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1 Section of Cardiology, Department of Medicine, Baylor College of Medicine, and Debakey Heart Center, The Methodist Hospital, Houston, TX, USA
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(Received 2 February 2005;
accepted after revision 3 March 2005; first published online 15 March 2005)
Corresponding author S. F. Nagueh: Methodist DeBakey Heart Center and Baylor College of Medicine, 6550 Fannin Street, SM-1246, Houston, Texas 77030-2717, USA. Email: sherifn{at}bcm.tmc.edu
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Introduction |
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Because of its versatility and non-invasive nature, echocardiography has been the modality applied in many of these reports. Earlier on, fractional shortening (FS) and ejection fraction (EF) were utilized, whether by M-mode or 2-D imaging. However, both FS and EF are heavily influenced by loading conditions and are not sensitive enough to detect a more subtle change in contractility. Colour kinesis which detects endocardial motion and displays it in a coloured 2-D-image format was recently examined. However, this technique has several limitations including its critical dependence on image quality and frame rate as well as its detection of endocardial motion only rather than myocardial thickening (Mor-Avi et al. 2000). In more recent years, tissue Doppler imaging (TDI) was investigated and systolic velocities during isovolumic contraction or ejection were reported to decrease with normal ageing (Alam et al. 1999). However, velocity measurements and even strain rate and strain (Urheim et al. 2000) are heavily affected by left ventricular preload and afterload, similar to FS and EF. Therefore, the question remains as to whether such changes reflect an actual deterioration of LV intrinsic myocardial contractility. This is particularly important because a true decline in contractility with ageing can render us more susceptible to systolic heart failure.
This study was designed to evaluate the effect of age on normal humans using the recently validated acceleration rate during isovolumic contraction (IVA). This index which embodies one of the earliest events in systole and is therefore much less affected by loading conditions was recently validated in an animal model. It related well to LV maximal elastance and was not significantly altered by an acute reduction in LV volume or a significant increase in systolic pressure (Vogel et al. 2003).
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Methods |
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Eighty consecutive healthy subjects, without cardiovascular disease who were referred to the The Methodist Hospital echocardiography laboratory (Houston, TX, USA) were imaged in a supine position with an ultrasound system equipped with harmonic imaging, a multi-frequency transducer and tissue Doppler imaging (TDI) capability. All subjects gave informed consent. These subjects were referred because of cardiac murmur or for the evaluation of left ventricular ejection fraction. Inclusion criteria were the absence of hypertension, diabetes mellitus or coronary artery disease and presence of normal cardiac dimensions, wall thickness, EF (Schiller et al. 1989) and the lack of significant valvular pathology (defined as more than mild mitral or tricuspid regurgitation and more than trace aortic regurgitation) in the complete Doppler examination. Patients with cardiac risk factors for diabetes, hypertension or smoking, and with known cardiac disease (valvular, myocardial or coronary artery disease) were excluded. The group had a mean body surface are (BSA) of 1.94 ± 0.27 m2. Systemic blood pressure and heart rate were measured at the time of the echocardiographic examination.
Echocardiographic studies
All the examination procedures were carried out to provide a comprehensive echocardiographic examination that would enable us to assess LV systolic and diastolic function using several indices. The standard indices (see below) were selected on the basis of their routine availability, performance and application in previous reports (for systolic function, EF and systolic velocities by TDI; for diastolic function, mitral inflow, pulmonary venous flow and TDI of the mitral annulus). While all of the systolic indices, except for IVA, are load-dependent, we believe that these measurements are nevertheless important in this study as they serve for comparison with IVA and previous studies. The diastolic indices are not the primary focus of this report but were included to provide a complete characterization of LV function in the study sample. Non-invasive assessment of LV diastolic function by echocardiography using the combination of several velocities and time intervals (as opposed to a single index), can provide a reliable assessment of LV diastolic function and filling pressures and therefore, several diastolic measurements were applied in this study (Ommen, 2001).
