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(Circulation. 2001;104:221.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Exercise Training Attenuates Age-Associated Diastolic Dysfunction in Rats

Daniel A. Brenner, MA; Carl S. Apstein, MD; Kurt W. Saupe, PhD

From the Cardiac Muscle Research Laboratory, Boston University School of Medicine, Boston, Mass.

Correspondence to Kurt W. Saupe, PhD, Cardiac Muscle Research Laboratory, 650 Albany St, X720, Boston, MA 02118. E-mail ksaupe{at}aol.com

	Abstract

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Background—— In contrast to systolic function, which is relatively well preserved with advancing age, diastolic function declines steadily after age 30. Our goal was to determine whether changes in diastolic function that occur with aging could be reversed with exercise training.

Methods and Results—— Adult (6-month-old) and old (24-month-old) Fischer 344/BNF1 rats were studied after either 12 weeks of treadmill training or normal sedentary cage life. Three aspects of diastolic function were studied: (1) left ventricular (LV) filling in vivo via Doppler echocardiograph, (2) LV passive compliance, and (3) the degree of ischemia-induced LV stiffening. Maximal exercise capacity was lower in the old rats (18±1 minutes to exhaustion on a standard treadmill) than in the adult rats (25±1 minutes). Training increased exercise capacity by 43% in the old rats and 46% in the adults (to 26±1 and 37±1 minutes, respectively). Echocardiographic indices of LV relaxation were significantly lower in the old rats, but with training, they increased back to the levels seen in the adults. LV stiffness measured in the isolated, perfused hearts was not affected by age or training. Also in the isolated hearts, the LV stiffened more rapidly during low-flow ischemia in the old hearts than in the adults, but training eliminated this age-associated difference in the response to ischemia.

Conclusions—— Our findings indicate that in rats, some age-associated changes in diastolic function are reversible and thus may not be intrinsic to aging but instead secondary to other processes, such as deconditioning.

Key Words: aging • ischemia • exercise • diastole

	Introduction

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In contrast to systolic function, which is relatively well preserved with advancing age, diastolic function declines steadily after age 30 years.¹ The age-associated decline in diastolic function occurs even in the absence of cardiovascular disease and is thought to be a major reason why the incidence of diastolic heart failure increases exponentially with age.^1–3 It is unclear whether the age-associated decline in diastolic function is caused by aging or by other factors that change with age, such as cardiovascular fitness, which is known to correlate with diastolic function.^4–6 In isometrically contracting papillary muscle and trabeculae carneae from rats, age-associated slowing of contraction and relaxation can be reversed with exercise training.^7,8 How these effects of training are manifested in the whole hearts of aged animals is unclear. Likewise, it is unclear how training affects other important aspects of diastolic function in the aged heart. These include left ventricular (LV) compliance and the rate of LV stiffening during ischemia, which is of particular interest because of the increased prevalence and poor prognosis of ischemic heart disease in the elderly.⁹

Accordingly, our goal was to determine whether age-associated changes in diastolic function could be reversed with exercise training. To accomplish this, 6- and 24-month-old Fischer 344/BNF1 rats were studied. An exercise training protocol was designed so that after 12 weeks of training, old trained rats were matched in maximal exercise capacity to adult untrained rats. Thus, any differences in diastolic function would be due to aging and not differences in cardiovascular capacity. Because diastolic function consists of 2 distinct parameters, relaxation and compliance,¹⁰ we evaluated multiple aspects of diastolic function both in vivo and ex vivo. These included LV filling in vivo with Doppler echocardiography of mitral inflow, and in isolated perfused hearts, baseline LV compliance and the ischemia-induced loss of compliance.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Animals
Male Fischer 344/Brown Norway F1 rats were studied in accordance with the guidelines of the Animal Care and Use Committee of the Boston University School of Medicine and the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health. A hybrid, as opposed to an inbred, strain of rat was used because of the longer life span reported in these rats, which is probably a result of their lower rates of the pathological conditions associated with inbreeding.¹¹ Rats were purchased at 3 (n=18) and 21 (n=17) months of age and were studied after 3 months (at 6 and 24 months of age). These 2 age groups were chosen for study because the 6-month-olds represent a group of mature rats, as indicated by the fact that their rapid growth phase is over, and at 24 months of age, there is as yet relatively little mortality (<15%).¹² Thus, the effects of 18 months of aging can be studied with minimal effects from confounding factors such as growth, a "survivor effect," or overt pathology.

