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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55:B440-B447 (2000)
© 2000 The Gerontological Society of America

Age-Related Changes in Pumping Mechanical Behavior of Rat Ventricle in Terms of Systolic Elastance and Resistance

Kuo-Chu Changa, Ying-I Penga, Shou-Huang Daia and Yung-Zu Tsengb

a Departments of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
b Departments of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

Kuo-Chu Chang, Department of Physiology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan E-mail: kcchang{at}ha.mc.ntu.edu.tw.

Decision Editor: Jay Roberts, PhD


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Both the maximal systolic elastance (Emax) and the theoretical maximal flow (Q.max) can quantify the systolic mechanical behavior of the ventricular pump. Physically, Emax can reflect the intrinsic contractility of the myocardium as an intact heart. The quantity in Q.max is inversely related to the internal resistance of the left ventricle. How great the effects of age are on these Emax and Q.max has never been examined, however. This study was to determine the ventricular pumping mechanics in terms of the systolic elastance and resistance in male Fischer rats at 6, 12, 18, and 24 months of age. We measured left ventricular (LV) pressure and ascending aortic flow waves using a high-fidelity pressure sensor and an electromagnetic flow probe, respectively. Those two parameters that characterize the systolic pumping mechanics of the left ventricle are obtained by making use of an elastance–resistance model. The basic hemodynamic condition in those animals with different ages is characterized by (i) no significant change in cardiac output and (ii) a decrease in basal heart rate, LV end-systolic pressure, as well as effective arterial volume elastance. Changes that take place in the left ventricle with age include a decline in Emax and an increase in Q.max, especially at 24 months. These results demonstrate that the impaired intrinsic contractility of an aging heart may be compensated to some extent by the diminished ventricular internal resistance. Such compensation in aging rats may maintain normal blood flow essential for the metabolic needs of tissues and/or organs before heart dysfunction and failure occur.

THE aging process of the heart involves a number of interrelated events including biochemical, electrical, mechanical, and structural modifications (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). The effects of alterations in myocardial structure and biochemical process on cardiac mechanics can be quantified by making use of an elastance–resistance model. Parameters generated by this model to characterize the systolic pumping mechanics of the left ventricle are maximal systolic elastance (Emax) and theoretical maximal flow (Q.max). Physically, Emax, a parameter derived from the ventricular pressure-volume relation, can reflect the elastic behavior of the myocardium as an intact heart. It has been suggested that Emax could characterize the intrinsic contractile status of the left ventricle because of its independence of preload, afterload, and heart rate in a given contractile state of the ventricle (11). The quantity in Q.max is the amount of outflow generated by the ventricle if it were to eject under zero load condition and is inversely related to the ventricular internal resistance (12)(13). An inverse relation between Q.max and percent slow myosin has been observed, suggesting that isomyosin composition is one of the determinants of ventricular resistive behavior (12). One would expect that biochemical, electrical, mechanical, and structural modifications of an aging heart might be associated with an impairment in cardiac systolic mechanics in terms of Emax and Q.max.

The systolic elastance and resistance describe two independent facets of the left ventricle as a mechanical pump. Although the effects of aging process on cardiac mechanics in rats have been documented (1)(2)(3)(4)(5)(6)(7), the systolic mechanical behavior of the ventricular pump has never been explored in terms of the systolic elastance and resistance. Thus, the goal of the current study was to examine how great the effects of age are on those Emax and Q.max in male Fischer 344 rats at 6, 12, 18, and 24 months of age. The elastance–resistance model is employed to characterize the systolic mechanical behavior of the ventricular pump. Those two parameters that describe the systolic pumping mechanics of the left ventricle are obtained by making use of the elastance–resistance model. Thus, the effects of age on both the maximal systolic elastance and the theoretical maximal flow are determined.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Subjects
The specific pathogen-free male Fischer 344 rats used in this study were obtained from the colony maintained in the barrier facilities at the Animal Center of Medical College, National Taiwan University. Rats aged 6, 12, 18, and 24 months were individually referred to as young, adult, middle-aged, and senescent rats. All rats were allowed free access to the Purina chow and water and housed two to three per cage in a 12-hour light/dark cycle animal room. Periodic checks of the cages and body weights ensured that the food was administered properly. Rats at the ages of 6 (), 12 (n = 7), 18 (), and 24 ( months were anesthetized and thoracotomized for the study of age-related changes in cardiac systolic mechanics. The animal experiments were conducted according to the Guide for the Care and Use of Laboratory Animals of the American National Council and approved by the Animal Care and Use Committee of the National Taiwan University.