After acquiring 2-D images in the parasternal and apical views, pulse-Doppler was utilized to record transmitral and pulmonary venous flow (PV) in the apical 4-chamber view as previously described (Nishimura & Tajik, 1997) during normal respiration. The pulse Doppler sample volume was placed at the mitral valve tips and five to 10 cardiac cycles were recorded. Pulmonary venous flow was recorded from the right pulmonary vein guided by colour Doppler echocardiography. TDI was applied to record the mitral annular velocities at the septal and lateral areas. Filters were set to exclude high frequency signals, and the Nyquist limit was adjusted to a velocity range of –15 to 20 cm s–1. Gains were minimized to allow for a clear tissue signal with minimal background noise. Figure 1 shows three examples of myocardial velocities by TDI from subjects included in this study. The echocardiograms were stored digitally and analysed off-line.
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The analysis was performed off-line without knowledge of subjects' age and gender. LV end diastolic dimension (EDD), septal thickness (ST), posterior wall thickness (PW), ejection fraction (EF), LV mass and left atrial (LA) maximum volume were measured according to the recommendations of the American Society of Echocardiography (Schiller et al. 1989). While formulae using M-mode-derived measurements can be applied to derive LV mass, the M-mode approach uses a small sample from the LV posterior wall or septum with the assumption that this represents global thickness. To avoid this important limitation, we applied the area–length method by 2-D echocardiography.
All Doppler measurements represent the average of three beats. Mitral inflow was analysed for peak early diastolic (E) velocity, peak late diastolic (A) velocity, E/A ratio and deceleration time (DT) of E velocity (peak E velocity: inter-observer variability, 4 ± 2%). From the pulmonary vein (PV) flow signals, the velocity of peak systolic, peak diastolic and peak atrial flow (peak systolic, diastolic and atrial velocity inter-observer variability, from 5 ± 3% to 8 ± 5%) were determined (Nishimura & Tajik, 1997). Mitral annulus early diastolic (Ea) velocity and mitral annulus late diastolic (Aa) velocity at the septal and lateral areas of the mitral annulus (inter-observer variability for these signals in our laboratory have been previously reported by Nagueh et al. (1997): for Ea, 5 ± 2%; for Aa, 5.5 ± 3%) were measured.
Systolic function was assessed using the peak velocity signals (at septal and lateral sites of mitral annulus) during isovolumic contraction (SIVC) and systolic ejection (Sa) as well as IVA. Systolic IVA rate was calculated as the difference between baseline and peak velocity during isovolumic contraction divided by the time interval between them (Vogel et al. 2003).
Statistical analysis
Data showed a normal distribution. The echocardio-graphic measurements between male and female subjects were compared with a two-tailed unpaired t test. Regression analysis was applied to examine the relation between age and the different echocardiographic measurements of LV function. This study had an 80% power to detect a correlation coefficient of 0.3 between age and systolic IVA at an 
level of 0.05. Statistical significance was defined with a P value 
0.05.
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Results |
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With ageing, there was no significant increase in LV end diastolic dimension, wall thickness or mass (all P > 0.3). Likewise, LA volume showed no significant relation to age (r = 0.11, P = 0.5).
Systolic function
All indices of systolic function (Table 2, Fig. 2) had no significant correlation with age. Weak correlations were noted between EF and average Sa velocity (r = 0.5, P = 0.05), average SIVC velocity (r = 0.4, P = 0.05) and average IVA (r = 0.4, P = 0.05). Better correlations were noted between average Sa velocity and average SIVC velocity (r = 0.57, P < 0.001), and between average IVA and average Sa velocity (r = 0.46, P = 0.001) and average SIVC velocity (r = 0.8, P < 0.001).
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Mitral E/A ratio decreased significantly with age as did the pulmonary venous flow diastolic velocity (the latter velocity has similar determinants to mitral E velocity; r = –0.65, P = 0.04). Of importance, the atrial reversal (Ar) signal in pulmonary venous flow did not increase with age. As expected, annular diastolic velocities changed significantly with age with the Ea velocity decreasing and the Aa velocity increasing, leading to a significant inverse correlation between the mitral annulus Ea/Aa ratio and age.
