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HIGHLIGHTED TOPICS
Physiology of Aging

Echocardiographic assessment of age-associated changes in systolic and diastolic function of the female F344 rat heart

¹Division of Kinesiology, Laboratory of Molecular Kinesiology, and ²Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, The University of Michigan, Ann Arbor, Michigan 48109-2214

Submitted 24 September 2003 ; accepted in final form 7 October 2003

	ABSTRACT

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Aging is associated with hypertrophy, dilatation, and fibrosis of the left ventricle (LV) of the heart. Advances in echocardiographic assessment have made it possible to follow changes in cardiac function in a serial, noninvasive manner. The purpose was to determine whether there is echocardiographic evidence of age-associated changes in chamber dimensions and systolic and diastolic properties of the female Fischer 344 (F344) rat heart. On the basis of previous invasive studies, it was predicted that echocardiographic assessment would detect age-associated changes in indexes of systolic and diastolic function. Rats were sedated with 1.5% isoflurane and placed in the supine position. Two-dimensional images and two-dimensionally guided M-mode, Doppler M mode, Doppler tissue, and pulsed-wave Doppler recordings were obtained from the parasternal long axis, parasternal short axis, and/or apical four-chamber views as per convention by using a 15-MHz linear array or 8-MHz phased-array transducer or a GE S10-MHz phased-array transducer. Compared with young adult 4-mo-old rats, there is a significant decrement in the resting systolic function of the LV in 30-mo-old female F344 rats as evidenced by declines in LV ejection fraction (80 ± 9 vs. 89 ± 5%; mean ± SD), fractional shortening (43 ± 9 vs. 54 ± 8%) and velocity of circumferential fiber shortening (2.43 ± 0.53 vs. 2.99 ± 0.50 circ/s). Evidence for age-associated differences in diastolic function included an increase in isovolumic relaxation time (25.0 ± 7.6 vs. 17.2 ± 4.4 ms) and decreases in the tissue Doppler peak E waves at the septal annulus and at the lateral annulus of the mitral valve. The modest changes in systolic and diastolic LV function that occur with advancing age in the female F344 rat are likely to reduce the capacity of the heart to respond to hemodynamic challenges.

systolic dysfunction; diastolic dysfunction; left ventricular dilatation

Advances in echocardiographic assessment have overcome these difficulties, but only a few studies have leveraged these capabilities to examine age-associated changes in heart chamber remodeling and function (5, 7). The purpose of this investigation was to determine whether there is echocardiographic evidence of age-associated changes in chamber dimensions, chamber volumes, systolic function, and diastolic properties of the female F344 rat heart. On the basis of previous invasive studies of cardiac structure and function, it was predicted that noninvasive echocardiographic assessment might detect age-related changes in indexes of systolic and diastolic function.

	MATERIALS AND METHODS

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Animals. Specific pathogen-free female Fischer 344 rats were obtained from the National Institute on Aging-sponsored colony at Harlan Industries, Indianapolis, IN, at 3 (n = 21), 13 (n = 8), 22 (n = 10), and 30 mo postpartum (n = 25) and studied at 4, 13, 22, and 30 mo of age. Rats were housed 2-3 per cage, fed a standard laboratory diet 5001 (PMI Nutrition International) and water ad libitum, and maintained on a 12:12-h light-dark cycle. All animal protocols were approved by the University Committee on Use and Care of Animals at the University of Michigan (protocol nos. 7953 and 8089). All animal protocols conformed to the Guiding Principles in the Care and Use of Animals of the American Physiological Society.