Measurements of Hemodynamic Data
Each rat was anesthetized with pentobarbital sodium intraperitoneally (35 mg/kg). The femoral vein was cannulated for the administration of supplemental pentobarbital (30 mg/kg every 2 hours). We monitored animal's rectal temperature and used a heater to maintain the rat's body temperature. Tracheotomy was performed to provide artificial ventilation with a tidal volume of 5–6 ml/kg and respiratory rate of 50–70 breaths/min (14). The chest was opened through the right second intercostal space. An electromagnetic flow probe (model 100 series, internal circumference 8–10 mm, Carolina Medical Electronics, King, NC) was positioned around the ascending aorta to measure the pulsatile aortic flow. A Millar catheter with a high-fidelity pressure sensor (model SPC 320, size 2F, Millar Instruments, Houston, TX) was used to measure the pulsatile left ventricular (LV) pressure. Before inserting the catheter, the pressure sensor was prewarmed in 37°C saline for at least 1 hour. The catheter was inserted via the isolated right carotid artery into the left ventricle. After withdrawing the catheter from each rat, the catheter was reimmersed in the bath to check for baseline drift. At the end of the experiment, the pressure reading from the sensor submerged in the saline of less than 10 mm in depth was used as the zero pressure reference. The electrocardiogram (ECG) of lead II was recorded with a Gould ECG/Biotach amplifier (Gould Electronics, Cleveland, OH).

The analogue waveforms were sampled at 500 Hz using a 12-bit simultaneously sampling analog-to-digital (A/D) converter interfaced to a personal computer. Selection of signals of 5–10 beats at steady state was made on the basis of the following criteria: (i) recorded beats with optimal velocity profile that is characterized by a steady diastolic level, maximal systolic amplitude, and minimal late systolic negative flow; (ii) beats with an RR interval (cardiac cycle length) less than 5% different from the average value for all recorded beats; (iii) exclusion of ectopic and postectopic beats. The selective beats were averaged in the time domain, using the peak R wave of ECG as a fiducial point. The resulting LV pressure and ascending aortic flow signals were subjected to further analysis using the procedure previously described (15)(16). First, the isovolumetric pressure curve is obtained from the instantaneous pressure of an ejecting contraction by a curve-fitting technique. Next, the elastance–resistance model with the estimated isovolumetric pressure is applied to measure the systolic mechanical properties of the ventricular pump.

Estimation of the isovolumetric pressure from an ejecting contraction.-- To estimate the isovolumetric pressure curve Piso(t) from an ejecting beat, a nonlinear least-squares approximation technique derived by Sunagawa and colleagues (17) is used:

(1)
where Pisomax is an estimated peak isovolumetric pressure point, {omega} is an angular frequency, c is a phase shift angle of the sinusoidal curve, and Pd is the LV end-diastolic pressure. Piso(t) is obtained by fitting the measured LV pressure curve segments from the end-diastolic pressure point to the peak positive dP/dt and from the pressure point of the peak negative dP/dt to the same level as the end-diastolic pressure of the preceding beat (18). The peak of the ECG R wave is used to identify the LV end-diastolic point. The upper panel of Fig. 1 schematically represents the relation between the ejection contraction and estimated isovolumetric contraction in the pressure-time diagram.



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  		Figure 1. The solid curves show the measured left ventricular (LV) pressure waveform (upper panel) and ascending aortic flow signal (lower panel) in a 24-month-old rat. In the upper panel, dashed line represents the isovolumetric pressure curve at an end-diastolic volume, which is estimated by fitting a sinusoidal function to the isovolumic portions of the measured LV pressure.

