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Cardiovascular Research 2000 48(1):111-119; doi:10.1016/S0008-6363(00)00144-9
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Effects of aging on the work output and efficiency of rat papillary muscle

Helen Kiriazis and Colin L. Gibbs*

Department of Physiology, Monash University, Clayton, Victoria 3168 Australia

* Corresponding author. Tel.: +61-3-9905-2513; fax: +61-3-9905-5583 c.gibbs{at}med.monash.edu.au

Received 6 December 1999; accepted 29 May 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objectives: This study aimed to investigate the effect of aging on the work output and efficiency of rat papillary muscle. Methods: The mechanical and energetic properties of left ventricular papillary muscle preparations isolated from 6-, 15-, and 27- to 32-month-old Sprague–Dawley rats were measured in myothermic experiments at 27°C at a stimulus frequency of 0.167 Hz. Results: We found that the basal metabolism measured in quiescent papillary muscles was significantly reduced in the 27- to 32-month-old group (4.9 mWg–1 compared to 7.7 and 7.0 mWg–1 in the 6- and 15-month groups). In isotonic experiments, the work output (at a range of afterloads) was significantly depressed for the 27- to 32-month group being only 52% of the work output of the 6-month group. This outcome was due to a decrease in both the extent of muscle shortening only, 66% of 6- and 15-month data, and in the maximum force developed. The reduced work was accompanied by a parallel decrease in energy consumption (enthalpy) and hence, the net mechanical efficiency (work/active enthalpyx100%) was not altered. A force–length– area (FLA) analysis was applied to the isotonic data and an energy: FLA regression line was obtained for each preparation. We found that there were no significant differences in either the intercept or slope of the energy: FLA relation with age. Contractile efficiency (39±3%) in the 27- to 32-month group was not significantly different to that found in the 6-month (43±4%) or 15-month (40±3% group). Conclusion: There are no changes in the mechanical performance or efficiency of cardiac muscle from young (6-month-old) or adult (15-month-old) rats but in the aged and senescent rats (27–32-month-old) there is a pronounced decline in stress development and shortening ability leading to a fall in work output. Mechanical and contractile efficiency however remain unchanged in old age and the data resembles that obtained in pressure overload hypertrophy.

KEYWORDS Aging; Energy metabolism; Hypertrophy

This article is referred to in the Editorial by N. Westerhof (pages 4–7) in this issue.


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Biochemical, mechanical and electrophysiological properties of the myocardium are altered in aging in a similar fashion to that observed as a consequence of pressure overload hypertrophy (see Ref. [1] for review). Although there are numerous studies in the literature on the mechanical and energetic effects of cardiac overload, there are few which have investigated the energetic consequences of aging in the working myocardium.

It is well known that with aging there is a clear decline in cardiac function such that in old age or senescence there is a progressive prolongation of contractile duration and time to peak tension and a diminished ability to generate force [1–5]. There are also changes in cellular Ca+2 kinetics [6,7] but the data in respect of systolic [Ca2+]i are not consistent [8], cross-bridge turnover rate is decreased [9,10]. The age-associated changes in calcium cycling have been clearly documented by several groups [4,6,7,11,12] and it has been shown that there are age-dependent changes in the calcium transient such that under β-adrenergic-stimulated senescent hearts have a decreased ability to increase the [Ca2+]i transient [7].