Echocardiography. Rats were sedated with 1.5% isoflurane and placed in the supine position. Two-dimensionally guided M-mode recordings were obtained from the short-axis view at the level of the papillary muscles by using either an Acuson Sequoia system and an Acuson 15-MHz linear-array transducer (Fig. 1, A and B) or a GE Vivid 7 system with a GE S10-MHz phased-array transducer (General Electric). LV end-systolic and end-diastolic dimensions, as well as systolic and diastolic wall thickness, were measured from the M-mode tracings by using the leading-edge convention of the American Society of Echocardiography. For each M-mode measurement, at least three consecutive cardiac cycles were sampled. LV mass and ejection fraction were calculated from these short axis wall thickness and chamber dimension measurements by assuming a spherical LV geometry. Mitral valve inflow velocities were measured in the apical four-chamber view at the level of the chordal attachments to the papillary muscles (Fig. 1C). Velocity of flow propagation was measured in the same view by using an Acuson 8-MHz phased-array transducer (Fig. 1D) or a GE S10-MHz phased-array transducer. Pulmonary venous Doppler tracings of the left lower pulmonary vein were obtained in the parasternal long axis view and measured at the entrance of the vein into the left atrium (Fig. 1E). Doppler tissue imaging from the apical four-chamber view was used to assess mitral valve annular velocities (Fig. 1F). All measurements were made in accordance with the conventions of the American Society of Echocardiography and were determined by a single echocardiographer who was blinded to the age of the animal. Equations and abbreviations are defined in Table 1.

View larger version (40K): [in this window] [in a new window]   Fig. 1. Representative images depicting how the echocardiographic measurements were made. Two-dimensionally guided M-mode recordings were obtained from the short axis (SAX) view at the level of the papillary muscles by using an Acuson Sequoia system and a 15-MHz linear-array transducer (Acuson). A: left ventricular (LV) mass and ejection fraction were calculated from the short axis wall thickness and chamber dimension measurements by assuming a spherical LV geometry. B: LV end-systolic and end-diastolic dimensions, as well as systolic and diastolic wall thickness, were measured from the M-mode tracings by using the leading-edge convention of the American Society of Echocardiography. For each M-mode measurement, at least 3 consecutive cardiac cycles were sampled. C: Doppler spectra of mitral valve inflow. Mitral valve inflow velocities were measured in the apical 4 chamber view at the level of the chordal attachments to the papillary muscles. E, early inflow wave; A, atrial inflow wave. D: color M-mode of mitral valve inflow obtained from the apical 4-chamber view. Note the 2 distinct inflow jets (in orange) corresponding to the E and A waves. E: Doppler spectra of pulmonary venous flow pattern in the left lower pulmonary vein. F: tissue Doppler spectra of lateral wall motion at the septal annulus.

Statistics. Values are expressed as means ± SD. Age differences were assessed with one-way ANOVA (Systat), and group differences were determined with the Tukey's procedure. Differences were considered significant if P < 0.05. Intraobserver reproducibility was measured in 11 rats for selected variables and expressed as the mean percent error (absolute difference divided by the average of the two observations).

	RESULTS

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Body weight, heart rate, and calculated LV mass. Ontogenic growth accounts for the age-associated differences in body weight (Table 2), as documented previously (3). Sedation with 1.5% isoflurane resulted in resting heart rates that averaged 340 beats/min and did not differ significantly between young and old rats. Thus the comparisons of echocardiographic parameters between animals of different ages were made at similar resting heart rates. LV mass was progressively greater as a function of age (Fig. 2, bottom) and was proportional to body weight for the 4-, 13-, and 22-mo groups (Fig. 2, top). In contrast, the 30-mo group exhibited disproportionate rise in calculated LV mass as indicated by an increase in the slope of the LV mass plot between 22 and 30 mo of age and by a marked increase in LV-to-body weight ratio. These findings are consistent with a previous study of female F344 rats in which heart chambers of rats aged 3 through 27 mo were dissected and weighed (3).

View larger version (14K): [in this window] [in a new window]   Fig. 2. Calculated LV mass (bottom) and LV mass-to-body weight ratio (LV/BW; top) for female Fischer 344 rats by echocardiography. Values are means ± SD. *P < 0.05 vs. 4-mo value; P < 0.05 vs. 13-mo value; P < 0.05 vs. 22-mo value, ANOVA and Tukey's procedure.

