hypertension or narrowing of the aortic valve by aortic stenosis, the peak systolic pres- sure in the left ventricle must increase, and pressure power increases. However, because of the complex way in which the muscle fibers of the myocardium run, a greater proportion of the work is against the internal resistance. The result is that the efficiency falls. An extreme example of the loss of efficiency during pressure work would be if the aorta were completely occluded, so that none of the work would be external and all would be internal. Internal work is done against the non- contractile elements of the myocardium and is not useful work in terms of calculating efficiency.
When the heart is subject to a chronic volume load, as in mitral regurgitation, the increased work that the heart must perform is met by an increased end-diastolic volume. The myofibers stretch, and length-dependent activation occurs. The primary adaptation to increased heart volume is an in- creased fiber length and not increased pressure development, so that the amount of external work done is more, but that against the internal resistance is unchanged so that the efficiency of work rises.
(The efficiency of work relates the amount of work performed to the myocardial oxygen uptake.) LEFT VENTRICULAR FUNCTION
Maximal Rate of Left Ventricular Pressure Generation
In relation to the cardiac contraction-relaxation cycle, it is easiest to consider left ventricular func- tion during the early period of isovolumic contraction. During this period of isovolumic contraction, the preload and afterload are constant, and the maximal rate of pressure generation should be an index of the inotropic state:
inotropic index = dP/dt max
where P is left ventricular pressure, t is time, and d indicates rate of change. Unfortunately, this index, which has stood the test of years, is not fully load-independent—as Frank showed (Fig. 5), increasing the preload enhances the contractile state by length-activation.
In humans, the measurements required for dP/dt can be obtained only by left ventricular catheter- ization except in mitral regurgitation, when Doppler echocardiography can measure changes in
niques, is one of the most frequently used indices and one of the least sensitive. The ejection frac- tion relates stroke volume to end-diastolic volume and is therefore an index of the extent of left ventricular fiber shortening. Nonetheless, this index is easy to obtain and particularly useful in evaluating the course of chronic heart disease. Because the ejection fraction measures the contractile behavior of the heart during systole, it is by definition afterload-sensitive. Another defect is that the ejection fraction relates the systolic emptying to the diastolic volume without measuring that volume, and the left ventricle could theoretically be markedly enlarged yet have reasonable systolic function by this measure. Thus, the correlation between the degree of clinical heart failure and the decrease in the ejection fraction is often only imperfect.
Echocardiographic Indices of Contractile State
The major advantages of echocardiographic indices is that the techniques are widely available and relatively rapid. Fractional shortening uses the percentage of change of the minor axis (defined in the next paragraph) of the left ventricular chamber during systole. An approximation often used by clinicians is to estimate the ejection fraction from fractional shortening. Despite obvious defects, this easily defined index is pragmatically useful in the management of heart failure. More accurately, ejection fraction can be determined from volume measurements.
The end-systolic volume reflects contractile state because the normal left ventricle ejects most of the blood present at the end of diastole (ejection fraction exceeds 55%). Impaired contractility, shown by an abnormally increased end-systolic volume, is a powerful predictor of adverse prog- nosis after myocardial infarction (17). The end-diastolic volume is a less powerful predictor but essential for the accurate measurement of the ejection fraction.
Increasingly sophisticated and noninvasive measurements of the pumping function of the heart can be obtained with echocardiographic techniques. The velocity at which the circumference of the heart in its minor axis (the distance from the left side of the septum to the posterior endocardial wall) changes during systole is one useful index of myocardial contractility. The mean velocity of circumferential fiber shortening (mean Vcf) can be determined from echocardiographic measure- ments of the end-diastolic and end-systolic sizes and the rate of change. The difference between the calculated circumferences is divided by the duration of shortening, which is the ejection time. Even more sophisticated are the data now being generated by tissue Doppler imaging. This technique that records high-amplitude, low-frequency Doppler shifts, from which the endocardial and mid- myocardial velocity of systolic change can be calculated, is currently one of the best indices of con- tractility of the human heart in situ.
Contractility Indices Based on Pressure-Volume Loops
There are two fundamental aspects of the Frank-Starling relationship that can be seen readily in a pressure-volume loop. First, as the preload increases, the volume increases. On the other hand,
for any given preload (initial volume of contraction), a positive inotropic agent increases the amount of blood ejected, and for the same final end-systolic pressure, there is a smaller end-systolic vol- ume. Thus, in response to beta-adrenergic stimulation the slope of the end-systolic pressure-volume relationship is increased at the same time that the venous return rises and the left ventricular end-sys- tolic pressure increases (Fig. 9). It follows that relating pressure to volume is one way of assessing both the Starling effect and the contractility of the left ventricle.
Accordingly, measurements of pressure-volume loops remain among the best of the current approaches to the assessment of the contractile behavior of the intact heart, and hence the key to one of the major determinants of the myocardial oxygen demand. The end-systolic pressure- volume relation can be estimated noninvasively from the arterial systolic pressure and the end- systolic echocardiographic dimension. Invasive measurements of the left ventricular pressure are required for the full loop, which is an indirect measure of the Starling relationship between the force (as measured by the pressure) and the muscle length (measured indirectly by the volume).