It has been established that with aging and with pressure overload hypertrophy there are alterations in ventricular myosin heavy chain expression [10,13,14] and this leads to an increase in the economy with which isometric force is maintained. There has however been no isotonic energetic investigation of work output per beat and mechanical efficiency in senescence. In the present investigation we have measured the work output in isotonic contractions and have analysed our data using both a conventional definition of mechanical efficiency and have made a force–length–area (FLA) analysis of the same data to calculate contractile efficiency [15]. The FLA analysis not only allows contractile efficiency to be measured but also provides an independent estimate of the activation or tension-independent heat associated with Ca2+-ATPase of the SR [16,17]. In order to allow estimates of gross mechanical efficiency (work/active + basal enthalpyx100%) to be made, which can then be compared with in vivo mechanical efficiency estimates, we also measured the basal metabolism or resting heat production of papillary muscles from the different age groups.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Dissection of rat left ventricular muscle preparations
Three age groups were studied. Young adult (5.7- to 6.5-month-old, n = 6; 6-month group), mature adult (14.3- to 15.7-month-old, n = 6; 15-month group) and senescent (26.6- to 32.2-month-old, n = 6; 27- to 32-month group) male Sprague–Dawley rats were studied. All rats were killed by cervical dislocation, and their hearts rapidly removed and placed into warm (~34°C) physiological solution until the heart vented the blood from its chambers. The dissection then took place in Krebs solution containing 30 mM BDM at room temperature. Krebs–Henseleit solution composed of (in mM) 118 NaCl, 4.75 KC1, 1.18 MgSO4, 1.18 KH2PO4, 24.8 NaHCO3, 2.5 CaC12, 11.1 glucose and insulin (10 IU/l) at room temperature. This solution was aerated with 95% oxygen–5% carbon dioxide and had a pH of 7.4. The investigation conforms with principles outlined in the Declaration of Helsinki and was approved by the Monash University Animal Ethics Committee. BDM protects the myocardium against dissection damage [18] and viable, (cross-sectional area ~0.5 mm2) rat myocardium preparations have been obtained in the presence of BDM by splitting (cutting) left ventricular papillary muscles longitudinally [18,19]. The same dissection method was employed in the present study as it allowed myocardial preparations with a relatively uniform cross-sectional area and of a size suitable for isolated muscle experiments, to be obtained even from large (old) rats. The right ventricular free wall was removed, and the interventricular septum was bisected and pinned open. After allowing the heart to be exposed to BDM for ~10–15 min, one of the left ventricular papillary muscles was split longitudinally, separating a strip of muscle around one-third to one-half of the papillary muscle. Ties (braided noncapillary 5-0 silk thread) were placed around both ends of the split muscle strip and the free ends of the ties were then hooked onto a small C-shaped spring, which kept the muscle close to its resting length upon isolation from the heart. The preparation was ready to be mounted onto the thermopile and immersed in normal Krebs–Henseleit solution (i.e., without BDM). Only one muscle preparation was obtained from each heart. Mean muscle mass, length, and cross-sectional areas, respectively, were (mean±S.E.): 3.2±0.3 mg, 6.2±0.4 mm, 0.53±0.05 mm2 for the 6-month group; 2.2±0.3 mg, 6.4±0.4 mm, 0.34±0.04 mm2 for the 15-month group; 3.1±0.5 mg, 5.9±0.4 mm, 0.52±0.07 mm2 for the 27- to 32-month group.

2.2 The muscle–thermopile system
Details on heat measurements and the experimental set-up have been described in earlier papers [13,18]. The muscles were mounted on a wire-wound electroplated thermopile, enabling measurements of heat production. One muscle tie was clamped to the frame of the thermopile and the other tie was attached, via a tungsten connecting wire, to the lever system of an ergometer (model 300 H, Cambridge Technology) which measured force and changes in the length of the preparation. The total compliance of the ergometer, tungsten wire, and silk ties was 1.6x10–3 mN–1. Force, length and heat, could be measured simultaneously. The preparations were stimulated through platinum electrodes. Stimulation per se (7.0–8.0 V d.c. pulses of 0.2–0.5 ms duration, at 0.167 Hz), did not produce any measurable heat (i.e., stimulus heat was negligible).

The muscle–thermopile system was enclosed in a glass chamber containing 45–50 ml of aerated (95% oxygen–5% carbon dioxide) Krebs–Henseleit solution (no BDM). As heat produced by the muscle is quickly lost to the surrounding solution, heat measurements were made only when the solution was drained out of the muscle–thermopile chamber into an adjacent glass chamber. This considerably reduces the rate of heat loss. For any one muscle, the time-course of heat loss, with the solution drained away from the muscle, was exponential, and reproducible over the course of the experiment: the average heat rate loss of all muscles in the four main groups was 23.9±1.5%s–1 (n = 18). Heat signals recorded from contracting muscles were electronically corrected for heat loss. Both chambers were immersed in a thermostatically controlled water bath maintained at 27°C.

2.3 Experimental protocol
Initially, preparations were continuously stimulated to contract isotonically at 0.167 Hz, while in solution, under a light preload (0.5–1.0 g) for a ~1-h period of equilibration, after which muscle length was set to optimum (Lmax) for isometric force production.