Effect of gender on LV structure and function
There were no significant differences in age, heart rate and blood pressure between men and women. Likewise, LV septal and posterior wall thickness and LA volume were not significantly different between the two groups (Table 3). However, LV end diastolic dimension and LV mass showed a trend to be larger in men (P = 0.07 and 0.06, respectively). While isovolumic velocity and acceleration were higher in men than women, these differences were not significant (P = 0.12 and 0.37, respectively). No significant differences were noted between men and women regarding mitral inflow E/A ratio and annular Ea/Aa ratios. Results were similar with comparison limited to subjects older than 60 years. No significant relation was observed between age and measurements of LV systolic function by regression analysis in women (P > 0.1). However, in men, a positive correlation was noted between average IVA and age (r = 0.63, P = 0.007; equation: average IVA = 139 + 3.5 (age)), and septal Sa and age (r = 0.46, P = 0.049; equation: septal Sa = 6.9 + 0.05 (age)) but no significant correlation was noted between the other measurements (SIVC and EF) and age (Table 4).
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Discussion |
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Effect of age on cardiac structure
Previous investigations in humans have reported different effects of age on LV wall thickness and mass. Some reports suggested that LV mass increases with ageing (Dannenberg et al. 1989), except in very old subjects with a sedentary life style, where it may decrease. Others have reported no change in heart weight of men with ageing (Kitzman et al. 1988). In our study, there was no significant relation between LV mass (and LV mass to height2.7) and age.
As for LV end diastolic dimension, some studies reported an increase in this measurement with ageing. We did not notice such a change. This may be due to the fact that in our study, there was no significant change in myocardial contractility and afterload with ageing and overall LV filling was maintained by LA compensation despite the reduced filling in early diastole.
Effect of age on LV systolic function
Several echocardiographic methods have been applied in the investigation of the effects of age on LV systolic function. Most studies have used FS or EF and different findings were noted; some showed no change in EF while others reported a decrease in LV systolic function (Salmasi et al. 2003). Given the dependence of EF on loading conditions and given the difficulty of reliably assessing these conditions, uncertainty remains about the validity of any conclusions surmised through EF measurements.
Other indices were applied more recently. One of the recent methods is based on the use of acoustic quantification for determining LV endocardial border which is then tracked during the cardiac cycle. Using this technique, Mor-Avi et al. (2000) reported a change in LV ejection dynamics with age, whereby late ventricular contraction played a more important role in ejection. However, this technique is affected by translation and merely tracks motion rather than actual myocardial thickening.
A combination of time intervals was recently proposed (Tei index: isovolumic contraction time + isovolumic relaxation time/ejection time) to identify the presence and severity of myocardial disease. One group reported, using the Tei index, a decline in global LV function with age (Spencer et al. 2004). However, the Tei index is a combination of both systolic and diastolic time intervals and a change in either can adversely affect it. Furthermore, recent work showed that it was heavily affected by preload and afterload and could not reliably detect acute changes in contractility (Cheung et al. 2004).
TDI which detects velocity, displacement and deformation in a given area of the myocardium was also applied for the same purpose. However all of the above measurements are heavily influenced by load and the significance and validity of observations showing an inverse correlation between age and systolic velocity is questionable.
Unlike all of the above measurements, systolic IVA is a pure measure of LV systolic function, appears not to be influenced by loading conditions and relates well with invasive gold standards of contractility (Vogel et al. 2003). We therefore selected this index for our investigation and were able to show no relation between systolic IVA and age (Fig. 2). Our finding of normal systolic function in healthy ageing subjects utilizing not only EF but also the load-independent index, systolic IVA, supports the conclusion that in humans, age-induced deterioration in systolic function is not present, and in that regard, does not necessarily pose an adverse biological change that renders this population susceptible to systolic heart failure. However, the changes in diastolic function can predispose this population to pulmonary congestion symptoms and a reduction in cardiac output with a decline or absence (due to atrial fibrillation) in LA function.