 
Prediction of the LV pressure using an elastance–resistance model.-- Model-derived pressure of the left ventricle P(t) can be calculated by using the elastance–resistance model if the model parameters are previously identified (19)(20). The relationship between instantaneous LV pressure, flow, and isovolumetric pressure can be written as follows:

(2)
where Vej(t) is instantaneous ejected volume computed by numerically calculating the running integral of the aortic flow signal Q.(t); Veed is an effective end-diastolic volume; Q.max is the theoretical maximum flow (i.e., the amount of outflow generated by the ventricle if it were to eject under zero load condition). Piso(t ) is the isovolumetric pressure obtained by occluding the ascending aorta near the sinuses of Valsalva at the end of diastole. Herein, Piso(t ) is replaced with Piso(t) that is derived from the measured pressure of an ejecting contraction by making use of 1.

Both Veed and Qmax are the model parameters that remain to be determined by curve-fitting techniques. Campbell and colleagues (21) found that 2 can be used to fit the measured LV pressure of an ejecting beat very well, if the fitting interval is tej < t < tpisomax, where tej is the onset of ventricular ejection, and tpisomax is the time of peak isovolumetric pressure. The normalized root-mean-square ep is

(3)
where P(i) and P(i) are the sampled values of observed and model-calculated pressure of the left ventricle, respectively. Initial values of Veed and Q.max are chosen first. The Nelder-Meade simplex algorithm (22) is then used in a nonlinear least-squares parameter-estimation procedure to iteratively adjust Veed and Q.max to minimize the normalized root-mean-square value. The parameters coincident with the minimum objective function are taken as the model estimates of the systolic pumping mechanics of the left ventricle. Fitness of the data generated by the model is judged by the magnitude of ep and by indices from a linear regression of the model-generated pressure P(i) on the measured pressure P(i). Two indices are used to evaluate the goodness-of-fit: (i) the coefficient of determination, r2, and (ii) the standard error of the estimate, SEE. We look for r2 to be close to 1 and for SEE to be on the order of less than 5% when expressed relative to the mean of pressure observations confined to the fitting interval (23). Fig. 2 shows the similarity between the computed and measured pressure waveforms during the interval tej < t < tpisomax. The LV systolic elastance E(t) can be calculated by the formulation of E(t) = Piso(t)/Veed. The maximal systolic elastance Emax is, therefore, quantified in terms of its maximal value, Emax = Pisomax/ Veed, and the internal resistance R in terms of the theoretical maximum flow Q.max, R(Piso) = Piso(t)/Q.max.



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  		Figure 2. The measured data (solid line) and model-generated data (dashed line) when the elastance–resistance model is fitted over tej < t < tpisomax. Little distinction can be made between the model-generated and observed data. The LV pressure is normalized to the estimated isovolumetric pressure.

 
Effective arterial volume elastance as arterial chamber property.-- The effective arterial volume elastance (Ea ) could be calculated as follows. The peak isovolumetric pressure of the left ventricle at the end-diastolic volume is estimated by 1. The pressure-ejected volume loop can be obtained by the time integration of aortic flow and the measured LV pressure (Fig. 3). Drawing a tangential line from the estimated peak isovolumetric pressure to the right corner of the pressure-ejected volume loop yields a point referred to as the end-systolic equilibrium point (24)(25). The pressure of the left ventricle at this end-systolic equilibrium point is the LV end-systolic pressure. Therefore, the slope of the end-systolic pressure versus stroke volume relation (the dashed line in Fig. 3) represents the effective arterial volume elastance.



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  		Figure 3. End-systolic pressure-stroke volume relation. Drawing a tangential line from the estimated peak isovolumic pressure to the right corner of the pressure-ejected volume loop yields a point referred to as the end-systolic equilibrium point. The pressure of the left ventricle at this point is the LV end-systolic pressure. The slope of the dashed line connecting the end-diastolic point to the end-systolic equilibrium point represents the effective arterial volume elastance.