2.4 Basal metabolism
The resting heat rate measurements (basal metabolism) were made with the muscle quiescent (i.e., unstimulated), by draining the solution out of the muscle–thermopile chamber. The output of the muscle–thermopile system when immersed in solution was zero. Upon draining the solution, the heat signal rose, and within a few minutes, reached a steady-state from which the magnitude of the basal metabolism was determined. Resting heat rate measurements were made at the beginning of each experimental run. The recording runs which were made out of solution in a moist aerated environment were separated by equilibration periods, back in solution of ~30-min duration. For each preparation, resting heat rate data were plotted against time post-cardiac excision. As the time at which basal metabolism was measured varied between muscles, values were interpolated at specific time-points (150, 180, 240 and 300 min) from graphs of the experimental data, allowing comparison between groups. Active muscle heat production, recorded when stimulated, was measured above the basal metabolism baseline. During experimental runs, muscles were stimulated by trains of 15 stimuli at 0.167 Hz and the total heat production (i.e., initial plus recovery heat) was measured over a 2- to 3-min period. Up to six such runs were made in any recording period. There was little sign of deterioration in the muscles' contractile performance over the recording period but in both the isotonic and isometric experiments mirror image load (isotonic) or length (isometric) runs were usually made in the next recording session and the data from two identical runs was averaged.

2.5 Isotonic experiments
For each preparation a number of isotonic runs were performed. Additional afterloads were progressively added to the fixed preload, such that the total load (preload and afterload) was increased in steps of ~0.5–1.0 g until it was equal to Po (the load at which contractions became isometric). Thereafter the afterload was progressively decreased to zero. An afterload stop prevented the muscle from being stretched at increased afterloads; therefore, the initial muscle length remained at Lmax. To obtain measurements at very light loads, occasionally loads lighter than the preload were used. Mechanical and heat measurements were made at each set load. As a train of contractions was used, values for muscle shortening were averaged for each set. In addition, the total heat production (normalised for muscle mass) in a train of contractions was divided by 15 to obtain the average heat production per contraction. With the isotonic contractions, the measured heat production is actually the enthalpy (heat plus work), because during relaxation work is done by the load as it stretches the muscle back to Lmax, and the energy that appeared as mechanical work is returned to the muscle as heat (due to a slow relaxation rate, negligible energy is lost into the afterload stop). From the data obtained, enthalpy, external work (loadxdistance shortened; normalised for muscle mass), mechanical efficiency (work/enthalpyx100%), and muscle shortening (as a percentage of Lmax) were calculated. These parameters were plotted against the total load, which was normalised by expressing it as a fraction of Po. As the loads used were not usually an exact fraction of Po, values of enthalpy, work etc., were interpolated at 0.1, 0.2,...,1.0 Po from graphs of the experimental data.

2.6 Force–length area analysis
As part of the current study, a force–length–area (FLA) analysis was performed as previously detailed [19]: (i) For each preparation length–tension curves were obtained (see Fig. 1). An active length–tension (load) curve was established for each preparation using the isotonic data, by plotting the average distance the muscle shortened at each load. A passive length–tension curve was established using data obtained by progressively shortening the muscle until passive force was negligible, see above. (ii) The FLA was calculated for each load. FLA is determined by the sum of two energy terms, external work and potential energy, except for the isometric case where it is described by a single term, that for potential energy [15]. In Fig. 1 an example is shown for a load of 19.6 mN, the work term is represented by the area enclosed by ABCDA and the potential energy is determined from the adjacent area, DCZD; therefore, the area enclosed by ABCZDA, is the FLA for the load. When the load is equal to or greater than Po, the area enclosed by the path ABYCZDA, represents the potential energy (work is zero in the isometric case), and also gives the FLA. (iii) the FLA (work plus potential energy) data were normalised for muscle mass, and plotted against the total energy (enthalpy) data for the individual loads. A linear regression line was fitted to the total energy: FLA data obtained for each preparation.


Figure 1
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  		Fig. 1 Active and passive length–tension curves for one preparation. The active length–force (load) relation (upper curve) was established using isotonic data and plotting the shortening that took place under the various afterloads. The passive length–tension relation (lower curve) was established from isometric studies and plotting passive force values obtained at lengths less than Lmax (the length at which maximum force was generated). At Lmax (origin, X), Po denotes the load at which contractions became isometric (i.e., no shortening). Similar graphs were established for each preparation and used to calculate the force–length area (FLA). See Section 2.6 for details.