Effect of age on LV diastolic function
Similar to previous studies (Malkowski et al. 1995), we noted a decline in the E/A ratio with age, consistent with a shift towards an increased LA contribution to LV filling. As expected, pulmonary venous flow changed with ageing due to a decline in antegrade pulmonary venous flow into the LA during diastole. This change has been previously reported (Malkowski et al. 1995) in normal individuals with ageing and is largely due to the decreased emptying of the LA in early diastole (due to slowed LV relaxation with ageing) when the LA would be receiving flow from the pulmonary veins. However, similar to previous studies (Klein et al. 1998), Ar which is a measure of LV end diastolic pressure (Rossvoll & Hatle, 1993), showed no significant correlation with age.
As for TDI diastolic velocities, Ea decreased and Aa increased with ageing as previously reported (Alam et al. 1999; Munagala et al. 2003; Tighe et al. 2003), again reflecting the slower LV relaxation with ageing and the increased LA contribution to LV filling, respectively.
Effect of gender on LV structure and function
Previous reports indicated an impact of gender on LV function. More recently, this difference was highlighted in an animal study of ageing female rodents (Boluyt et al. 2004) that were imaged from 3 months of age up to the elderly age of 30 months. A deterioration in LV systolic function was noted along with LV dilatation. However, this study may have been limited due to the use of sedatives/anaesthetics (1.5% isoflurane) than can depress myocardial contractility. In our investigation, we noted that men showed a trend, albeit non-significant, towards a larger LV end diastolic dimension and mass. However, similar to ageing female rodents, systolic isovolumic contraction velocity and acceleration were lower in women, though this did not reach the level of statistical significance. Of more importance, regression analysis showed a significant positive relation between age and IVA in men (r = 0.63, P = 0.007), but no relation was noted in women. A number of factors may have accounted for these observations. These include differences in myocyte loss, trophic effects of androgens versus oestrogens and different expression of genes that regulate LV contractility and calcium homeostasis. Additional studies to explore these potential mechanisms are needed.
There are two possible interpretations for the difference in the effect of age on LV systolic function between men and women. On one hand, this may represent a liability for women because of the lack of an increase in systolic parameters with age. On the other hand, this observation may not account for the results seen in epidemiological studies, because systolic function in women does not deteriorate with age and actually remains preserved. Either way, these findings are of interest in light of the well recognized higher incidence of heart failure with normal EF in older women (Chen et al. 2002) and the recent observations that normal EF can be present despite impaired myocardial contractility that can be readily detected by other tests (Yu et al. 2002). Additional studies are needed to examine systolic IVA not only in healthy older women but more importantly in the group with normal EF and congestive heart failure.
Limitations
The ideal assessment of LV systolic function would be invasively acquired using pressure–volume loops. However, this is not carried out in the daily evaluation of cardiac patients. Furthermore, it is unjustified in normal subjects.
More recently measured indices of myocardial function, such as strain rate and strain were not acquired. However, these indices have been shown to be dependent on preload and afterload (Urheim et al. 2000) and therefore are suboptimal in comparison with the IVA which has been shown to be load-independent in carefully performed validation studies.
We did not assess RV systolic function in this study, mostly due to the geometric complexity of RV structure which makes it difficult to correctly determine RV volume and to the lack of TD signals from the RV free wall. Based on a previous report (Vogel et al. 2002), systolic IVA of the RV free wall may provide valuable insights in this regard.
Conclusions
In conclusion, age is not associated with an overall change in cardiac structure and LV systolic function, but is accompanied by a decline in echocardiographic indices of diastolic function. With respect to gender, age does not appear to influence LV systolic function in women, but is associated with an increase in IVA and septal Sa in men. Additional studies with a larger number of patients are warranted to further explore these observations and their potential clinical impact.
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