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(Circulation. 1997;95:917-923.)
© 1997 American Heart Association, Inc.

Articles

Effects of Aging on Left Ventricular Relaxation in Humans

Analysis of Left Ventricular Isovolumic Pressure Decay

Tetsu Yamakado, MD; Eiji Takagi, MD; Setsuya Okubo, MD; Kyoko Imanaka-Yoshida, MD; Toshiaki Tarumi, MD; Mamoo Nakamura, MD; Takeshi Nakano, MD

The First Department of Internal Medicine and the Department of Pathology (K.I.-Y.), Mie University, Tsu, Japan.

Correspondence to Tetsu Yamakado, MD, The First Department of Internal Medicine, Mie University, 2-174 Edobashi, Tsu 514, Japan. E-mail yamakado@clin.medic.mie-u.ac.jp.

	Abstract

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Background Some experimental studies in animals have shown that myocardial relaxation is prolonged with aging. However, it is not known whether aging alters ventricular isovolumic relaxation in human subjects.

Methods and Results We analyzed high-fidelity left ventricular pressures, measured by use of a catheter-tipped manometer, and biplane left ventriculograms in 55 normal subjects who underwent diagnostic cardiac catheterization but who were found to have normal cardiac anatomy and function. There were 38 men and 17 women, ranging in age from 20 to 77 years. Left ventricular isovolumic relaxation was assessed by the exponential time constants of isovolumic pressure decay with (Tb) and without (Tw) an asymptote pressure. Left ventricular volume, ejection fraction, and wall thickness or mass were calculated from left ventricular angiograms. Neither of the time constants of left ventricular relaxation correlated with age (Tb: r=.001 to .10, P=NS; Tw: r=.02 to .05, P=NS). Left ventricular systolic function (ie, ejection fraction and end-systolic volume index), heart rate, and left ventricular wall thickness or mass, which are major hemodynamic determinants of left ventricular relaxation, were not significantly affected by aging. The multivariate analysis of age and hemodynamic variables against the time constants of left ventricular relaxation also indicated that no significant relation was found between age and left ventricular relaxation.

Conclusions In the absence of coronary artery disease, systemic hypertension, left ventricular systolic dysfunction, or hypertrophy, left ventricular relaxation assessed by the time constant of isovolumic pressure decay remains essentially unchanged with normal adult aging, at least until the eighth decade.

Key Words: myocardial relaxation • aging • pressure • hemodynamics

	Introduction

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The normal aging process is associated with changes in myocardial structure and function.^{1 2} It is well known that LV systolic function at rest appears to be unaffected by aging.^{3 4 5 6 7} In contrast, many studies in human subjects have shown that LV diastolic function, as estimated by analysis of early diastolic filling velocity, deteriorates with aging.^{8 9 10 11 12 13 14 15} The mechanisms underlying this change in diastolic function are not fully understood, but the change may result in part from age-related decreases in the rate of LV relaxation. Previous experimental studies^{16 17 18} demonstrated that the duration of isometric contraction and the time to peak tension were prolonged in senescent rats. These findings were thought to reflect age-related decreases in Ca²⁺ uptake by the SR.^{19 20 21 22} However, there are no consistent experimental data on whether relaxation time is also prolonged with aging.^{23 24 25 26 27 28} To date, there are few data on age-related alterations in ventricular relaxation assessed by isovolumic pressure decay in human subjects,²⁹ mainly because invasive studies are required to analyze high-fidelity ventricular pressures. It is also necessary to exclude patients with heart disease, especially those with coronary artery disease.

The purpose of this study was to investigate whether LV relaxation is altered with aging in humans. We did this by analyzing high-fidelity LV pressures with a catheter-tipped manometer and biplane cineangiograms in normal subjects who had undergone diagnostic cardiac catheterization but who were found to have normal cardiac anatomy and function.