 
Statistics
Results are expressed as means ± SE. When multiple comparisons were made for the effects of age on the systolic mechanical behavior of the left ventricle, statistical significance was determined by analysis of variance (ANOVA). Significant differences are assumed at the level of p < .05. If ANOVA for a hemodynamic variable reached the significant level, then the Tukey method was used to determine the groups of rats having different mean values of the variable.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
The effects of age on body weight, ventricular performance, and arterial chamber properties are shown in Table 1 and Fig. 4 and Fig. 5. The body weight of rats increased until 18 months, with a little decline in weight at 24 months. Although the weight of the LV increased with increasing age, a significant rise was observed in LV weight only at 24 months when compared to 6-month-old rats. Basal heart rate exhibited an age-related gradual decline with a significant fall in rate at both 18 and 24 months. No change was noted in cardiac output as a function of age, whereas LV end-systolic pressure showed a significant drop at 24 months when compared with 12-month-old animals. Estimated peak isovolumetric pressure was similar among rats at the ages of 6, 12, 18, and 24 months (Fig. 4). However, there was an age-associated progressive decline in effective arterial volume elastance, having a significant fall at both 18 and 24 months (Fig. 5).


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  		Table 1. Hemodynamics and Left Ventricular Performance in 6-, 12-, 18-, and 24-Month-Old Rats

 


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  		Figure 4. Effects of age on the peak isovolumic pressure of the left ventricle estimated by 1. No change was noted in the estimated peak isovolumic pressure as a function of age ( p > .05).

 


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  		Figure 5. Effects of age on the chamber properties of the vasculature. There was an age-associated progressive decline in the effective arterial volume elastance showing a significant fall at both 18 and 24 months ( p < .01).

 
The results of fitting the elastance–resistance model to LV pressure show little distinction between the model-generated and measured signals. The averaged values for ep as an indication of the quality of fit was 0.0035 ± 0.0002. Goodness of the model fit can also be reflected in the coefficient of determination and the relative SEE calculated from a linear regression of the model-generated P(t) on measured P(t) values (r2 0.9848 ± 0.0039 and ± 0.23 averaged over all rats studied).

The model-estimated parameters that quantitate the systolic mechanical behavior of the left ventricle are depicted in Fig. 6 Fig. 7Fig. 8. A significant rise was seen in effective LV end-diastolic volume at 24 months when compared to 6-, 12-, and 18-month-old rats, respectively (Fig. 6). Maximal systolic elastance showed an age-related gradual decline with a significant drop in this parameter at 24 months (Fig. 7). Because alteration in LV mass with age may affect elastic behavior of the left ventricle, we compared normalized Emax (i.e., maxn max/LV weight) between the four groups and found it to be still significantly lower for senescent animals (Fig. 7). On the contrary, theoretical maximal flow exhibited a significant rise in an aging heart, suggesting that ventricular internal resistance tends to be significantly lower for senescent rats (Fig. 8). It is interesting that there was an inverse relation between theoretical maximal flow Q.max and effective arterial elastance Ea when a linear regression of Q.max on Ea was performed over all animals studied (, p < .001; Fig. 9).



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  		Figure 6. Effects of age on the effective end-diastolic volume of the left ventricle (LV) estimated by 2. A significant rise was seen in the effective LV end-diastolic volume at 24 months when compared to 6-, 12-, and 18-month-old rats, respectively ( p < .01).

 


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  		Figure 7. Effects of age on the maximal systolic elastance of the left ventricle computed by the use of Pisomax/Veed. Both the maximal systolic elastance Emax and the normalized Emaxn showed an age-related gradual decline with a significant drop at 24 months ( p < .01). The results indicated that the aging process of the heart deteriorated the intrinsic contractile status of the rat ventricle, especially at the age of 24 months. Note: maxn max.

 


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  		Figure 8. Effects of age on the theoretical maximal flow of the left ventricle estimated by 2. The theoretical maximal flow exhibited a significant rise in an aging heart ( p < .01), suggesting that the ventricular internal resistance tended to be significantly lower for senescent rats.

 


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  		Figure 9. Theoretical maximal flow .Qmax for Fischer 344 rats from 6 to 24 months of age plotted against effective arterial volume elastance Ea. No significant relation between .Qmax and Ea was observed within each age group ( p > .05). However, an inverse relation between .Qmax and Ea is evident after pooling the data of all age groups. The solid line is obtained when a linear regression of .Qmax on Ea is performed over all animals studied, having the linear equation .Qmax a , p < .001.