Exercise Training and Measurement of Exercise Capacity
Rats were acclimated to the treadmill by walking at a speed of 10 m/min, 10 min/d, for 2 weeks on a 4-lane Columbus Instruments treadmill. After this acclimatization period, 8 rats in each age group were randomly assigned to training (45 min/d, 5 d/wk, for 12 weeks). Training consisted of running at a speed of either 26 m/min (adult) or 17 m/min (old). These different speeds were necessary to ensure that both age groups trained at approximately the same relative intensity, estimated at 70% to 85% of maximal oxygen uptake.^13,14 The remaining rats (untrained groups) walked 10 min/d once or twice per week during the 12-week period to maintain treadmill familiarity. At the end of the 12-week period, maximal exercise capacity was measured twice in each rat in tests separated by 2 days. The protocol for the maximal exercise capacity test consisted of walking at 10 m/min for 5 minutes followed by 2 m/min increases in speed every 2 minutes until the rat reached exhaustion. Rats were considered exhausted when they failed to stay off of a shock bar. The grade of the treadmill was set at 15° during walking, training, and maximal exercise capacity tests.

In Vivo LV Function Evaluation by Echocardiography
Echocardiograms were recorded during light ketamine/xylazine (35 and 5 mg/kg) anesthesia in 8 rats from each of the 4 groups. A 7.5-MHz short-focus transducer with a 60-Hz acquisition rate was used (Hewlett-Packard Sonos 5500). Images were obtained in the parasternal long-axis and short-axis and apical 2-chamber and 4-chamber views. Images were recorded and analyzed by an experienced sonographer blinded to the experimental design.

M-mode recordings were obtained through the septal and posterior walls. Left ventricular end-diastolic (EDD) and end-systolic (ESD) diameters and septal and posterior wall thicknesses were measured from leading edge to leading edge, according to recommended guidelines.¹⁵ Endocardial percent fiber fractional shortening was calculated as (EDD-ESD)/EDDx100.

Pulsed-wave Doppler spectra of mitral inflow were recorded from an apical 4-chamber view with the sample volume placed at the tips of the mitral leaflets in diastole. Measurements were made of peak flow velocity of the early filling wave (E) and peak flow velocity of the late filling wave (A) as well as the rate of decrease in the early flow (E_dec slope).

Isolated Perfused Heart Studies
After rats were euthanized, their isolated hearts were studied. In these isolated heart studies, the LV pressure-volume relationship was measured, as was the response to low-flow ischemia. Isolated-heart studies were performed in an isolated isovolumically beating (balloon-in-LV) heart preparation perfused with bovine red blood cells as previously described.¹⁶ Hearts were paced at 5 Hz (Grass Instruments, model 59). The coronary perfusate consisted of bovine red blood cells at a hematocrit of 0.40 washed and resuspended in Krebs-Henseleit buffer (in mmol/L: NaCl 118, KCl 4.7, CaCl₂ 2.0, KH₂PO₄ 1.2, MgSO₄ 1.2, NaHCO₃ 26.6, glucose 5.5, lactate 1.0, and palmitic acid 0.4, and 40 g/L BSA. Perfusate was equilibrated with 20% O₂, 3% CO₂, 77% N₂ for a PO₂ of 120 to 140 mm Hg, pH 7.4.