	Methods

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Study Subjects
This study was based on a retrospective review of our cardiac catheterization data for 16 years between April 1979 and May 1995. During diagnostic cardiac catheterization, as a rule, we performed biplane cineventriculography and simultaneously measured LV pressure using a catheter-tipped manometer. Of the 2560 subjects who underwent cardiac catheterization, the following selection criteria were met in 55 subjects: (1) they had undergone cardiac catheterization by use of biplane cineventriculography and simultaneous LV pressure measurements with a catheter-tipped manometer; (2) they had no significant coronary artery stenosis (ie, no more than 25% diameter narrowing in the major coronary arteries); (3) they had normal LV systolic function; (4) they had no vasospastic angina; (5) they had no history of systemic hypertension; (6) they had not engaged in regular exercise; (7) they had not taken cardioactive medications before catheterization; and (8) they did not have chronic pulmonary disease, diabetes mellitus, valvular heart disease, cardiomyopathy, right or left bundle-branch block, or other cardiac disease. There were 38 men and 17 women, ranging in age from 20 to 77 years (mean±SD, 49±13 years). These subjects had undergone diagnostic catheterization for evaluation of atypical chest pain or discomfort. Intravenous ergonovine or intracoronary acetylcholine were used to exclude vasospastic angina during catheterization.

Cardiac Catheterization
Fasting subjects were premedicated with intramuscular hydroxyzine hydrochloride (50 mg). All subjects underwent routine catheterization of the right and left sides of the heart (via the percutaneous femoral approach), biplane cineventriculography, and coronary angiography. Biplane left ventriculograms were obtained in the 30° right anterior oblique and 60° left anterior oblique projections by injecting 40 mL of contrast agent at a rate of 10 to 12 mL/s. LV pressures were measured simultaneously with the use of a 7F or 8F pigtail angiographic micromanometer catheter (Miller Instruments) and were recorded at a paper speed of 150 mm/s (Electronics For Medicine VR-l2) along with the first derivative of pressure (dP/dt). The micromanometer-tipped catheter was calibrated against luminal pressures by use of a fluid-filled system (model P23XL, Statham-Gould). After left ventriculography, selective coronary angiography by the Judkins technique was performed. To exclude vasospastic angina, coronary angiography was performed before and after intravenous ergonovine (0.05 to 0.2 mg) or intracoronary acetylcholine (20 to 100 µg) injection in all subjects.

Data Analysis
To assess LV relaxation, we calculated the time constant of isovolumic pressure decay. LV pressure was measured every 5.00 to 6.66 ms from the point of minimal dP/dt to a level 5 mm Hg above the end-diastolic pressure of the next beat. Two different time constants (Tb-1 and Tw-1) of LV pressure decay during this interval were derived from two different exponentially fitted curves. Tb-1 was calculated from a monoexponential curve fit with a variable asymptote pressure to the following equation^{30 31 32}

(E1)

where P is LV pressure (mm Hg), t is time (ms), c is the asymptote of pressure decay (mm Hg), a is a constant, and -1/b is the time constant of relaxation (Tb-1). Tw-1 was calculated from a monoexponential curve fit with zero asymptote³³

(E2)

where d is a constant and –1/f is the time constant of relaxation (Tw-1). To avoid erroneous changes in the time constant induced by a shift of the starting point or of the end point of the time-constant analysis, we also calculated individual time constants (Tb-2 and Tw-2) from curve fits to Equation 1 (Tb-2) and Equation 2 (Tw-2) with identical starting points (the lower pressure at which LV peak negative dP/dt occurred) and end points (the pressure that equaled the higher LV end-diastolic pressure plus 5 mm Hg), as proposed by Paulus et al.³⁴ In the present study, the pressures of the starting point and end point were 53 mm Hg and 22 mm Hg, respectively. The correlation coefficients of the exponential curve fit for the two equations always exceeded 0.998.

We calculated LV end-diastolic and end-systolic volume indexes and ejection fraction from digitized LV silhouettes using the biplane area-length method.³⁵ LV wall thickness was measured on an end-diastolic frame by averaging wall thickness at approximately the junction of the apical and middle third of the free wall in the right anterior oblique projection.³⁶ LV mass was derived from the formula by Rackley et al.³⁶ All data reported were analyzed during normal sinus rhythm; postextrasystolic beats were excluded.

Statistical Analysis
Linear regression analysis was used to test the relation between age and the time constants of LV relaxation and other hemodynamic variables and to assess the influence of hemodynamic variables on LV relaxation. The data obtained in men and women were compared by use of the t test for unpaired data. To assess whether the effect of age on the time constant of LV relaxation was independent of the influence of other variables, we used a multivariate linear regression analysis. The influence of the following variables was assessed: heart rate, LV peak systolic and end-diastolic pressures, LV systolic function (ie, end-systolic volume index and ejection fraction), LV wall thickness, wall mass index, and asymptote pressure. Significance was indicated by a value of P<.05. Data are expressed as mean±SD unless otherwise stated.

	Results

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LV hemodynamic data in this study population are summarized in Table 1.