 
From Table 1 and Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8 we concluded that no significant changes were observed in arterial chamber property, ventricular performance, and cardiac systolic mechanics, when comparison was made on rats between 6 and 12 months old. Although there was no significant alteration in either ventricular performance or in arterial chamber property between middle-aged and senescent rats, a different picture between these two groups emerged when we examined the systolic mechanical behavior of the left ventricle in terms of Emax and Q.max.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The assessment of age-associated changes in the cardiovascular system has long interested clinicians and physiologists (26)(27)(28)(29). Many recent studies look at the effect of aging on myocardial muscle and some aspects of intact ventricular function (1)(3)(30)(31). However, there are few data on how aging affects ventricular pressure–volume and/or internal resistance in an intact cardiovascular system. To our knowledge, this is the first study to examine the effects of age on cardiac mechanics in terms of the systolic elastance and resistance. A striking finding of this study is that with advancing age there is a decline in maximal systolic elastance associated with an enhancement in theoretical maximal flow in Fischer 344 rats.

The basic hemodynamic condition and ventricular performance in rats at the ages of 6, 12, 18, and 24 months are characterized by (i) no significant change in cardiac output, and (ii) a significant decline in basal heart rate, LV end-systolic pressure, as well as effective arterial volume elastance. If a small difference between LV end-systolic pressure and mean aortic pressure is ignored, then LV end-systolic pressure can approximate mean aortic pressure (32). A fall in hydraulic load with age can be reflected in the fact that there is an age-associated drop in LV end-systolic pressure in the absence of age-related alteration in cardiac output. In this study, we treated the arterial system like an elastic chamber with the effective arterial volume elastance Ea. Since Ea is directly related to physical arterial resistance (32), the age-related fall in hydraulic load may account for the reduction in Ea with age. These results of age-related changes in cardiac output, basal heart rate, and hydraulic load are in accordance with other reports in the literature (33)(34)(35).

The properties of the contractile unit along with the activation process (i.e., availability of Ca2+) and extramyocytic components determine the elastic behavior of the ventricle (13)(36). Although a gradual decline in maximal systolic elastance Emax occurs in rats with increasing age, a significant fall is observed in Emax only at 24 months relative to other groups. Because no alteration is noted in estimated peak isovolumetric pressure as a function of age, a significant rise in effective LV end-diastolic volume accounts for the diminished Emax in 24 month-old rats. We also compared the normalized Emax (i.e., axn max weight) between the four groups and found it to be still significantly lower for senescent rats. Recently, Klebanov and colleagues (37) calculated the pressure-normalized volume relation using isolated heart preparation and showed similar results: that younger rats (10 weeks of age) had higher slope of the relation than did older rats (10–13 months of age). Thus, the aging process of the heart involving alterations in activation process and extramyocytic components may profoundly affect Emax, deteriorating the intrinsic contractile status of the rat ventricle, especially at the age of 24 months.

Change that takes place in another aspect of the cardiac systolic mechanics with age is an increase in theoretical maximal flow Q.max. Shroff and associates (12) showed the relation between LV systolic resistance and ventricular rate process in spontaneous hypertensive rats with hypo- and hyperthyroidism. They found that myosin isoenzyme composition, rather than LV hypertrophy or muscle mass per se, could affect Q.max; they believed that myosin isoenzyme composition was one of the determinants of ventricular resistive behavior. Many reports in the literature demonstrate the occurrence in the aging myocardium of the shift of the myosin isoenzyme profile from the fast V1 isoform toward the slow V3 isoform (3)(5)(6)(7)(8). One would expect that this isoenzyme shift in the aging heart might cause a decline in Q.max and then a rise in ventricular internal resistance to diminishing ventricular outflow. On the contrary, we show data quite different from that speculation, based on the biochemical changes in the aging heart. That is because Q.max of the left ventricle is also sensitive to change in arterial chamber property: the higher the chamber stiffness, the lower the Q.max of the left ventricle and vice versa (16). Thus, the age-related decrease in arterial chamber stiffness implicated in the age-associated reduction in Ea may be the major factor responsible for the increased Q.max with increasing age. The increased Q.max associated with unaltered Piso max with age accounts for a decrease in ventricular internal resistance of an aging heart.