 
2.7 Isometric experiments and calibrations
At certain times during the day, isometric experimental runs were made. The data was needed for the FLA analysis and allowed checks to be made that there was no deterioration of the preparations with time. At the end of each experiment the muscle–thermopile system was calibrated as described previously [14,17], and the muscle mass and length at (Lmax) were measured.

2.8 Statistics
Results are expressed as mean±S.E. Statistical analysis of the data was performed using SPSS (Chicago, IL, USA). Tests for homogeneity of variances (Bartlett-Box, Cochrans) were carried out, and revealed that some data required square root or logarithmic (log10) transformation prior to statistical testing. One-way, or two-way repeated-measures analyses of variance (ANOVA) were performed on the raw data, or transformed data (when appropriate), to test for differences between the groups. Statistical significance was indicated by P<0.05. Where the ANOVA revealed a significant difference between groups, the least significant difference multiple range test [20] was used to identify differences between mean values.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Resting heat rate
Many measures of resting heat rate or basal metabolism were made in each quiescent muscle over the course of an experiment (5 h). To allow comparison at specific times e.g., 150, 180, 240 and 300 min post cardiac excision, values were interpolated from heat rate versus time plots made for each preparation. Fig. 2 shows the mean data for the 6-, 15- and, 27- to 32-month groups. The resting heat rate data collected for the 15-month group had a large variance compared to the other two groups and, analysis of variance performed using the 6-, 15-, and 27- to 32-month groups and incorporating the four time-points (i.e., two-way repeated-measures ANOVA), revealed no significant differences between groups (P = 0.063). There was, however, a significant decrease in the resting heat rate with time (P<0.001) for all age levels. Analysis performed using the first time-point (150 min; one-way ANOVA), did show a statistically significant decrease in the resting heat rate for the 27- to 32-month group in comparison to the 6-month group (7.65±0.41, 7.04±1.12 and 4.98±0.38 mWg–1 for the 6-, 15- and 27- to 32-month groups respectively; P = 0.047). To investigate whether the magnitude of the drop in basal metabolism with increasing time post-cardiac excision was affected by age, the resting heat rate data at 180, 240 and 300 min were expressed as a fraction of the 150 min data. The effect of time was significant (P<0.001) but there was no significant difference between the groups (P = 0.252) implying that the proportional decrease in resting heat rate with time was similar for the three groups.


Figure 2
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  		Fig. 2 Resting heat rate at 150, 180, 240 and 300 min post cardiac excision for 6-, 150- and, 27- to 32-month groups. There was a significant effect of time on the magnitude of the resting heat rate. The mean resting heat rate was lower for the 27- to 32-month group compared to the 6-month group (see Section 3.1 for details).

 
3.2 Isometric and isotonic mechanical data
Developed stress at Lmax, Po, was significantly decreased for the 27- to 32-month group in comparison to preparations obtained from the 6- and 15-month animals (52.7±5.3, 64.7±4.7, and 31.4±1.2 mNmm–2 for the 6-, 15- and 27- to 32-month groups, respectively; P<0.001).

Mean muscle shortening data (expressed as a percentage of Lmax) against load, are presented in Fig. 3. There was a significant attenuation in the degree of muscle shortening for the 27- to 32-month group in comparison to the 6- and 15-month groups (P = 0.005). Data obtained for the 27- to 32-month-old animals were scaled down by a factor of 0.66 in comparison to the 6- and 15-month-old animals.


Figure 3
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  		Fig. 3 Muscle shortening against load. Shortening has been expressed as a percentage of Lmax, and the load has been expressed as a fraction of Po. The extent of muscle shortening for the 27- to 32-month group is quite depressed, in comparison to the 6- and 15-month groups. The difference was statistically significant.