Chamber and wall dimensions. LV dimension and calculated volume at end systole increased in a nearly linear fashion from 4 to 30 mo of age (Fig. 3). In contrast, LV dimension and calculated volume at end diastole exhibited a marked increase between 13 and 22 mo of age. Thickness of the LV posterior and septal walls, measured in the parasternal short axis view, did not differ at end systole but exhibited a significant increase at end diastole between 22 and 30 mo of age (Fig. 4). Taken together, these observations are consistent with a pattern of dilatation of the LV between 13 and 22 mo of age and thickening of the walls between 22 and 30 mo of age.

View larger version (13K): [in this window] [in a new window]   Fig. 3. LV chamber dimensions measured by M-mode echocardiography. A: LV dimension at end systole (LVDs) and end diastole (LVDd). B: calculated LV volume at end systole (Vol s) and end diastole (Vol d). Values are means ± SD. *P < 0.05 vs. 4-mo value; P < 0.05 vs. 13-mo value, ANOVA and Tukey's procedure.

View larger version (12K): [in this window] [in a new window]   Fig. 4. LV wall dimensions measured by M-mode echocardiography. A: dimensions of the posterior wall at end systole (PWs) and end diastole (PWd). B: dimensions of the interventricular septum at end systole (IVSs) and end diastole (IVSd). Values are means ± SD. *P < 0.05 vs. 4-mo value; P < 0.05 vs. 22-mo value, ANOVA and Tukey's procedure.

Systolic function. To examine age-associated changes in LV systolic function, noninvasive echocardiographic measurements of wall thickness and chamber dimensions at end diastole and end systole were obtained. Representative images from which these measurements were obtained are shown in Fig. 1. Compared with 4 mo rats, LV dimension was 25% and 54% greater in the 30 mo rats at end diastole and end systole, respectively (Fig. 3). Accordingly, calculated LV end-diastolic and end-systolic volumes were increased 88 and 226% between 4 and 30 mo of age, respectively. The greater increase in end-systolic dimension was reflected in a 10% decrease in LV ejection fraction between 4 and 30 mo of age (Table 2). The rates of circumferential fiber shortening and fractional shortening were each 20% lower in aged vs. young rats. Relative wall thickness was 21% lower in hearts of 22-mo rats but was not different from that of younger rats at 30 mo of age. There was a 70% increase in the LV stroke volume in both groups of aged rats compared with either 4- or 13-mo-old rats; however, the calculated cardiac index was unchanged as a function of age. The percentages of posterior and septal wall thickening during systole were reduced as a function of age. Taken together, these changes indicate that there is a modest age-associated decline in LV systolic function in the female rat heart. Moreover, the data suggest that the rate of age-related systolic function loss may accelerate between 22 and 30 mo of age in female F344 rats.

Diastolic function. Age-associated changes in diastolic function were assessed by using Doppler flow and Doppler tissue imaging. Isovolumic relaxation time of the LV did not differ between 4 and 22 mo of age but increased 30% between 22 and 30 mo of age (Fig. 5). Early filling velocity of the LV across the mitral valve (peak E) did not differ as a function of age (Fig. 1, Table 3). Late filling velocity of the LV (peak A) tended to be greater in the eldest three groups compared with 4-mo rats (mean increase of 24%, P = 0.08), and the E wave-to-A wave (E/A) ratio declined slightly, suggesting a trend toward a greater fraction of ventricular filling in late diastole, but the differences did not reach statistical significance (Table 3). Peak mitral valve annular velocity measured at the septal annulus during early ventricular filling was 32% less in the 30-mo compared with either the 4-mo or 22-mo groups (Table 4). Similarly, the peak mitral valve annular velocity measured at the lateral portion of the annulus from the apical four-chamber view was 34% less than that at either 4 or 22 mo of age. There was a decrease in the ratio of peak early LV filling velocity of mitral inflow to the mitral valve annular velocity measured at the septum. Most other flow parameters were not significantly different as a function of age. Collectively, these findings indicate mild diastolic dysfunction in the aging female F344 rat that becomes apparent after 22 mo of age.

View larger version (11K): [in this window] [in a new window]   Fig. 5. Isovolumic relaxation time (IVRT) of the LV measured by echocardiography. Values are means ± SD. *P < 0.05 vs. 4-mo value; P < 0.05 vs. 22-mo value, ANOVA and Tukey's procedure.

