Chapter 11 part a
In relaxing buffer, the sarcomere-length inhomogeneity of skinned cells increased linearly with . around a Nikon Diaphot-TMD inverted microscope, fully activates the Cardiac Muscle Sarcomere Length–tension Relation. Figure 1. The relation between muscle length or sarcomere length and developed tension for lengths up to the optimal for contraction (Lmax) is much steeper in cardiac. The maximal active tension corresponds in cardiac muscle to a sarcomere length of microns. Cardiac muscle, unlike skeletal muscle, does not display a.
The length-tension diagram shows that as preload increases, there is an increase in active tension up to a maximal limit.
The maximal active tension corresponds in cardiac muscle to a sarcomere length of 2. Cardiac muscle, unlike skeletal muscle, does not display a descending limb on the active tension curved because the greater stiffness of cardiac muscle normally prevents its sarcomeres from being stretched beyond 2. There is no single, unique active tension curve in the length-tension relationship.
The active tension curve depends upon the inotropic state of the muscle.
- Length-Tension Relationship for Cardiac Muscle (Effects of Preload)
- Length-tension relationship
If, for example, inotropy is increased by applying norepinephrinethe total tension curve shifts up and to the left as shown in Figure 2. This results in an increase in active tension development at any given preload length.
The opposite occurs when inotropic state is reduced. Therefore, effects of preload on active tension development depends on the inotropic state of the contracting muscle. The above discussion describes how changes in preload and inotropy affect the force generated by cardiac muscle fibers during isometric contractions i.
Cardiac muscle fibers, however, also undergo shortening when they contract i. Note the difference in scaling of the two graphs. The abscissae show sarcomere lengths, relative to the lengths Lmax, at which the maximum active tension was developed; in these experiments Lmax was 2. After Spiro and Sonnenblick This is true for a wide variety of muscle, and in skeletal muscle and probably also cardiac muscle the peak of the length-tension relation comes when the degree of stretch brings sarcomere length to about 2.
This may be more apparent than real, since heart muscle contains a greater bulk of non-contractile tissue such as collagen and mitochondria, and the muscle fibres are not all parallel.
In muscle which has contracted at sarcomere lengths of less than 2. This overlap lessens as the muscle is stretched, until at a sarcomere length of 2. It is at this length that the maximum active tension can be developed. As the sarcomere is stretched beyond this, the actin rods are progressively withdrawn from between the myosin rods, and fewer cross-linkages can form.
In this length range, the active tension developed in a contraction declines linearly with length increase, until at a sarcomere length of about 3. In skeletal muscle this relationship between sarcomere length and tension has been firmly established, and its functional significance is generally agreed.
The behaviour of sarcomeres in cardiac muscle has been investigated much less thoroughly; under physiological conditions they appear to operate in the length range from about l.
However, relatively few observations have been made on the relationship between sarcomere length and developed tension in cardiac muscle, and these are to some extent conflicting.
This may be because of technical problems, particularly those of tissue distortion during histo logical preparation; methods have recently been developed to measure sarcomere length in vivo, and these may resolve the question.
At present, it seems well established that no active tension is developed at sarcomere lengths less than about 1.
There was a problem providing the content you requested
In between it is not clear whether increasing tension is the result of successive increments in sarcomere length as in skeletal muscle, or recruitment of increasing numbers of sarcomeres in muscle-fibres which were buckled at short muscle-lengths and are straightened and then stretched as the muscle lengthens. Furthermore, there is recent evidence that the curve relating tension and sarcomere length Fig.
We need a more detailed knowledge of the behaviour of actin-myosin cross-linkages to settle these uncertainties. In skeletal muscle, the linear relationship between muscle-length and sarcomere length is maintained until the latter reaches at least 3.
For heart muscle, the situation at high degrees of stretch is different. Sarcomeres will lengthen to only about 2. This situation does not arise in the normal heart and seems very unlikely even in the failing or pathological heart; in acute experiments where the relaxed left ventricle was distended with pressures as high as mm Hg far in excess of the levels reached even in severe heart disease the sarcomeres in the ventricular wall had an average length of only 2.