When considering the integrated cardiovascular function, one requires not only information about cardiac dynamics but also knowledge of vascular mechanics. As mentioned earlier, changes that take place in an aging ventricle include a decline in maximal systolic elastance and an increase in theoretical maximal flow. Alteration that takes place in the arterial system as a chamber with age is a fall in effective arterial volume elastance. These results demonstrate that the impaired intrinsic contractility of an aging heart may be compensated to some extent by the diminished ventricular internal resistance and hydraulic load, when the ventricle is coupled with the arterial system. Such compensation in aging rats probably maintains normal blood flow essential for the metabolic needs of tissues and/or organs before heart dysfunction and failure occur.

Some limitations of the current study deserve consideration. In this report, the results pertain only to measurements made in the open-chest rat with anesthesia. This setting induced a fall in blood pressure and may introduce reflex effects not found in the closed-chest setting. It is uncertain how great the effects of anesthesia and thoracotomy are on cardiac systolic mechanics in rats. However, studies on other animal models suggest that the effects are small relative to biological and experimental variability among animals (38).

It should be noted that isovolumic beats were not obtained by occluding the ascending aorta at the end of diastole; instead, the isovolumetric pressure was estimated by the use of curve fitting of the ejecting beat. It has been reported that the duration of the isovolumic contraction by abruptly clamping the aortic root is significantly longer than that of the ejecting contraction (17)(19). The cardiac cycle length of the estimated isovolumetric pressure is therefore shorter than that of the measured isovolumetric pressure. However, Sunagawa and colleagues (17) have shown that the estimated Pisomax is quite close to the Pisomax actually measured by occluding the ascending aorta in diastole. They have reached the conclusion that quantitative contribution of the different durations of contraction to the Pisomax estimation appears insignificant under the basal, vasoconstricted, and vasodilated conditions. Consequently, the Pisomax could be estimated reasonably well by the nonlinear parameter estimation technique.

Another concern is that the elastance–resistance model is not a perfect model in the evaluation of the LV systolic mechanics. Hunter and colleagues (36)(39), using the flow-pulse response technique, demonstrated that, besides elastance and resistance, there are at least two or more processes involved in the description of mechanical properties of the ventricular pump. One is the volume influence factor that has a value of 1.0 during early systole and gradually declines to a lower value during late systole. The other is the irreversible loss of pressure caused by change in volume. Moreover, Campbell and colleagues (19) found that the elastance–resistance model failed to describe the instantaneous LV pumping behavior, especially during late ejection period and from the predictive point of view. However, in an earlier article (21), they showed that the elastance–resistance model could be used to fit the measured LV pressure of an ejection beat very well, if the fitting interval was from the onset of ventricular ejection to the time of peak isovolumetric pressure. Shroff and colleagues (13) believe that elastance–resistance is a useful model to quantify LV systolic mechanical properties, provided one clearly understands its limitations.

In summary, the major changes that take place in the left ventricle with age are (i) decrease in basal heart rate; (ii) decrease in LV end-systolic pressure; (iii) decrease in maximal systolic elastance; (iv) increase in effective LV end-diastolic volume; (v) increase in theoretical maximal flow. Change resulting from aging arterial system as a chamber includes decrease in effective arterial volume elastance. Those aspects of LV function that appear to show little or no age-related alteration are cardiac output and peak isovolumetric pressure. From these measurements it is clear that the impaired intrinsic contractile status of an aging heart may be compensated to some extent by the diminished ventricular internal resistance and hydraulic load, when the ventricle is coupled with the arterial system. Such compensation in rats with age may maintain normal blood flow essential for the metabolic needs of tissues and/or organs before heart dysfunction and failure occur.


   Acknowledgments
 
This study was supported by grants from the National Science Council of Taiwan (NSC 87-2314-B-002-274 and NSC 88-2314-B002-209).

Received July 6, 1999

Accepted February 17, 2000


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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