Intraobserver reproducibility. Reproducibility of the measurement expressed as mean percent error was as follows: fractional shortening, 5.79 ± 4.80%; ejection fraction, 2.23 ± 1.81%; circumferential shortening, 6.93 ± 6.21%; peak E wave velocity, 0.88 ± 1.58%; peak A wave velocity, 1.24 ± 1.46%; E/A ratio, 0.66 ± 0.73%; peak pulmonary vein A wave velocity, 86.03 ± 91.35%.

	DISCUSSION

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This study provides detailed echocardiographic evidence of a progressive, mild decrement in multiple aspects of resting systolic function of the LV in female F344 rats with advancing age that appears to accelerate after 22 mo of age. Diastolic dysfunction, on the other hand, was not readily evident until after 22 mo of age, and evidence thereof was observed only in selected parameters. These data represent the first noninvasive echocardiographic assessment of systolic and diastolic function in aging female rats. As such, they provide noninvasive echocardiographic correlates of the well-documented features of myocardial aging in rats and provide baseline information for future studies of age-associated changes in the response to pathological challenges (e.g., pressure overload-induced heart failure) and the efficacy of pharmacological or exercise interventions.

The present study was conducted on female rats because they have served as a useful model to examine age-associated changes in the extracellular matrix of the heart (12-14) and in the cardiac response to pressure-overload hypertrophy (1, 4). A major goal of this study was to set the stage for future studies in which the interaction of age and various challenges and treatments will be examined. Relative extremes in age (4 and 30 mo) were chosen to correspond with or exceed ages that exhibit significant differences in collagen content and cross-linking (12-14) and expression of myosin isoforms (3). Groups of rats at intermediate ages were included to distinguish progressive from abrupt age-associated changes in heart function (3, 12-14).

The changes in chamber dimensions observed by using echocardiography reinforce and extend current information on age-associated changes in cardiac structure in female F344 rats. Studies on postmortem rat specimens have documented ontogenic increases in cardiac mass, but data on end-diastolic and end-systolic ventricular chamber dimensions and wall thicknesses have not been available. The present data indicate a disproportionate dilatation of the LV between 13 and 22 mo of age, as reflected in LV dimension, LV volume at end diastole, and stroke volume. Dilatation of the LV is followed by disproportional increases in thickness of the posterior and septal walls in diastole between 22 and 30 mo of age. The only other studies that have examined age-associated changes in heart chamber dimensions to date (5, 11) did not report wall thickness data, so it remains to be determined whether this is a general phenomenon among strains of rats irrespective of sex or is unique to the female F344 rat.

The age-associated changes in systolic function observed in the present study were modest and not unexpected. Although some of the measured changes, such as those observed in the fractional shortening and the calculated ejection fraction, may be influenced by the larger chamber dimensions and stroke volumes in the larger, older rats, the evidence for mild systolic decline is supported by the decrement in the velocity of circumferential fiber shortening. The velocity of circumferential fiber shortening is less dependent on preload than the other measures of ventricular function but is influenced by wall stress, which may be elevated in the aged rat as suggested by the decrease in relative wall thickness that was noted at 22 mo of age. Interestingly, the relative wall thickness increased in the 30-mo-old rat but not back to the levels noted in the younger rat, possibly indicating that there was some compensatory hypertrophy of the ventricle in response to this increased wall stress. The possibility of compensatory hypertrophy during aging is further supported by the marked increase in the LV mass-to-body weight ratio that was noted at 30 mo compared with 22 mo of age. The small age-associated decrease in systolic function is likely attributable, at least in part, to the well-documented shift in myosin gene expression from -myosin heavy chain to the lower velocity -myosin heavy chain in the female F344 rat heart (3). It is consistent with the previously observed decrease in the first derivative of pressure in isolated hearts of female F344 rats (1, 4). Baseline cardiac output normalized to body weight (cardiac index) was not different as a function of age. Preservation of cardiac output with advancing age is consistent with previous studies that employed isolated perfused hearts of adult and aged female F344 rats to examine cardiac function (1, 4).

