Abnormalities of Doppler Measures of Diastolic Function in the Healthy Elderly Are Not Related to Alterations of Left Atrial Pressure
http://www.100md.com
循环学杂志 2005年第3期
the Institute for Exercise and Environmental Medicine, Presbyterian Hospital and the University of Texas Southwestern Medical Center at Dallas (A.P., K.O., A.A.Z., Q.F., B.D.L.)
Department of Integrative Physiology, University Medical Center, Nijmegen, the Netherlands (E.D.)
Cleveland Clinic Foundation, Cleveland, Ohio (J.D.T.).
Abstract
Background— Normal healthy aging results in changes in Doppler indexes of diastolic function. One widely accepted explanation for these alterations that is based on animal data is an age-associated impairment of myocardial relaxation resulting from abnormal myocyte calcium handling. However, an alternative theory based on altered left atrial compliance with aging has been proposed in which early left atrial pressure could be low in the aged heart but rise rapidly during atrial diastole, resulting in a higher late atrial pressure and thus a normal mean pressure. We sought to explore this issue directly by performing a detailed analysis of the pulmonary capillary wedge pressure waveform obtained by right-heart catheterization during 5 different loading conditions.
Methods and Results— Twelve healthy elderly sedentary subjects (mean age, 69.8±3 years) were recruited for the seniors group. An additional 12 young sedentary subjects (mean age, 35±8 years) made up the young group. All subjects were rigorously screened for comorbidities. All subjects underwent transthoracic echocardiography to determine Doppler variables of early and late transmitral filling (E and A velocities) and isovolumetric relaxation time. Each subject also underwent pulmonary artery catheterization with measurement of pulmonary capillary wedge pressure waveform during 5 different loading conditions: baseline, lower-body negative pressures of –15 and –30 mm Hg, and rapid saline infusions of 10 to 15 and 20 to 30 mL/kg. Pressure was measured at 6 points of the waveform: point 1, peak of the atrial contraction (a wave); point 2, the left atrial pressure during the start of ventricular systole; point 3, peak of atrial filling (v wave); point 4, earliest left atrial pressure during ventricular filling; and the line between points 5 and 6, pressure during diastasis. Aging resulted in a decrease in the E/A ratio (P<0.001) and a prolongation of the isovolumetric relaxation time (P<0.001) as assessed by echocardiography, but there was no effect of age on pulmonary capillary wedge pressure at any point throughout the cardiac cycle (P=0.290). Specifically, at no measured point at any level of cardiac filling volume was the pulmonary capillary wedge pressure of the seniors lower than that of the young subjects.
Conclusions— We conclude that the age-related echocardiographic change of decreasing E/A ratio is not the result of a lowering of early diastolic left atrial pressure.
Key Words: aging ; diastole ; heart diseases ; heart failure ; pulmonary wedge pressure
Introduction
Normal healthy aging results in changes in Doppler indexes of diastolic function, including a prolongation of the isovolumetric relaxation time (IVRT), a reduction in the E-wave velocity of early mitral inflow compared with the late atrial wave (A), and a slower deceleration time of early mitral filling.1–3 These parameters depend, in part, on the relationship between left atrial pressure (LAP) and the ventricular properties of relaxation and compliance.4
Although elevation of mean LAP can be seen in patients with congestive heart failure, normal healthy aging does not lead to an increase in mean LAP.5 Furthermore, mean LAP is normal in the elderly, despite marked alterations of mitral inflow velocities. These findings suggest that the origin of abnormal Doppler indexes of diastolic function in the aged population lies in the ventricle, not the atrium. Recently, however, Hees et al,6 extrapolating from indirect, noninvasive Doppler measurements, suggested that early diastolic LAP might be lower in the elderly compared with young subjects and then rise rapidly during late diastole, resulting in a normal mean pressure. A low early diastolic LAP would result in a smaller driving force for early mitral filling, which would then manifest as abnormal Doppler filling indexes.