View this table: [in this window] [in a new window]   Table 1. Hemodynamic Data in 55 Normal Subjects

Effect of Age on LV Relaxation
All four time constants of LV relaxation (Tb-1, Tw-1, Tb-2, and Tw-2) remained unchanged with age (Figs 1 and 2). There was also no significant age-related change in the time constants of LV relaxation or the asymptote pressure in either men or women (men: Tb-1, r=.25; Tw-1, r=.21; C-1, r=.04; Tb-2, r=.17; Tw-2, r=.07; and C-2, r=.13; all P=NS; women: Tb-1, r=.14; Tw-1, r=.20; C-1, r=.20; Tb-2, r=.02; Tw-2, r=.30; and C-2, r=.11; all P=NS).

View larger version (17K): [in this window] [in a new window]   Figure 1. Relation between age and the time constants (Tb-1 and Tw-1) of LV isovolumic relaxation. Top, Tb; bottom, Tw.

View larger version (17K): [in this window] [in a new window]   Figure 2. Relation between age and the time constants (Tb-2 and Tw-2) of LV isovolumic relaxation. Top, Tb; bottom, Tw.

There were no differences in hemodynamic variables between men and women in this or subsequent analyses, and therefore their data are combined.

Effect of Age on LV Systolic Function and Other Hemodynamic Variables
LV peak systolic pressure had a weakly positive but significant correlation with age (r=.47, P<.01) (Table 2). However, LV systolic function, as measured by end-systolic volume index and ejection fraction, was almost unchanged with age. There was no significant change in heart rate with age. LV free-wall thickness and mass index also did not vary with age (Table 2; Fig 3).

View this table: [in this window] [in a new window]   Table 2. Relation Between Age and Hemodynamic Variables in 55 Normal Subjects

View larger version (16K): [in this window] [in a new window]   Figure 3. Relation between age and ejection fraction (top) and LV free-wall thickness (bottom). LVEF indicates LV ejection fraction.

Influence of Hemodynamic Variables on LV Relaxation and Multivariate Analysis
Of the hemodynamic variables studied, only LV end-diastolic pressure and asymptote pressure (C-1) influenced Tb-1 on univariate linear regression analysis. LV end-diastolic pressure and heart rate influenced Tw-1. The final independent variables that remained significantly related with Tb-1 or Tw-1 after multivariate linear regression analysis were LV end-diastolic pressure for both Tb-1 and Tw-1 and asymptote pressure (C-1) for Tb-1, respectively (Table 3). In univariate analysis, Tb-2 was influenced by heart rate, LV end-diastolic pressure, and asymptote pressure (C-2). Tw-2 was influenced by heart rate, LV peak systolic and end-diastolic pressures, and LV end-diastolic volume index. In multivariate analyses, the final independent variables were LV peak systolic and end-diastolic pressures for Tb-2 and Tw-2 and asymptote pressure (C-2) for Tb-2 (Table 4).

View this table: [in this window] [in a new window]   Table 3. Univariate and Multivariate Regression Analyses of the Relation Between the Time Constants of LV Relaxation and Age and Other Hemodynamic Variables in 55 Normal Subjects

View this table: [in this window] [in a new window]   Table 4. Univariate and Multivariate Regression Analyses of the Relation Between the Time Constants of LV Relaxation and Age and Other Hemodynamic Variables in 55 Normal Subjects

However, the multivariate analysis of age and several hemodynamic variables against the time constants of LV relaxation indicated that no significant correlation was found between age and LV relaxation (Tb-1, Tw-1, Tb-2, and Tw-2) or asymptote pressure (C-1 and C-2) (Tables 3 and 4).

	Discussion

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The primary finding of this study is that LV relaxation assessed by the time constants of isovolumic pressure decay does not change with adult aging between the ages of 20 and 77 years in normal humans.

There are few data on age-related alterations in ventricular relaxation in human subjects, mainly because such studies require invasive techniques and high-fidelity LV pressure recordings. Prior noninvasive studies assessing LV isovolumic relaxation time in humans yielded various results.^{12 14 37 38} Isovolumic relaxation time has been proposed as an index of the rate of LV relaxation, but it is influenced by both the rate of LV diastolic relaxation and the difference between LV pressure at aortic valve closure and mitral valve opening. Alterations in vascular and left atrial properties due to aging might affect this index. In addition, recent studies^{39 40} showed that isovolumic relaxation time does not correlate closely with the rate of LV relaxation. Thus, direct examination of LV isovolumic pressure decay (the time constant of relaxation) would be a more reliable assessment of LV relaxation.