Dynamic mechanical properties of cardiac muscle. The length-tension curve describes an important property of muscle under static conditions - held at a constant length both before and during activity - but it throws no light on the dynamics of muscular contraction, which are of fundamental importance to any understanding of heart muscle performance.
A stimulated muscle goes through a period of mechanical activity the 'active state' which reflects the release of energy derived from chemical reactions and has measurable properties both of duration and intensity. Enormous progress has been made in elucidating and measuring both the biochemical steps which yield energy, and the mechanical behaviour which is the expression of this energy release. The literature is voluminous, reflecting both the technical difficulties involved in research on the myocardium and its innate complexity, and the subject can only be briefly surveyed here.
The commonest material used for experimental study of the mechanical properties of heart muscle has been papillary muscle, removed from the right ventricles of young animals under anaesthesia. It can be obtained in this way as extremely thin strips a few millimetres in length, and made up of numbers of fairly parallel muscle fibres. When such papillary muscles are mounted in oxygenated, nutrient media of appropriate ionic and osmotic properties, they preserve their contractile properties in response to electrical stimulation for long periods.
These contractile properties have been interpreted largely in terms of very simple mechanical models; to demonstrate why such models were chosen it is necessary briefly to describe some early experimental work carried out on skeletal muscle. Intact skeletal muscles can be removed easily from small animals such as the frog, and a number of workers in the early years of the twentieth century studied these muscles, stimulating them electrically and examining the mechanical properties and heat production during contraction the latter phenomenon having been demonstrated by Helmholtz over fifty years previously.
As was mentioned earlier, electrical stimulation of muscle leads to tension development. In the resting state, a potential difference of about 90 mV is maintained across the membrane of the muscle-cell - the resting potential. An externally applied shock can cause transient reversal of polarity of this potential, followed by slow recovery. This discharge, which is known as the action potential, triggers the release of calcium ions from stores within the muscle-cell, and these somehow activate the cross-linkages between the actin and myosin rods in the contractile apparatus of the sarcomeres.
This whole process occurs within milliseconds, and the muscle cell is then capable of contracting i. Thus a single electrical stimulus applied to a muscle-fibre causes a short-lived contraction appropriately known as a twitch. A chain of stimuli causes repetitive twitches, and in skeletal muscle if the stimulation frequency is high enough the twitches will fuse together to give a sustained contraction. This is known as a tetanus, and the corresponding train of shocks is a tetanic stimulus.
For a given muscle preparation, the tension generated in each twitch or tetanus will increase with increasing stimulus strength until a maximum is reached which is highly reproducible over long periods of time.
If the muscle is held at constant length, the twitch or tetanus is known as isometric; if it is allowed to shorten, the force if any opposing shortening is described as the load or afterload and if this force is constant, which implies that all accelerations of the load are very small compared to that due to gravity, the contraction is called isotonic.
Since maximal isometric contractions were found to be highly reproducible, they were used experimentally as the baseline condition; in this case the muscle generated heat during the course of a stimulation cycle, but since no shortening occurred, no external work was done work, or energy, is equivalent to force times distance.
When muscles were allowed to shorten by a distance x against a load or force P, not only were Px units of work done, but an extra amount of heat was released. This effect of shortening on heat production is known as the 'Fenn effect' after its discoverer; Fenn an American physiologist who did this work in also demonstrated the converse to be true - if a muscle was stretched during stimulation, it gave out less heat than when held at constant length. In describing this experiment, Fenn coined a phrase, 'negative work', which has given pain to physical scientists ever since; this is unfortunate, since the implication of the experiment - that the mechanical conditions during contraction control the amount of energy released - is fascinating and appears to have been little explored.
The explanation of this liberation of excess heat on shortening came some years later when instruments capable of following heat-production instant by instant through the contraction and relaxation cycle became available. It was then shown in a famous series of experiments carried out by A. Hill that the extra heat associated with shortening is proportional to the distance x shortened; thus it is equivalent to ax units of work where the constant a has the dimensions of force.
This rate of energy liberation was found experimentally to increase as load diminished, having its highest value when the load was zero and being zero when the muscle exerted its maximum force in an isometric contraction. Thus the properties predicted from thermal measurements were open to confirmation by purely mechanical experiments, and were indeed verified when the velocity with which a muscle could shorten isotonically against various loads was examined Fig.