To determine how age and training affect the passive compliance (reciprocal of stiffness) of the LV, the relationship between LV volume and LV end-diastolic pressure (EDP) was measured in each heart by filling the balloon with saline in increments of 0.05 mL until LV EDP reached 40 mm Hg. The relationship between LV volume and EDP was plotted to a single exponential for values between 3 and 40 mm Hg in a modification of the technique of Fletcher et al.¹⁷ The stiffness constant (k) was derived for each heart from the equation EDP=be^kV. The relationship between EDP and LV volume was well fit by this equation, with average r² values >0.96 for each group of hearts.

After the LV pressure-volume measurements, coronary perfusion pressure was set between 80 and 85 mm Hg in each group of hearts for a 30-minute baseline period. Coronary flow was then decreased to 15% of baseline for the 45-minute period of low-flow ischemia. Increases in EDP during ischemia indicate a stiffening of the LV.¹⁸ Data from hearts that demonstrated >10 minutes of fibrillation during the 45 minutes of low-flow ischemia (1 adult untrained, 3 old untrained, 2 old trained) were excluded.

Statistical Analysis
Data are presented as mean±SEM. A 2-factor (age, training) ANOVA was performed on the data presented in Tables 1 and 2 and Figure 2. In Figures 3 and 4, 2-way ANOVA with 1 repeated measure were used, followed by a Fisher’s least significant difference post hoc teSt. Probability values of P<0.05 were considered statistically significant.

View this table: [in this window] [in a new window]   Table 1. Physical Characteristics of the 4 Experimental Groups

View larger version (16K): [in this window] [in a new window]   Figure 2. Twelve weeks of exercise training significantly increased maximal exercise capacity, defined as time to exhaustion on a standardized treadmill running protocol, in both age groups. Note that adult untrained and old trained groups were well matched for maximal exercise capacity. Probability values are based on a 2-factor (age, training) ANOVA.

View larger version (17K): [in this window] [in a new window]   Figure 3. Relationship between LV volume and EDP was not affected by training in either adult or old rats. Rightward shift without a change in slope in old hearts relative to adults indicates an increase in LV chamber volume without a change in passive LV stiffness. Neither age nor training altered passive LV stiffness. At each volume, EDP was significantly lower in old hearts than in adults by 2-way ANOVA for repeated measures.

View this table: [in this window] [in a new window]   Table 2. Echocardiographic Characteristics of the 4 Experimental Groups

	Results

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Animal Characteristics
Body weight increased with age and was modestly decreased by training (Table 1). Heart weight and the ratio of heart weight to tibia length (an index of LV hypertrophy) increased with age but were not affected by training. Heart rate and tail-cuff systolic blood pressure, measured just after the echocardiograms in the anesthetized rats, were not affected by age. Training decreased systolic pressure in both age groups.

Exercise Capacity
The reproducibility of measuring maximal exercise capacity was high, as demonstrated by the r² value of 0.77 for the correlation of the 2 measurements of maximal exercise capacity made in each rat at the end of the 12-week period of training or sedentary cage life (Figure 1). Exercise capacity decreased significantly with age and increased with training, as expected (Figure 2). In adult rats, exercise capacity was 46% (11.5 minutes) greater in the trained than the untrained group, whereas in old rats, exercise capacity was 43% (7.8 minutes) greater in the trained than the untrained group. The 12-week training protocol generated a group of old rats with a maximal exercise capacity that was well matched to a group of untrained adult rats (25.2±1 minutes in adult untrained and 25.9±1 minutes in old trained).

View larger version (17K): [in this window] [in a new window]   Figure 1. Maximal exercise capacity was measured twice in each rat at end of 12 weeks. Reproducibility of measuring maximal exercise capacity is demonstrated by large r2 value, near unity of slope, and small intercept.