Our own studies have not demonstrated a significant difference in mean LAP in aged subjects compared with young control subjects.7 In the present study, we sought to determine whether LAP is altered with aging, at any point in diastole, by performing a detailed, point-by-point analysis of the pulmonary capillary wedge pressure (PCWP) waveform obtained by right-heart catheterization in healthy young and senior subjects during 5 different loading conditions.
Methods
Subject Population
Twelve healthy seniors subjects (mean age, 69.8±3 years; 6 men, 6 women) and 12 young subjects (mean age, 35±8 years; 9 men, 3 women) were recruited as previously described.7 All participants were sedentary and were excluded if they engaged in endurance exercise for >30 minutes 3 times a week. Both groups had similar resting blood pressures (mean blood pressure, 123/73 mm Hg in the seniors, 114/74 mm Hg in the young) and heart rates (62±9 bpm in the seniors, 66±3 bpm in the young).
All subjects were screened for comorbidities, including systemic hypertension, obstructive coronary artery disease, and structural heart disease, through 24-hour ambulatory blood pressure measurements, exercise ECG testing, and transthoracic resting and postexercise echocardiograms. Exclusion criteria included mean daytime blood pressure >140/90 mm Hg, ECG changes suggestive of ischemic heart disease, left bundle-branch block, atrial flutter/fibrillation, AV block more than first degree, depressed systolic function, baseline or exercise-induced wall motion abnormalities, valvular heart disease other than mild valvular insufficiency, right or left ventricular hypertrophy, untreated thyroid disease, chronic lung disease, cigarette smoking within the past 10 years, body mass index >30 kg/m2, cardiovascular medications, and anticoagulation with warfarin. All subjects signed an informed consent approved by the institutional review boards of the University of Texas Southwestern Medical Center and Presbyterian Hospital of Dallas.
Experimental Protocol
Catheterization
The subjects were studied in the resting, supine position. A 6F balloon-tipped fluid-filled catheter (Edwards Lifesciences) was placed under fluoroscopic guidance through an antecubital vein into the pulmonary artery. The catheter was connected to a physiological pressure transducer with the zero reference point set at 5.0 cm below the sternal angle. The wedge position of the catheter tip was confirmed by fluoroscopy and the presence of an appropriate PCWP waveform. The balloon was inflated briefly, and the baseline pressure waveform was recorded at end expiration.
Testing Protocol
Cardiac filling was decreased by applying lower-body negative pressure as has been previously described.7 The PCWP waveform was recorded after 5 minutes each of –15 and –30 mm Hg lower-body negative pressure. The negative pressure was then released. After baseline measurements were repeated to confirm a return to a hemodynamic steady state, cardiac filling was increased by rapid infusion (100 mL/min) of warm (37°C) isotonic saline. The PCWP waveform was then recorded after 10 to 15 and 20 to 30 mL/kg had been infused.
Frequency Response Determination of Catheter-Pressure Transducer System
A catheter-pressure transducer setup, which was identical to the one used in the testing protocol, was assembled with the tip of the catheter connected via a 3-way stopcock to a column of water that generated a pressure of 25 mm Hg. The stopcock was then rapidly switched from atmospheric pressure (0 mm Hg) to the column pressure to generate a step input of 25 mm Hg. The resulting output signal was recorded by a computer program (Acknowledge, Biopac) at a sampling rate of 1 kHz. A fast-Fourier transform was then applied to the first derivative of the output signal, assuming a step input, and the gain was calculated in decibels. The frequency at which the output gain fell by 3 dB was considered the maximum frequency response of the catheter system.8 This procedure was repeated 5 times, and the results were averaged. Figure 2 shows a typical frequency-response curve, with the 3-dB level evident at 8 Hz.
In addition, we acquired true LAP recordings using a large (7.5F), stiff (Goodale-Lubin) catheter in a 60-year-old patient undergoing percutaneous closure of an atrial septal defect. In this same patient, we also measured PCWP using a Swan-Ganz catheter and assessed the frequency characteristics of both waveforms. First, we applied a fast-Fourier transform, followed by spectral analysis of the LAP signal (mean pressure, 8 mm Hg; minimum y descent, 5 mm Hg), which showed that the peak power was present at 1.70 Hz, with smaller degrees of power (one-fifth magnitude) at 2.45 and 3.40 Hz. There was virtually no power contained in this signal at frequencies >4 Hz. For the PCWP waveform (mean pressure, 7 mm Hg; minimum y descent, 6 mm Hg), the peak power was present at 1.68 Hz, with a smaller degree (one-fifth magnitude) of power at 2.46. As with the true LAP waveform, there was no substantive power in this signal >4 Hz.