 
3.3 Work enthalpy and mechanical efficiency
As described in the Methods, the muscles were made to shorten against a range of afterloads. Mean enthalpy (heat+work), work and mechanical efficiency data plotted against (normalised) load, are shown in Fig. 4. There was a significant decrease in both enthalpy and work for the 27- to 32-month group in comparison with the 6- and 15-month groups (P<0.001 for both parameters). Relative to the 6-month group data, enthalpy was decreased by 52% and work by 55% for the 27- to 32-month group. The mechanical efficiency profile was not significantly different between groups (P = 0.396). Although mechanical efficiency appears to be lower for the 27- to 32-month group than the 6- and 15-month groups at the light loads (0.1, 0.2 Po), this difference was not significant even when analysis of the data was restricted to these loads alone (P = 0.082).


Figure 4
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  		Fig. 4 Enthalpy (heat plus work), work (loadxdistance shortened) and mechanical efficiency (work/enthalpyx100%) per contraction against load (expressed as a fraction of Po. There was no significant differences in enthalpy and work for the 6- and 15-month groups. Enthalpy and work were significantly attenuated for the 27- to 32-month group compared to the adult (6-, 15-month) groups. Mechanical efficiency was similar for the three groups.

 
It should be noted that the work term calculated in the results described above, excludes the work done by the stretched parallel elastic component work (PECW), see also Fig. 1. (The PECW is determined from the area under the passive length–tension curve used to calculate the FLA), whereas the area XABCDX represents the work (loadxshortening). It should also be pointed out that external work is commonly calculated as loadxmuscle shortening, as this is simple to determine, and when passive tension is low, the PECW is relatively small compared to the work term.

As there was a marked decrease in muscle shortening for the 27- and 32-month group in comparison to the adult animal groups (Fig. 3), this implied that the PECW at each load represented a relatively greater portion of the work (loadxshortening) for this group. In order to take into account this difference, the work-PECW data were also analysed, see Fig. 5. There was no significant difference between the 6- and 15-month groups, whereas, work-PECW was significantly attenuated for the 27- to 32-month group (P<0.001): mean work-PECW values were 60% lower than those of the 6-month group. In comparison to the work data shown in Fig. 4 (i.e., work calculated as: loadxdistance shortened), the work-PECW data were, on average, decreased by 17±3%, 18±3% and 26±3% for the 6-, 15- and 27- to 32-month groups, respectively; however, there was no significant difference between the groups (P = 0.084). As ‘work-PECW’ values were less than ‘work’ values, mechanical efficiency data evaluated using work-PECW were also proportionally lower in comparison to the mechanical efficiency data shown in Fig. 4. Statistical analysis on these mechanical efficiency data (obtained for 0.1, 0.2,...,0.9Po) reached the same conclusion stated above namely, there were no significant differences between the different age groups.


Figure 5
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  		Fig. 5 Mean work excluding the parallel elastic component work (i.e., work-PECW), versus fractional load for the different age groups. In contrast, the work shown in Fig. 4 includes the energy stored in the parallel elastic component (due to the passive force exerted by the preload). There was a significant depression in work-PECW for the preparations obtained from the 27- to 32-month-old animals in comparison to 60 and 15-month-old animals.

 
3.4 FLA analysis and contractile efficiency
The isotonic data were also subjected to a different form of analysis. The FLA for each load was calculated as explained in the Methods and plotted against the total energy (enthalpy) obtained for each load level. The data were fitted with a linear regression line details are given in Table 1. The reciprocal of the slope of the line (x100%) represents the contractile efficiency [15]. There were no significant differences in intercept (P = 0.105), or slope (P = 0.765) and, hence, no difference in contractile efficiency (P = 0.658), between the groups. The intercept on the total energy axis provides an estimate of the activation heat, see Discussion.


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  		Table 1 Details on mean total energy: FLA (force–length area) regression lines, and contractile efficiencya

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
As mentioned in the Introduction there are very clear effects of aging on several of the cellular ATPases that have been shown to underwrite rat cardiac expenditure [16,21]. There are changes in both cellular Ca2+ kinetics and in cross-bridge turnover rate and these changes must and do affect cardiac function and energetics [13–15]. It has been known for some time that when myosin heavy chain alters, that the economy and even the mechanical efficiency of a contraction can be altered [10,13,14,22]. Since there are significant age-induced alterations in ventricular myosin heavy chain expression [9,10], one would predict aging would alter the economy of a contraction. However, it is much less clear from the literature whether mechanical efficiency alters with aging or pressure overload hypertrophy. Likewise the clear changes in cellular calcium handling [1,6,12] that have a large effect on contractile duration have not always produced clear changes in activation heat magnitude.