Echocardiography
Resting LV function was evaluated echocardiographically at the end of the 12 weeks (Table 2). Diastolic function was evaluated by pulsed Doppler echocardiography of mitral inflow. With age, early diastolic filling was impaired, as indicated by decreased E-wave amplitude, decreased E deceleration slope, and increased E deceleration time (Table 2). In addition, the E/A-wave ratio was modestly decreased (P=0.06) with age because of the decrease in the E-wave amplitude. With training, early relaxation improved in the aged hearts, as indicated by an increased E-wave amplitude, increased E deceleration slope, increased E/A-wave ratio, and decreased E deceleration time (Table 2). In the adult hearts, these changes in early relaxation with training did not occur, although A-wave amplitude did decrease modestly with training.

Isolated Hearts: Passive LV Stiffness
To determine the effects of age and training on LV stiffness, the relationship between LV volume and EDP was measured (Figure 3). LV volume was 0.10 mL larger in old hearts than in the adults, as indicated by the rightward shift in the pressure-volume curves. Passive LV stiffness, however, defined as the exponential slope of the pressure-volume relationship, did not differ among the 4 groups, being 10.8±1.6 and 10.2±1.0 in the adult untrained and trained hearts, respectively, and 9.3±1.3 and 9.2±1.1 in the old untrained and trained hearts. Thus, neither age nor training altered passive LV stiffness.

Isolated Hearts: Ischemic Diastolic Dysfunction
LV systolic function during the preischemic baseline period was not different among the 4 groups, although there was a tendency for LV developed pressure to be greater in the 2 trained groups (Figure 4, top). During the 45 minutes of low-flow ischemia, developed pressure decreased similarly in all 4 groups of hearts. In contrast, EDP increased more rapidly during low-flow ischemia in the old untrained hearts than the other groups, indicating a more rapid ischemia-induced stiffening of the LV (Figure 4, bottom). EDP was 33±4 mm Hg after 25 minutes of low-flow ischemia in the old untrained group, compared with 24±2 mm Hg in the adult untrained group, 23±3 in the adult trained group, and 23±4 in the old trained group. The final degree of LV stiffening (EDP) at the end of the 45 minutes of low-flow ischemia, however, did not differ among the 4 groups of hearts, ranging from 38±3 mm Hg in the old untrained group to 31±4 mm Hg in the old trained group (P=NS).

View larger version (27K): [in this window] [in a new window]   Figure 4. During 45 minutes of low-flow (15% of baseline) ischemia, LV developed pressure decreased similarly in all 4 groups of hearts (top). EDP increased most rapidly in old untrained group, but by end of ischemic period, EDP was not different among 4 groups (bottom). *Significantly greater than adult trained group; **significantly greater than either trained group by 2-way ANOVA with 1 repeated measure.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
LV Relaxation
Diastolic function is adequate when the LV can fill to an appropriate volume at a low filling pressure. For this to occur, myofilament tension must be rapidly released at the end of systole. Studies in isolated papillary muscles have shown that with aging, release of tension is slowed secondary to prolonged calcium transients and diminished calcium reuptake mechanisms.^8,19 Clinically, diastolic function is evaluated by measuring the flow from the left atrium into the left ventricle (transmitral flow) by Doppler echocardiography.¹⁰ Despite the limitations, including heart rate- and load-dependence, Doppler echocardiography of mitral inflow has proved useful for studying changes in diastolic function with age and disease in humans.^1,4,5,10,20 Surprisingly, Doppler echocardiographic assessment of diastolic function has not previously been performed in aged rats, despite their frequent use as an animal model of aging. Here, we report that LV filling early in diastole was impaired in the aged hearts, even though systolic function was not. This pattern of normal systolic function with impaired filling in early diastole is similar to what has been reported to occur in humans with aging.¹ The impaired diastolic filling in the aged hearts that we observed may represent the whole-heart phenotype of the impaired isometric relaxation reported in isolated rat papillary muscle.^7,8,21