Echocardiography
A resting and postexercise transthoracic echocardiogram (HDI 2000, ATL) was performed to screen for depressed ventricular function, structural abnormalities, and ischemic heart disease. At baseline, immediately after measurement of the PCWP, apical 4-chamber views were obtained for analysis of Doppler signals. If necessary for image quality, the subjects were turned 15° to 20° in the left lateral decubitus position via a motorized table that rotated the subject around the long axis of the body. Every effort was made to ensure that the images were not foreshortened and that there was optimal endocardial definition. Pulse-waved Doppler, with a sample volume of 2.0 mm placed at the tips of the mitral valve leaflets, was used to determine the peak velocities of mitral inflow (E, A velocities). The time interval between aortic outflow during systole and the opening of the mitral valve (IVRT) was also determined after the sample volume had been increased to 4.0 mm. All images were evaluated offline by a blinded sonographer.
Statistical Analysis
Data are presented as mean±SD. Results for the young and senior subjects were compared by use of 2-way repeated-measures ANOVA for the pressure points (SigmaStat, SPSS). Echocardiographic data were compared by use of an unpaired t test. A value of P<0.05 was considered statistically significant.
Results
Echocardiographic Data
As expected, aging resulted in a decrement of the E/A ratio (0.821±0.21 in the senior versus 1.71±0.36 in the young; P<0.001). There was a prolongation of the IVRT with aging (146.8±19.7 in the seniors versus 107.7±19.7 in the young; P<0.001). The results are summarized in the Table.
Echocardiographic Data
Catheterization Data
The comparisons for each pressure point across filling conditions are shown in Figures 3 and 4. There was no significant effect of age on PCWP throughout the cardiac cycle at baseline (Figure 3) (P=0.290) or during any level of cardiac unloading (–15 mm Hg, P=0.137; –30 mm Hg, P=0.08) or loading (Figure 4) (10 to 15 mL/kg, P=0.726; 20 to 30 mL/kg, P=0.775). In particular, the pressure during early diastolic filling (point 4) was 10.8±1.9 mm Hg in the elderly versus 9.5±2.0 mm Hg in the young at baseline, and there was no difference in this point between the 2 groups during any cardiac filling condition.
Discussion
The primary new finding from this study is that there was no significant difference in LAP between healthy young adults and healthy elderly adults at any point in diastole. This relationship was maintained over a wide range of cardiac filling conditions. Therefore, the age-related echocardiographic change of decreasing E/A ratio is not the result of a low early diastolic LAP. Rather, this change may be the result of alterations of ventricular processes such as myocardial relaxation or ventricular compliance.
Technical Considerations
To use the PCPW waveform derived from a fluid-filled catheter to approximate LAP, the catheter-pressure transducer system must have an adequate frequency response to accurately detect the signal of interest. The PCWP waveform must not only provide an accurate representation of mean LAP but also should reflect the dynamic cyclical changes in the magnitude and contour of the LAP waveform.
Frequency Response Validation
As described in Methods, the 6F catheter system used in this experiment had a frequency response of 8.0 Hz. A resolution of 8.0 Hz allows the accurate sampling of signals occurring at a frequency of 4.0 Hz without an aliasing error. This frequency corresponds to a Nyquist limit of 250 ms. The baseline mean period of early diastolic filling in this study, as measured by the Doppler derived E-wave duration, was 285±29 ms; thus, it is unlikely that a pressure differential occurring during early diastolic filling that could alter the pattern of mitral inflow velocity would be missed by our catheter system.