Relationship between load P grams-weight and velocity of shortening v cm s-1 in isotonic shortening of frog skeletal muscle. The points were obtained experimentally; the line was derived from Equation The thermal observations were, however, of great importance in another way, since they suggested the first conceptual mechanical model of the muscle fibre. Observations on the course of heat release in the very early stages of stimulation revealed that it was similar for both isometric and isotonic contractions.
This suggested that similar mechanical events were occurring in the early stages of both types of contraction, and since the length of the muscle fibre could not change in an isometric contraction, the idea arose of a contractile element in the muscle, which shortened on stimulation but which was linked in series to an elastic element that could lengthen if muscle length was held constant Fig.
Mechanical models of muscle. The force-velocity relationship described above was assumed to describe the properties of the contractile element, since in steady shortening under isotonic conditions the elastic element would have constant length and would not contribute. It should be stressed that Hill was examining the properties of skeletal muscle under very particular conditions. First, the muscle was stimulated with trains of high frequency shocks tetaniso that a prolonged and maximal response occurred.
Thus each observation was carried out with a constant load and a steady velocity of shortening. The real physical properties of the series elastic element were not considered, since it was at constant length throughout.
Similarly, the time-course of development or decay of force was ignored. Furthermore, resting tension was very small at the muscle-lengths used approximately 2 per cent of active tensionand therefore a model with two elements was adequate.
The addition of a component to account for tension in the resting state parallel elastic component, as in Fig. Finally, the exact nature and location of the contractile element and the series elastic element also remained undefined; structures such as tendons might represent a genuine elastic element, or the internal contractile mechanisms might be elastic.
Nonetheless, this 'two-element' model of active skeletal muscle achieved widespread acceptance, since it explained a range of mechanical and thermal observations. It was natural, in view of the structural similarity which exists between sarcomeres in cardiac and skeletal muscle, to consider its applicability also to cardiac muscle. First, cardiac muscle preparations exhibit appreciable tension throughout the range of lengths from which they will contract; thus the parallel elastic element becomes an essential part of the model, and the force-velocity relation can be examined only incompletely, since forces at and near zero cannot be achieved.
CV Physiology: Length-Tension Relationship for Cardiac Muscle
Second, and far more important, is the fact that under normal conditions it is not possible to tetanize cardiac muscle like skeletal muscle and get a sustained and highly reproducible isometric contraction. Cardiac muscle repolarizes relatively slowly, and repeated stimuli do not produce a steady, maintained contraction. Instead, they produce twitches which even at high stimulation frequency only partially merge, giving a 'saw tooth' time-course of tension or shortening.
Thus an incomplete cycle of relaxation and contraction occurs with each stimulus. At lower frequencies, stimuli evoke twitches which are clearly separated and may be highly reproducible, but neither of these types of response represents a steady state of activity, since the tension-generating and shortening capacity of the muscle its active state may be changing continuously during a contraction.
A series of twitch responses from a papillary muscle preparation is shown in Fig. A series of superimposed records showing the length and tension changes that occur in a cat papillary muscle which contracts against a series of different loads. The initial length was held constant; the lower family of curves shows that tension rose to match the load in each case, and then remained constant whilst shortening occurred.
The amount of shortening at each load is shown in the upper curve. The final tension curve shows the response when the muscle cannot lift the load; this is the isometric twitch response. This greatly complicates the design and interpretation of experiments. The intensity of the active state however it may be assessed is obviously an important property of the muscle; but it becomes extremely elusive if it is changing throughout a contraction. The problems are best illustrated by examples. Hill originally defined active state as the tension which the contractile element could bear without changing length; thus it could only be measured when the contractile element velocity was zero.
Even in skeletal muscle this was only easy when tension had reached a sustained maximum value in an isometric tetanus; in this situation the contractile element has moved right along the force-velocity curve Fig. If on the other hand the contraction is not steady, but takes the form of an isometric twitch in which the active state rises and then falls, it is obviously extremely unlikely that the contractile element would be brought to rest by the load just at the time when activity was maximal.