The effect of chronic exercise on the age-associated decline in diastolic function in humans is controversial. In cross-sectional studies, Fleg et al⁵ found that physical condition did not have an effect on the decline in echocardiographic indices of diastolic function with age. In contrast, Takemoto et al⁶ reported that trained subjects had better resting diastolic function than age-matched untrained subjects. In a longitudinal study, Levy et al⁴ reported that training improved early diastolic filling in older men as assessed with radionuclide ventriculography. Less controversial is the finding that exercise training improves resting diastolic function in patients with dilated cardiomyopathy and impaired LV relaxation.²⁰

We found that 12 weeks of exercise training in the aged rats largely reversed the age-associated impairment in early diastolic filling. The underlying molecular mechanism for this improvement could be either reversal of the age-associated changes that resulted in the impaired diastolic function, or alternatively, some beneficial effect of training on diastolic function in general. Because an equivalent degree of training in the adult group did not improve LV filling during diastole, our data favor, but do not prove, a reversal of the molecular changes that occur with aging. More definitive proof that training improves LV relaxation in the aged by reversing the effects of aging comes from Tate et al,⁸ who demonstrated in rats that training reverses the age-associated decline in myocardial calcium reuptake. Our finding that exercise improved echocardiographic indices of LV filling in the aged rat heart probably represents the in vivo, whole-heart manifestation of the improved calcium reuptake and relaxation that others have reported in isolated muscle strips from trained, aged rat hearts.^7,8

LV Passive Compliance
For the LV to fill to an adequate volume at a low filling pressure, not only must tension release rapidly at the end of systole, but passive LV compliance must also be high.¹⁰ In humans, determining the independent effect of age on LV compliance is complicated by the fact that age is associated with conditions that decrease compliance, such as hypertension. In the absence of hypertension or other cardiovascular disease, passive LV compliance does not appear to change with age.^22,23 This is in contrast to the vasculature, which clearly stiffens with age.²⁴ Thus, our finding that passive LV stiffness, quantified as the stiffness constant from the LV pressure-volume relationship, was not significantly altered with aging is consistent with the literature.

Effect of Ischemia on EDP
The extent to which aging affects the response to hypoxia/ischemia is controversial and highly model-dependent: some studies show a diminished ischemic tolerance in the aged,^25,26 whereas other studies have shown subtle, if any, effects of age.^27,28 We used a model in which the coronary perfusate contained a normal hematocrit and oxygen content and normal concentrations of the major substrates for myocardial metabolism (free fatty acids, glucose, and lactate). A degree of myocardial hypoperfusion was chosen (0.2 mL · min^-1 · g^-1) that approximates the level of flow reported in humans and dogs in a region of myocardium undergoing a myocardial infarction.^29,30

Using this model, we observed that the rate of LV stiffening during ischemia was accelerated in the old untrained hearts, resulting in an EDP that was transiently 8 to 12 mm Hg greater than that in the other groups (Figure 4). Although this age-associated acceleration in LV stiffening may appear modest, in patients, a transient ischemia-induced increase in LV EDP of only 5 mm Hg significantly increased pulmonary capillary pressure, airway resistance, and lung stiffness.³¹ The degree to which ischemic tolerance was impaired in our old rats was less than that reported in other studies, partly because we chose to study a strain of rats that at 24 months of age is presenescent, in contrast to the senescent rats used in many other studies.^25,27,28

The increased rate of diastolic stiffening during ischemia in the aged hearts was not present in the trained group, suggesting that it is not an inevitable consequence of aging but instead may be secondary to deconditioning. Again, the question of whether this improvement with training is due to reversal of the age effect or superimposition of some other effect is not addressed by our study. Because the increase in EDP during ischemia in this model is due to subendocardial rigor,^16,32 our data suggest that in the aged heart, training slows the rate at which rigor develops.

	Acknowledgments

 
This research was supported by NIH grants AG-16908, HL-55993, and HL-07224. The authors wish to thank Soeun Ngoy for his expert technical assistance and Dr Nancy K. Sweitzer for her thoughtful criticisms.

Received January 2, 2001; revision received March 15, 2001; accepted March 28, 2001.

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