It is proposed that conditions associated with a higher contractile activity (increased inotropic state) will have higher end-systolic pressures at any for a given end-systolic volume, will have a steeper slope Es and have correspondingly higher oxygen uptakes. Although useful, like all sys- tolic phase indices, it is still not fully afterload-independent.
DIASTOLE AND DIASTOLIC FUNCTION
Among the many complex cellular factors influencing ventricular relaxation, four are of chief interest. First, the cytosolic calcium level must fall to cause the relaxation phase, a process requir- ing ATP and phosphorylation of phospholamban for uptake of calcium into the sarcoplasmic retic- ulum. Second, the inherent viscoelastic properties of the myocardium are of importance. In the hypertrophied heart, relaxation occurs more slowly. Third, increased phosphorylation of troponin
Fig. 9. b-Adrenergic versus volume effects on pressure-volume (PV) loops. Contrasting effects of b-adrenergic stimulation and effects of volume loading on the slope Es (end-systolic point), which is a good index of contrac- tility. Upon b-adrenergic stimulation, the control loop with its end-systolic point number 1 becomes the loop with point number 2. Likewise, the volume-loaded loop with point number 3 becomes the loop with point num- ber 4 upon b-adrenergic stimulation. The mechanism of the volume response probably involves stretch of the molecular spring, titin (22). Note that b-adrenergic stimulation induces a marked positive inotropic effect (increased contractility) as shown by the increased slope of the line Es that joins the end-systolic points. By contrast, the effects of increased ventricular volume with increased PV loop area and increased external work occur with no early change in contractility as here, and with only a small delayed increase in contractility (Figs. 3–6). (Figure based on data extracted from ref. 24 with permission of Lippincott Williams & Wilkins.)
The isovolumic relaxation phase of the cardiac cycle is energy-dependent, requiring ATP for the uptake of calcium ions by the SR, which is an active, not a passive, process. Impaired relaxation is an early event in angina pectoris. A proposed metabolic explanation is that there is impaired generation of energy, which diminishes the supply of ATP required for the early diastolic uptake of calcium by the sarcoplasmic reticulum. The result is that the cytosolic calcium level, at a peak in systole, delays its return to normal in the early diastolic period. In other conditions, too, there is a relationship between the rate of diastolic decay of the calcium transient and diastolic relaxa- tion, with a relation to impaired function of the sarcoplasmic reticulum. When the rate of relaxa- tion is prolonged by hypothyroidism, the rate of return of the systolic calcium elevation is likewise delayed, whereas opposite changes occur in hyperthyroidism. In congestive heart failure, diastolic relaxation also is delayed and irregular, as is the rate of decay of the cytosolic calcium elevation.
Most patients with coronary artery disease have a variety of abnormalities of diastolic filling, prob- ably related to those also found in angina pectoris. Theoretically, such abnormalities of relaxation are potentially reversible because they depend on changes in patterns of calcium ion movement.
Phases of Diastole
Hemodynamically, diastole can be divided into four phases, using the clinical definitions of diastole according to which diastole extends from aortic valve closure to the start of the first heart sound. The first phase of diastole (see preceding section) is the isovolumic phase, which, by defi- nition, does not contribute to ventricular filling (Fig. 10). The second phase of early (rapid) filling provides most of ventricular filling. The third phase of slow filling or diastasis accounts for only 5%
of the total filling. The final atrial booster phase accounts for the remaining 15%.
Atrial Function
The left atrium, besides its well-known function as a blood-receiving chamber, also acts as fol- lows: First, by presystolic contraction and its booster function, it helps to complete LV filling (18).
Second, it is the volume sensor of the heart, releasing atrial natriuretic peptide (ANP) in response to intermittent stretch. Third, the atrium contains receptors for the afferent arms of various reflexes, including mechanoreceptors that increase sinus discharge rate, thereby making in humans only a small contribution to the tachycardia of exercise as the venous return increases (Bainbridge reflex).
The atria have a number of differences in structure and function from the ventricles, having smaller myocytes with a shorter action potential duration as well as a more fetal type of myosin (both in heavy and light chains). Furthermore, the atria are more reliant on the phosphatidylinositol signal transduction pathway, which may explain the relatively greater positive inotropic effect in the atria than in the ventricles in response to angiotensin II. The more rapid atrial repolarization is thought to be due to increased outward potassium currents, such as Ito and IkACh. In addition, some atrial cells have the capacity for spontaneous depolarization. In general, these histologic and
physiologic changes can be related to the decreased need for the atria to generate high intrachamber pressures, rather than being sensitive to volume changes, while retaining enough contractile action to help with LV filling and to respond to inotropic stimuli.