But unless this happens, the maximum recorded tension will not correspond to Po, and the intensity of the active state will be underestimated. The measurement is feasible if some means is devised to hold contractile element length constant, for example by controlled stretching of the muscle during the contraction; but the experimental difficulties are very great.
An alternative approach which to some extent added confusion, since it introduced another definition of active state has been to use the unloaded velocity of shortening as an index of active state. This is easier to examine experimentally; the muscle is released from its load at different points during successive twitch cycles and the velocity of shortening is measured immediately after the muscle has sprung back to unloaded length.
An example of the results obtained in such an experiment is shown in Fig. Time-course of active state in cardiac muscle as measured by released isotonic contractions.
The arrow shows the time at which peak tension was achieved in an isometric twitch. From Edman and Nilsson Recently, however, the techniques based on contractile element velocity have been shown to have a flaw because the duration of active state has been found to depend on length changes in the contractile element; if it shortens at any point in the contraction, the active state wanes earlier.
In recent experiments, therefore, the subject has been re-examined by a more sophisticated approach; the stress-strain characteristics of the series elastic element in a muscle are measured first, and then computer-controlled mechanical feedback is used to pull on the muscle during contraction so that it is continuously lengthened by just the amount necessary to keep the contractile element length constant; the tension on the muscle at each instant through the contraction cycle then defines the active state.
This method gives a time-course and intensity of active state which differ only a little from the isometric twitch response, the chief difference being a fractionally earlier rise and fall in active state.
Even this, however, is unlikely to be the last word, because it has been demonstrated still more recently that the series elastic element has time-dependent properties, and the amount of stretch needed at different times in the cycle to fix contractile element length will therefore not depend solely on instantaneous tension. These studies, culminating with the paradox that the contractility of a papillary muscle preparation is best defined by an experiment in which it is forced to lengthen, are described in some detail because they highlight the difficulties which arise in the experimental study of cardiac muscle mechanics at this level.
It should by now be apparent that at least four variables - time, length, tension, and velocity - are important; and a whole range of extraneous factors which affect contractility such as temperature, oxygenation, and ionic environment need stringent control. Blinks and Jewell have provided a useful recent survey of the subject; they point out that since the standard experiment explores the relationship between a pair of variables, six classes of experiment are needed to explore the inter-relationships between time, length, tension, and velocity.
We do not explore this subject in detail, but certain general conclusions are important enough to need stating. The inverse relationship shown to hold for skeletal muscle between developed force and velocity of shortening Fig. This must be immediately qualified by pointing out that the force-velocity relationship is influenced by muscle-length and by the active state of the muscle. The effect of length can be predicted qualitatively from the length-tension relationship shown in Fig.
Thus in order to present the properties of the muscle graphically, we would need a three-dimensional plot, with two of the axes being contractile element force and velocity as in Fig. Then at any level of active state in the muscle, the various possible combinations of these would form a three-dimensional surface within the axes. In practice, it is difficult to draw such graphs realistically, because they need to show both positive and negative velocities i.
In trying to understand how the properties of the muscle interact, it is easier just to consider two types of contraction - isometric and isotonic. The simpler example is an isometric twitch, since it avoids muscle-length changes. The contraction starts at some point on the resting length-tension curve Fig. Initially, the contractile element begins to shorten very fast, since it is relatively lightly loaded; thus velocity rapidly increases.
However, since shortening of the contractile element implies lengthening of the series elastic element, force builds up and the contractile element velocity is then reduced progressively until it becomes zero; at this point the maximum force equal to the sum of active plus resting tension in Fig. Thereafter, relaxation occurs, and the muscle returns to the original starting point on the resting length-force line.
If the muscle shortens against a load during contraction isotonic contraction the situation is slightly more complicated. At first the contractile element shortens and develops force, stretching the series element as for the isometric case.
Then a point is reached where the force equals the load; thereafter, force remains constant, and the whole muscle begins to shorten with the series elastic element at constant length. The demand for constant force at diminishing muscle-length can only be met by a diminishing contractile element velocity Fig. Curves illustrating the length dependence of the force-velocity relationship in cardiac muscle.
