1.2. SISTEMATIZACIÓN DEL PROBLEMA
2.2.9. MARCO CONCEPTUAL
2 .5 .1 . Stimulation regimes investigated
1) 10 Hz Paient
2) 2 Hz Paient
2 .1 . O v e rv ie w
T he m ajor aim of the laboratory com ponent of this study was to investigate specific ways of conditioning skeletal muscles in order to im prove both their long-term p ow er output w hilst developing a suitable degree of fatigue resistance. In order to do this it was necessary to identify those properties of skeletal m uscle w hich co n trib u te to these functions, and objectively assess those propeities in muscles which had undergone specific training regimes. Individual muscles would be com paied both with other stim ulated gioups and with untransfoitned controls. Since no equipm ent suitable for this task existed at our institution it was necessaiy to design and build a m uscle testing rig specifically for the purpose of this study.
The design of the apparatus took into account the requirem ent to study those physiological properties o f skeletal muscle which have been show n to alter with chronic electrical stim ulation, and classical physiological tests were used to effectively dem onstrate the way those properties changed with the stim ulation regim es used. In o rd er to assess the significance of the findings an understanding of the nature of pow er production, the factors influencing it and the implications for coupling that power to produce flow in the circulation w ere required, and these are briefly set out below.
2.2. Muscle physiology and force generation
T he force velocity properties of muscle (which dictate its pow er output capabilities) have been extensively studied since the 1920's (Hill, 1922) and the m ethods used to determ ine m uscle properties have become increasingly sophisticated. Many of the propeities of force generation by skeletal muscle are com plex and associated not only with the velocity of contraction (Fenn and Mai’sh 1935), but with the distance through which tlie m uscle moves a load and its length at the beginning of movement. If the m axim um potential of skeletal m uscle for cardiac assistance is to be realised an understanding o f the w ays in w hich norm al skeletal m uscle structure and function contribute to pow er production m u st be review ed. These can be broken down into the four broad aspects described below , which deal with the factors affecting force production and the speed at w hich that force can be applied. In addition these basic muscle propeities need to be placed in relationship with the co n strain ts asso ciated with the transform ation process, and the v ario u s o p erativ e procedures available to bring skeletal muscle into a circulatory assist role.
2.2.1. L en g th -ten sio n relationship and ejection fraction
T he total force produced by a muscle has two com ponents: The passive tension due to the elastic connective tissue elements (e.g. collagen and titin) and the active tension which results from sarcom ere shortening. Even when stretched to their ideal length sarcom ere shortening only approaches 30% - but relating this potential lineai* change in m uscle length to changes in the volum e of a cylindrical vessel around w hich the m uscle is w rapped
requires a consideration of the ejection fraction of the system. T he predicted ejection fraction is given by the equation:
(Initial vol. - Final vol.)/Initial vol. = Fractional shortening x (2 - FS)
and is approxim ately 0.5. for shortening of 30%. This figure is based upon m axim al shortening of all the sarcomeres in the wrap, which depends upon their contraction kinetics allow ing the full developm ent of tension within the tim e-fram e of stim ulation (250 to 300 m secs for cardiac systole) and all the saicomeres being at optimal length. It is im portant to realise that long-term stimulation in itself causes muscle shortening with loss of sarcom eres in series (Jarvis, 1993) and it is highly unlikely that much, if any of the m uscle wrap is at its ideal length when wrapped around the heart.