Diastolic Dysfunction in Hypertrophy and Failure
In hypertrophic hearts, as in chronic hypertension or severe aortic stenosis, abnormalities of diastole are common and may precede systolic failure, from which there are a number of important differences. The mechanism is not clear, although it is thought to be related to the extent of ven- tricular hypertrophy or indirectly to a stiff left atrium. Conceptually, impaired relaxation must be distinguished from prolonged systolic contraction with delayed onset of normal relaxation. Experi- mentally, there are several defects in early hypertensive hypertrophy, including decreased rates of contraction and relaxation and decreased peak force development. Loss of the load-sensitive com- ponent of relaxation may be due to impaired activity of the sarcoplasmic reticulum. Impaired relax- ation is associated with an increase of the late (atrial) filling phase, so that the ratio E/A (early to atrial filling phases) on the mitral Doppler pattern declines. In time, with both increased hypertrophy and the development of fibrosis, LV chamber compliance decreases and the E wave again becomes more prominent. Thus is becomes difficult to separate truly normal from pseudonormal patterns of mitral inflow.
In myocardial failure, there are also multiple abnormalities that can be detected in the trans- mitral flow pattern, including an early change in the E/A ratio. It must be stressed that the E/A ratio
Fig. 10. Diastolic filling phases. Top panel, recording of left ventricular pressure (PLV), left atrial pressure (PLA), and left ventricular volume (VLV). Middle panel, magnified scale of changes in PLV and PLA. Lower panel, rate of change of LV volume (dV/dt), an indication of the rate of left ventricular filling, which occurs early in diastole and then again during atrial systole in response to pressure gradient from the left atrium to the left ventricle. In between is the phase of slow filling or diastasis. The early diastolic pressure gradient shown in the middle panel is generated as LV pressure falls below left atrial pressure and the late diastolic gradient is generated as atrial contraction increases left atrial pressure above LV pressure. (Figure based on author’s interpretation of data presented in ref. 25.)
omyopathy. In angina, the increased temporary stiffness probably is caused by a combination of a rise of intracellular calcium and of altered myocardial properties. In myocardial infarction, the connective tissue undergoes changes after 40 min of occlusion. Eventually healing and fibrosis per- manently increase stiffness. When muscle stiffness increases, so will chamber stiffness (the chamber referred to is the ventricle).
The opposite of stiffness is compliance (dV/dP)—as the heart stiffens, compliance falls. The term diastolic distensibility may be used instead of compliance. Distensibility refers not to the slope of the pressure-volume relation but to the diastolic pressure required to fill the ventricle to the same volume. Thus, when stiffness increases and compliance falls, the distensibility is less, as in the failing human heart. The compliance of the heart influences the Starling curve in that a stiffer heart will be on a lower Starling curve. The pressure-volume loop and the early diastolic filling rate of the heart will also change, while the baseline of the pressure-volume loop will rise upward more steeply, so that a higher left atrial pressure will be required for early diastolic filling. For these reasons, stiff- ness and compliance are fundamental mechanical properties of the heart.
CONTRACTILE PROPERTIES IN HUMAN HEART DISEASE
The failing human myocardium has many impaired mechanical properties. Thus even though the venous filling pressure is more than adequate, the Starling mechanism is upset and the stroke volume is reduced when compared with normal, so that the blood pressure tends to fall. An increased heart rate provides some compensation to help maintain the cardiac output and, thereby, the blood pressure. However, the normal treppe or Bowditch effect, whereby a faster stimulation rate increases the force of contraction, is severely diminished or even lost so that the tachycardia of exercise fails to increase the stroke volume in heart failure. Homeostatic mechanisms that come into play, such as renin-angiotensin-aldosterone system activation, sustain the blood pressure usually at a lower level than previously but with an increased afterload. The severely failing myocardium undertakes this challenge at the cost of decreased efficiency of work. Thus the pressure-volume loop changes so that internal work is increased relative to the lesser output of external work. Other defects include an impaired response to an increased preload, defective generation of cyclic AMP in response to b-adrenergic stimulation and numerous defects of the patterns of handling of intracellular calcium.
These depend both on the abnormalities of the ryanodine receptor of the sarcoplasmic reticulum with hyperphosphorylation and on defects in the uptake of calcium from the cytosol by the calcium uptake pump. These changes result in a variety of different abnormalities of the patterns of contraction and relaxation of the failing myocardium, often with a delayed rise and fall in the calcium transients.
Furthermore, when there is an increase in the afterload of isolated human trabecular myocardium from the severely failing human heart, the intracellular calcium transient becomes abnormally pro- longed and exaggerated pattern of rise, despite poor generation of force (16). This discrepancy
between the patterns of the calcium transient and the contractile response of the severely failing heart could be explained by the abnormal mechanical properties of the myocytes, such as an increase in the stiffer isoform of titin.
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RECOMMENDED READING
Katz AM. Physiology of the Heart, 3rd ed. Chapters 8 and 11. Lippincott Williams & Wilkins, Philadelphia, 2001.
Opie LH. Heart Physiology: From Cell to Circulation. Chapter 12. Lippincott Williams & Wilkins, Philadelphia, 2004.
Opie LH. Mechanisms of cardiac contraction and relaxation. In: Zipes DP, Libby P, Bonow RD, Braunwald E, eds. Heart Disease, 7th ed. W. B. Saunders, Philadelphia, 2005, pp. 457–489.