This paper attempts to look at age-dependent changes in cellular mechanics and energetics in isotonically contracting papillary muscles from rat hearts. It is important to note that the mechanical and energetic characteristics of cardiac preparations obtained from the 6- and 15-month animal (adult) groups were similar, and this implies that the intrinsic properties of the Sprague–Dawley rat myocardium (assessed at 27°C, 1/6 Hz stimulation and 2.5 mM calcium) did not undergo changes over this age range. Hence, it is unlikely that any differences between the measured parameters in the senescent (27- to 32-month-old) and adult animals can be attributed to developmental changes.

4.1 Isotonic and isometric mechanical performance in senescence
In comparison to the 6- and 15-month groups, papillary muscle preparations dissected from 27- to 32-month animals had a markedly reduced work (or work-PECW) profile against load. This outcome was due to both a decrease in muscle shortening as a function of load and to reduced stress generation (i.e., heavy loads could not be lifted). A decrease in isotonic shortening has been observed previously in papillary muscles obtained from 24-month-old Fischer rats, in comparison to 6- and 12-month-old animals [5] and is also a prominent feature of long-term pressure overload hypertrophy [14]. Interestingly, this phenomenon does not seem to persist at the cellular level as the relative extent of shortening in myocytes (isolated from Wistar rats) during a twitch is not affected by advancing age [23]. It may be that age-related changes in the extracellular matrix of the myocardium (e.g., accumulation of collagen and fibrosis) impedes normal shortening of the myocytes in the whole heart or in papillary muscle preparations [24]. The fall in peak stress development in the senescent group is quite marked and the changes in the extracellular matrix may contribute. This decline in performance is also very similar to that seen in long-term pressure overload where the mechanical and biochemical consequences have been well documented [13,14].

Elzinga and Westerhof [25] established pump function curves for contracting feline hearts and showed that there was a curvilinear relationship between mean intraventricular pressure and flow when measured over the entire cardiac cycle and that changes in contractility or cardiac end-diastolic volume could shift the relationship. Our aging data, which show a decrease in stress generation and shortening would be explicable in terms of a decrease in contractility or an ‘apparent’ decrease in end-diastolic volume. The second explanation seems unlikely unless there has been an over-compensation of cell lengthening with too many sarcomeres in series and hence at less favourable points on their ascending length–tension curve.

4.2 Energetic consequences of senescence
4.2.1 Basal metabolism
The magnitude of the resting heat rate was reduced for the 27- to 32-month group in comparison to the 6-month group (see Fig. 2). The reasons underlying the time-dependent decrease in the magnitude of the resting heat rate post cardiac excision, though well documented in both saline perfused hearts and in myothermic investigations are unknown [26,27]; the phenomenon does not occur under some conditions [28] but has been seen in myothermic experiments on rat, rabbit and cat hearts and a time-dependent decline is even evident in saponin skinned rat cardiac trabeculae [21] where it was attributed to loss of membrane-bound ATPases.

It is important to realise that the basal metabolism accounts for 20–30% of the total cardiac metabolism and to assess why the basal metabolism of the senescent heart is depressed. There is recent experimental evidence in saponin skinned rat trabeculae that after the initial time-dependent decline, some 40% of the remaining basal ATPase is non-membrane bound and may reflect unregulated myosin ATPase activity, about 14% can be linked to the Na+–K+ pump and about 8% reflects basal SR Ca2+-ATPase activity. The remaining 38% is abolished by Triton treatment and hence is thought to be membrane bound possibly associated with T-tubules and microsomes.

Alternatively the attenuation of basal metabolism with age may relate to morphometric changes observed in the left ventricle for this rat strain. Anversa et al. [25] have reported (i) that there is a loss of myocytes and replacement fibrosis (hence, reducing the basal metabolism per g of tissue) and, (ii) that existing myocytes are hypertrophied. Less energy (ATP) is required to maintain ionic homeostasis in enlarged (hypertrophied) myocytes as there is a lower surface area to volume ratio so that the enlarged cells would require less Na+/K+-ATPase activity per unit surface area, resulting in a reduced energetic cost.