There has been one prior study²⁹ on age-related alterations in LV relaxation directly assessed by the time constant of isovolumic pressure decay in humans. Hirota²⁹ studied LV relaxation in 18 normal subjects from the second to the seventh decade of age. This group included athletes and subjects with functional murmurs and with pulmonary stenosis. The time constant of LV relaxation correlated significantly with age. Although his study population was small and the correlation coefficient was relatively low (r=.65), our finding clearly contrasts with the observations of Hirota. Several factors could be responsible for this discrepancy between our data and his. First, different methods were used to calculate the time constant of relaxation. Hirota did not assess the time course of pressure decline during the isovolumic-relaxation phase. The time constant was defined as the LV pressure at peak negative dP/dt divided by peak negative dP/dt, whereas ours was obtained by exponential curve fitting of pressure and time during the isovolumic-relaxation phase. We also calculated the time constants of LV relaxation according to his method but still did not observe a significant correlation between age and the time constant of relaxation (r=.004, P=NS). Second, the discrepancy may have resulted from differences in the study population. Hirota studied 5 subjects who were 20 years old. It is possible that people of that age might possibly have been in a high adrenergic state, particularly during cardiac catheterization, resulting in shortened isovolumic LV relaxation. In his subjects 25 years old, there does not seem to be a correlation between age and the time constant of relaxation, a finding similar to ours (see Reference 29; Fig 3). Thus, we can speculate that the discrepancies between his results and ours are caused mainly by differences in the study population rather than the methods used.

The kinetics of isovolumic relaxation more likely reflect myofilamentary detachment because of an imbalance between load and residual force potential in late systole.^{34 41} We found no significant changes in heart rate, end-systolic volume index, ejection fraction, or wall thickness with aging. We noted a slight but progressive increase in LV peak systolic pressure with aging, which might affect LV relaxation.^{42 43 44} The average increase of 35 mm Hg in peak systolic pressure in our 20- to 77-year-old subjects was relatively small to affect LV relaxation, because the time constants of LV relaxation are almost unaffected by increases in systolic pressure of the order of 43 mm Hg in normal human subjects.⁴³ Changes in LV pressure waveform may also affect isovolumic pressure decay.⁴¹ LV peak systolic pressure occurs in late systole in older subjects.^{45 46 47} In most experimental studies, a sudden increase in late systolic pressure or load decreases isovolumic LV pressure decay.^{48 49 50} However, because those studies were performed in isolated or anesthetized open-chest animals, caution should be exercised before extrapolating those findings to the more physiological condition in older humans. In fact, the time constant of LV relaxation in conscious dogs was unchanged with an increment in late systolic LV pressure, while the initial rate of LV pressure decline was accelerated.⁵¹ Moreover, the short-term effects of beat-to-beat LV pressure increases should be considered distinct from the more complicated effects of steady-state increases in LV pressure produced by the aging process. Additional studies will be needed concerning this point. Loss of synchrony between different LV segments might also slow LV relaxation.⁴¹ Bonow et al,¹³ using radionuclide angiography, showed that regional LV diastolic asynchrony, assessed as the time from end systole to peak diastolic filling, roughly correlated with aging. If age-related regional asynchrony had occurred in our subjects, the time constants of LV relaxation would have been prolonged with aging. However, we could not find any change in the time constant of relaxation, suggesting that regional LV diastolic asynchrony did not play an important role in our subjects.

The rat has been used in most studies of age-related changes in myocardial function. Experimental studies^{16 17 18} demonstrated that the duration of isometric contraction and the time to peak tension is prolonged in senescent rats. Prolonged myocardial contraction has been thought to reflect age-related decreases in Ca²⁺ uptake by the SR,^{19 20} which is associated with a decrease in the SR Ca²⁺–ATPase mRNA.^{21 22} On the other hand, there are no consistent data on whether relaxation time is also prolonged in aged rats compared with younger cohorts. Experimental studies using an LV papillary muscle preparation revealed that the time to half-relaxation as well as the duration of tension is prolonged in aged rats compared with their younger cohorts.^{23 25 27} Recent studies of isolated cardiac myocytes, however, showed that relaxation time does not change appreciably with aging, whereas contraction duration is prolonged with aging.^{24 26 28} Our data would support this conclusion. Although the diastolic decay of Ca²⁺ transients primarily reflects Ca²⁺ reuptake rate by the SR, it may also be affected by other processes, such as transsarcolemmal extrusion by Na⁺-Ca²⁺ exchange, or through an energy-dependent Ca²⁺ ATPase of the cell membrane, the binding of Ca²⁺ to intracellular proteins like troponin and calmodulin,⁵² or possibly the change of Ca²⁺ storing protein.⁵³ It has been suggested that the Na⁺-Ca²⁺ exchanger is more active in ejecting Ca²⁺ from the cells of older versus younger hearts during diastole.²⁰ Thus, it is possible that a change in any of the processes described above might compensate for the decrease in Ca²⁺ uptake by the SR in the elderly, resulting in no change in LV relaxation with aging.