Each curve is plotted from a series of contractions against different loads such as those shown in Fig. Successive increases in the initial length of the muscle displaced the curves farther and farther to the right. In the real heart, both isometric and isotonic phases occur during contraction, and, as will be seen later, the load i.
Furthermore, we have ignored a major factor which complicates all these relationships - the importance of time. Active state does not remain constant throughout the contraction, but waxes and wanes, so that the force-velocity curve, which has a shape like that in Fig.
The graphs relating force, velocity, and length are all moving with respect to their axes during the contraction and relaxation of the muscle. This kind of description has some value both in illustrating the complications that exist and in showing that however we examine a contraction whether in terms of velocity or force there are two main influences at work in deciding its level.
The first is the length of the muscle element, and the second is the intensity of the active state. The importance of this latter property is worth stressing; it is easy to see intuitively that a high level of active state will, other things being equal, produce a stronger contraction - however measured.
But it is much less easy to see how to express or measure this level, and in many situations we find that there is a property of the muscle—usually termed 'contractility' - which is not precisely measurable or definable. Even if we confine attention to the isolated muscle preparation there are a number of areas still in dispute. These are mainly related to the form of the 'edges' of the three-dimensional surface which is needed to describe graphically the inter-relations between force, velocity, and length described above, which cannot always be described directly from experimental evidence, but only by extrapolation.
Such extrapolation must be based on a model of the muscle such as Fig. One example, which has important practical implications, will serve to illustrate the problem. It concerns the maximum velocity of shortening which can be achieved by the unloaded contractile element. This velocity known as Vmax cannot be measured directly in cardiac muscle because, as shown in Fig.
Thus Vmm can only be established by extrapolation. Some years ago, the American physiologist E. Sonnenblick performed this extrapolation on force-velocity curves measured at a series of different muscle-lengths, and concluded that it was possible to extrapolate all the curves which are shown in Fig.
Thus Vmax appeared to be independent of muscle-length. This suggestion stimulated great interest because it implied that Vmax might be used to distinguish between the effects which changes in length and in active state intensity i. It will already be clear how useful such a measure would be in isolated muscle experiments; but in examining the performance of the whole heart chamber, where the difficulties of controlling and monitoring these separate influences increase, it would be even more valuable.
However, there are problems in performing the extrapolation which gives Vmnx, because some shape has to be assumed for the force-velocity curve which is being extrapolated, and it is in choosing this that the muscle model becomes important. Now Hill's model of muscle Fig. The details of this can be found elsewhere; it suffices here to say that the corrections needed depend upon which form of model is used Fig. This means that the original hypothesis that Vmax was independent of initial length, which was based on extrapolation of the curves in Fig.
During the decade or so in which these simple mechanical models have been used in cardiac research, much of the detailed ultrastructure of skeletal muscle has been described, and elegant techniques developed for making measurements at the sarcomere level.
Increasingly, the mechanical properties of skeletal muscle are being interpreted in relation to the known structure of the contractile apparatus; thus the sarcomere has become the model. So far, a lack of suitable preparations has prevented this in cardiac muscle research, and the mechanical models continue to be the only useful analogy to real cardiac muscle at present.
Before we go on to consider the behaviour of the intact heart-chamber, it is useful to summarize some of the findings on isolated muscle preparations.
Such muscles contain considerable numbers of muscle-cells, probably all lying reasonably parallel with the long axis. At rest, and over what can be assumed to be their normal operational length range, they resist stretching with a force which rises steeply with increasing length. The structural element responsible for this property has not been identified; in conceptual models it is called the parallel elastic element, and thought of as a spring though a simple spring is actually a poor representation of the real situation, since the muscle does not oscillate when it is released, and exhibits a good deal of creep when it is stretched; both these imply viscous as well as elastic properties.
Cardiac muscle-cells can be depolarized by an externally applied shock, and this depolarization is followed, after a delay of some milliseconds, by a period of mechanical activity during which the muscle will shorten.
If it is loaded to resist shortening then it develops tension, and shortens if and when tension matches the load; the velocity of shortening is then inversely related to the load moved.