2.2 .2 . Force velocity relationship o f skeletal m u scle
T he force generated by a muscle varies with the velocity at w hich it is shortening, the sustainable force falling as the velocity of contiaction increases, until a m axim um velocity is achieved w here no force can be sustained. The effects of transform ation on this relationship are shown in Fig. 2.1. These results indicate the capacity of skeletal m uscle to perfom i useful work under particular loading conditions, and the application (by Salm ons and Jarvis, 1991) of Lame's equations to this data provided some staitling general insights into the theoretical effect of reduced contraction velocities on ejection fraction. Lam e's equations consider the 'hoop stress' acting tangentially within the thick walls of a pressure vessel, and can be used to estimate the tension that would be required to be generated by a m uscle graft w rapping different radius vessels at different pressures in order to produce flow from the vessel into the circulation. The level of stress can be directly related to the force velocity plots for muscle to determine the degree of fractional shortening that could occur during the systolic phase of the caidiac cycle. The general conclusions indicated that for conditioned m uscle used in dynam ic cardiom yoplasty the shortening fraction is tim e lim ited, yielding ejection fractions of 0.17 for a left ventricular end diastolic volum e (LV ED V ) of 125 mis and even less (0.06) for a dilated ventricle of LV ED V 250 m is at a m ean systolic pressure of 100mm Hg. Even accounting for some assum ptions which over- and under-estim ated the working conditions of the graft, the clearest m essages em erging from this work were that shortening fraction is severely lim ited by the tim e-constraints of the cardiac cycle, that there is a further reduction in the assistance available when the heart is dilated since w all stress increases and that assistance is reduced still further w hen som e of the ventricle is covered by a non-contractile patch. Indeed it w ould seem that those with bigger hearts w ould have less to gain from cardiom yoplasty. A further analysis o f the p o ssible effects of transform ation on the power available for flow production in the circulation as opposed to ejection fraction alone are considered later.
Figure 2.1: Force-velocity and povver-velocity characteristics o f control and 11-week stim ulated rabbit tibialis anterior muscles, stim ulated continuously at 10 Hz. (Data from Salmons and Jarvis. 1990) (Control muscle - open symbols)
.-X 2 0 - 03 w 1 0 - t 0 1 0 0 2 0 0 3 0 0 300 - 200 - Ui 1 100 - o & 0 - 0 V elocity (mm/s) 1 00 2 0 0 3 0 0 4 0 0 V elocity (mm/s)
2.2.3. Force - bulk relationship for skeletal muscle
The force produced by a muscle is proportional to some extent to its cross sectional area, which may account for about 50% of the variation in strength between individuals (Jones and Rutherford 1987, 1989). The sliding filament theory provides a sim plistic view of why this is so - a single filament of say 100 sarcomere lengths would not allow summation o f the forces generated by the intennediate sarcomeres in the middle of the fibre, since they operate to oppose each other. This leaves only the terminal saicom eres to exert forces at the end of the filament. A filament with a similar num ber of saicom eres airanged as a fat bundle 10 sarcomeres wide would theoretically be able to exert 10 tim es the force o f the single filam ent one sarcomere wide. However the power produced by a m uscle is the product of force and velocity. Muscle length does therefore play a role in power production since the velocity of shortening is proportional to the num ber of sarc om ere s acting in series. A long thin muscle may not produce much force but its velocity of shortening may be higher than one containing fewer sarcomeres in series.
Since force is proportional to the cross sectional area of a m uscle, and velocity to the length, it follows that a short fat muscle will generate a high force but have a low velocity o f shortening, while the long thin muscle will generate little force but shorten quickly. In fact, both muscles may generate similar amounts of power, paiticularly if they have similar volumes, but the velocity at which m axim um power output is obtained will be different. Muscle transformation is known to result in a marked reduction in muscle bulk which plays a fundamental pan in the power generation calculations relevant to this discussion.
2.2.4. The relationship between fibre-type com position and power
The specific biochemistry of the muscle fibre types contribute significantly to a muscle's peifonnance. Slow contracting postural muscles composed predominantly of type 1 fibres are slower contracting and inu insically weaker than their faster activity-related counterpans. It is thought that type 2 fibres are capable of greater force generation per unit area, and athletes who train for power have been found to have large type 2 fibres in greater
proportions than in untrained individuals. However, there is dispaiity between the change in strength and m uscle size of the athlete and the degree o f fast fibre type hypertrophy (Edstrom and G rim by 1986). Strength training does not appeal" to lead to conversion of type 1 fibres to type 2 although endurance training does result in conversion o f type 2 fibres to type 1 and this is also seen during the transform ation achieved by chronic low frequency electrical stimulation. (Salmons and Vrbova, 1969; Pette, 1975).
The four factors affecting power generation outlined above aie each individually affected by the transform ation process and an appreciation of the relationships between these factors is crucial to the evaluation of skeletal m uscles w hich have been su bjected to novel transform ation protocols.