Prior noninvasive studies using echo-Doppler^{8 11 12 14 15} or radionuclide techniques^{9 10 13} indicated that early LV diastolic filling is markedly reduced with aging in healthy subjects. LV early diastolic filling is determined mainly by the isovolumic relaxation rate, the magnitude of the AV pressure gradient, diastolic compliance, and ventricular suction. We previously reported⁵⁴ that the LV peak filling rate during the rapid-filling phase, which was derived from frame-by-frame analysis of angiograms, was significantly decreased with aging in 27 of 55 normal subjects. Our findings suggest that the reduced early LV diastolic filling that accompanies aging may not be directly related to an age-related alteration in LV relaxation.

Study Limitations
We estimated LV thickness and mass on the basis of left ventriculography. This samples only a small area of the LV free wall and extrapolates it to represent the LV mass. Several recent studies^{3 55} suggested that aging is associated with increased cardiac mass, in which the interventricular septal thickness increases more with aging than does the LV free-wall thickness. Thus, it is possible that LV mass was underestimated in older subjects in the present study. To further assess this problem, we retrospectively reviewed echocardiography in all subjects. In 46 of 55 subjects, adequate echocardiograms could be obtained for measuring the thickness of the ventricular septum and posterior wall of the left ventricle. We found that neither the thickness of the ventricular septum nor the posterior wall at end diastole was associated with aging (both r=.01, P=NS), and both exceeded 13 mm in the present study. LV mass index estimated by echocardiography also did not change significantly with age (r=.14, P=NS). Therefore, our data might be interpreted as those of normal subjects in whom LV thickness and mass index remain unchanged with aging.

In the normal heart, there seems to be little or no afterload dependence of LV relaxation. In a recent study,⁵⁶ the individual relation between the time constant of LV relaxation and end-systolic force showed scatter in normal dogs ranging from a positive to a negative correlation. Therefore, a complete assessment of isovolumic relaxation kinetics might include a loading challenge in different study groups. We could not conduct a loading challenge because this was a retrospective study.

We did not include subjects older than 80 years in the present study. It has been shown recently that in rats at the very advanced age of 30 months, which is considered the same as a human aged >75 years,⁵⁷ the SR Ca²⁺–ATPase mRNA was markedly decreased by 60% compared with young (4-month-old) rats.²¹ Therefore, LV relaxation may possibly be prolonged in subjects >80 years old.

This is a cross-sectional study between different individuals at different ages, which neither quantifies nor controls for lifelong habits of nutrition and other birth cohort effects.^{1 2} It is possible that a trend might have emerged if the same subjects had been followed up over a period of years. However, it is not ethical to repeat invasive study in normal human subjects.

In conclusion, in the absence of coronary artery disease, systemic hypertension, LV systolic dysfunction, or hypertrophy, LV relaxation assessed by the time constant of isovolumic-pressure decay remains unchanged with normal adult aging at least until the eighth decade. This finding may provide insights into the understanding of adult myocardial aging and ventricular diastolic function and the pathophysiology of cardiac disease in the elderly.

	Selected Abbreviations and Acronyms

 

C-1, C-2 = asymptote pressure LV = left ventricular SR = sarcoplasmic reticulum Tb-1, Tb-2 = left ventricular time constant of isovolumic decay with an asymptote pressure Tw-1, Tw-2 = left ventricular time constant of isovolumic decay without an asymptote pressure

	Footnotes

 
Presented in part at the 42nd Scientific Sessions of the American College of Cardiology, Anaheim, Calif, March 14-18, 1993, and at the 68th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 13-16, 1995, and published in abstract form (Circulation. 1995;92(suppl I):I-201).

Received July 29, 1996; revision received October 3, 1996; accepted October 7, 1996.

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