Overt, severe diastolic dysfunction is characterized in a number of rat models of heart failure by a marked (5- to 6-fold) increase in the E/A ratio (6, 7, 10). In contrast, mild or early diastolic dysfunction is more commonly characterized by an increase in the A wave velocity and in the proportion of ventricular filling that occurs in late diastole. As LV enddiastolic pressures increase, the mitral valve inflow pattern begins to appear more normal (termed "pseudonormalization") with an increase in the E wave velocity and a decline in the A velocity, resulting in an increasing E/A ratio as the diastolic dysfunction becomes more severe. Therefore, in otherwise healthy aged female F344 rats the increased isovolemic relaxation time, the decreased peak velocity of the E wave at the septal annulus, and the trend toward increased mitral valve inflow A wave velocity may indicate very mild diastolic dysfunction. In two separate studies of male rats, significant decreases in the E/A ratio were observed (5). Pertinent to this point are studies of salt-sensitive Dahl S rats that progress serially through stages of compensated hypertrophy and overt heart failure (9). One month after the induction of hypertension with dietary salt, hypertrophy of the LV is associated with a decreased E/A ratio, which persists for another 2 mo. Three months after dietary salt is initiated, E/A ratio increases markedly and is associated with a threefold increase in LV enddiastolic pressure, a 25% increase in the stiffness constant, and a fivefold increase in fibrosis. Thus the mild diastolic abnormalities detected in the present study and in that of Brenner and coworkers (5) suggest that the hearts of aged rats may be progressing through a "prefailure" process and may therefore be at greater risk of developing severe diastolic dysfunction and heart failure than young adult rats when exposed to pathological stress.

The lack of overt diastolic dysfunction during aging is interesting to consider in light of the significant age-associated increases in collagen content and collagen cross-links reported for female F344 rats (12-14). It suggests that the age-related increases in collagen deposition and extracellular matrix organization precede significant measurable changes in diastolic dysfunction, providing a therapeutic window for preventing progression of diastolic dysfunction through inhibition of collagen deposition and/or cross-linking. Furthermore, because the set of factors that cause age-associated fibrosis may be at least partially distinct from those that underlie pressure overload and/or other pathologically related forms of myocardial fibrosis, it will be important to attempt to identify interactions between age- and pathologically induced fibrosis and their sequelae.

These data are the first to document age-associated changes in baseline function of female rat hearts. The measurements were made under light sedation and therefore at heart rates that are likely to be physiologically relevant. Because of their noninvasive nature, Doppler echocardiographic measurements allow serial measurements that can be used to follow the deterioration in heart function as a function of natural phenomena, such as aging, or experimentally produced stimuli, such as pressure-overload hypertrophy. Furthermore, the effects of experimental therapeutic interventions can be assessed in a serial manner in individual animals and can therefore be extremely useful in assessing the time course of cardiovascular changes in a noninvasive fashion. The present study provides baseline data that can be used to design experiments in the aged rat model that examine the interactive effects of age, pathological stimuli, and therapeutic interventions.

	GRANTS

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This study was supported by an American Heart Association Midwest Affiliate Scientist Development Grant to M. O. Boluyt and a Claude Pepper Older Americans Independence Center Pilot Grant (AG08808) to M. O. Boluyt and a National Institute of Child Health and Human Development R03 Award to M. W. Russell.

	ACKNOWLEDGMENTS

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The authors are grateful to Jason Satz, Joseph A. Lytle-Holmes, and Julie Brevick for help with technical aspects of the project.

	FOOTNOTES

 

Address for reprint requests and other correspondence: M. O. Boluyt, Division of Kinesiology, Laboratory of Molecular Kinesiology, 1209 CCRB, 401 Washtenaw Ave., Ann Arbor, MI 48109-2214 (E-mail: boluytm{at}umich.edu).

	REFERENCES

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This Article Abstract Full Text (PDF) Free All Versions of this Article: 96/2/822    most recent 01026.2003v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Boluyt, M. O. Articles by Russell, M. W. Search for Related Content PubMed PubMed Citation Articles by Boluyt, M. O. Articles by Russell, M. W.