It is important to establish the magnitude of any changes in basal metabolism since in most in vivo measurements of gross mechanical efficiency the basal metabolic rate is in the denominator of the efficiency calculation and a fall in the basal metabolism term could make the senescent heart look ‘efficient’ in spite of a possible decline in net efficiency.

4.2.2 Active metabolism
When a muscle contracts, additional energy is liberated above the basal metabolism. This active metabolism is made up of two components; an activation one related to the energetic cost of EC coupling and another related to cross-bridge activity [17,29]. In the present investigation activation heat was measured in isotonic experiments as the intercept on the energy:FLA curve. The activation energy term predominantly involves ATP usage by the calcium ATPases of the sarcoplasmic reticulum and sarcolemma and the cost of sodium pump activity [16,21]. There was no statistically significant change in the activation heat but we have been able to show [30] that when the senescent heart is challenged pharmacologically it can produce only a modest increase in activation heat compared with the several fold increments seen in the young and adult groups and this result is very much in line with expectations from calcium transient data [7].

4.3 Efficiency
There are several different efficiency definitions in use and the interpretative difficulties that result have been discussed in a recent review [31] where a comparison was made of mechanical and contractile efficiencies. Mechanical efficiency defined as work/total enthalpy must by definition be load-dependent i.e., it must be zero at zero load or at loads ≥Po. Mechanical efficiency was unaltered between adulthood (6-, 15-month-old) and senescence (27- to 32-month-old). The substantial decrease in work output, observed for the 27- to 32-month group in comparison to the adult groups, was offset by a decrease in enthalpy leaving net mechanical efficiency unaltered.

In isometric contractions, no external work is done and conventionally the energy cost of force production is assessed by measuring economy defined as the energy liberated for unit developed force or for unit force–time integral. We and others have found that the isometric economy is unchanged across the young and adult age groups but increases in the senescent hearts. This result would seem to be at odds with the isotonic results but it has been pointed out that economy and efficiency are different entities with efficiency being dimensionless and economy being proportional to 1/velocity and hence to the rate at which crossbridges are broken [32]. With age, the rate constant ‘g’ of the Huxley model would be predicted to decrease due to the shift to the slow myosin isoform and one would expect economy to increase since proportionally more cross-bridges will achieve a full power stroke before being detached at the lower velocity of sarcomere shortening.

In the present investigation, we also measured contractile efficiency. The contractile efficiency, derived from the FLA analysis, represents the proportion of energy used that can be converted to mechanical energy (work and potential energy); this value is reasonably constant regardless of the loading conditions [15]. The strength of the FLA model rests on its ability to accurately predict the oxygen consumption per beat (it is clearly better than other mechanical indices) and ‘contractile efficiency’ does measure the total mechanical energy rather than only external work. The major problem for the model relates to its unsatisfactory molecular explanation. There is however considerable modeling work being done to address this problem. In the present investigation, the contractile efficiency was found to be around 40%, the same value as for various other animals species (see Table 1 in [15]) and aging did not alter contractile efficiency and this is in agreement with the studies of Suga and colleagues who have measured contractile efficiency in puppies and adult dogs [15,33].

The poor in vitro isotonic mechanical performance noted for the senescent papillary muscles in the present investigation, might lead one to expect that in vivo the cardiac index (cardiac output per body surface area) would be very depressed. Much earlier experiments by Spann and colleagues [34] upon pressure-overloaded hypertrophic cat hearts showed that in vivo there was only a 20% depression of the feline cardiac index but when papillary muscles were isolated from the same hearts they had a greatly decreased ability to generate isometric stress (only 50% of normal). Presumably this means that in vivo the heart works at greater end-diastolic volumes and with its contractile performance stimulated by higher levels of sympathetic outflow, and can maintain an adequate cardiac index in spite of greatly reduced intrinsic contractility.

In a recent review it was concluded that the aged heart seems to resemble a pressure-overloaded heart [1]. The cardiac energetic profile of the senescent rat group in the present study is in line with many findings in the isolated perfused whole heart literature, reviewed by Lakatta [1], and for the most part our data resembles the results we and others have obtained in various models of pressure overload.

Time for primary review 29 days.


   Acknowledgements
 
This work was performed with the support of the National Health and Medical Research Council of Australia.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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