However, a waveform occurring during IVRT (100 to 200 ms) would not be measured accurately. Thus, we cannot exclude the possibility that LAP was lower in the elderly subjects at the very onset of relaxation. However, we can conclude with confidence that LAP was not lower at the point of mitral valve opening or throughout the early diastolic filling period. Therefore, a significant sustained drop in LAP during early diastole cannot explain the E/A reversal observed in elderly individuals.
Can the PCWP Waveform Be Used as a Representation of Dynamic Changes of LAP;
The use of PCWP to estimate mean LAP has been well validated and is commonplace in clinical practice.9 Given an adequate frequency response of the measurement system, the PCWP waveform can also be used to accurately determine both the magnitude and contour of the LAP waveform. Several studies involving patients with atrial septal defects or stenotic mitral valves have documented the close relationship between PCWP and directly measured LAP.10–12 Moreover, in the context of this study, direct recording of LA pressure with a large, stiff, fluid-filled catheter confirmed that there is little power in the LAP waveform at frequencies >4 Hz and that the mean, phasic, and power spectra of the pressure oscillations were very similar in the LAP and PCWP waveforms. Of course, to overlap the 2 pressure waveforms, a time delay representing transmission of the LAP through the pulmonary venous and capillary system must be considered.13 However, this issue does not apply to the present study because our interest was only in the absolute early diastolic pressure and not in the phasic delay.
Early Diastolic LAP Does Not Decrease With Aging
Our results counter the low early diastolic LAP theory proposed by Hees et al.6 In such a paradigm, a low early diastolic LAP would increase the amount of time required for the ventricular pressure to fall low enough for the mitral valve to open. This time delay would be reflected as a prolongation of IVRT. Furthermore, once the mitral valve opened, early filling would be reduced as a consequence of a smaller AV pressure gradient, resulting in a diminished E wave.
This theory is predominantly based on echocardiographic estimates of mean LAP such as the ratio of the peak E-wave velocity to the propagation velocity of early mitral inflow (E/Vp) and to myocardial motion velocities (E/Em). Although regression analysis has identified reasonable correlations between Doppler indexes and mean PCWP for groups of subjects, these measures have not been shown to precisely estimate mean LAP for individuals.14 Furthermore, they have never been shown to have the precision necessary to estimate LAP at multiple time points. Our detailed evaluation of the PCWP waveform did not demonstrate a difference in the early diastolic LAP, emphasizing the pitfalls in using Doppler measurements to estimate filling pressures.
Alternative Explanations for Abnormal Mitral Inflow Velocities With Aging
Myocardial relaxation and ventricular compliance likely both play important roles in the establishment of the AV pressure gradient necessary for ventricular filling. A large amount of animal data suggests that as the heart ages, relaxation becomes impaired. The physiological explanation for this finding is likely multifactorial, involving, in part, alterations of key Ca2+ handling proteins, which regulate energy-dependent myocyte contraction and relaxation.15,16
Unfortunately, few human data examine the effects of aging on myocardial relaxation. One of the few studies in this area by Yamakado et al17 did not show a change in ventricular isovolumetric pressure decay with aging. However, this study was clouded by the fact that it had few elderly participants. Only 9 of 55 patients in the study were >65 years of age. Furthermore, the experiment was not performed on normal healthy subjects but rather on patients referred for cardiac catheterization. Certainly, more human data are needed before this issue can be resolved.
Although myocardial relaxation likely plays an important role in early diastolic filling, the role of ventricular compliance remains unclear. Our laboratory has previously demonstrated that left ventricular compliance decreases with healthy sedentary aging.7 Whether this loss in compliance contributes to the Doppler abnormalities of mitral filling in the elderly remains to be examined. Overall ventricular stiffness may not, in fact, affect early diastolic filling because the ventricle is likely to be relatively compliant at the time of early mitral inflow. Chamber stiffness may become important predominantly at higher filling volumes later in the diastolic filling period or in instances of pericardial constraint.
Clinical Implications
We have demonstrated for the first time in normal healthy subjects, across a broad range of physiological filling conditions at rest, that neither early diastolic nor mean LAP is different in the elderly compared with the young, despite marked differences in Doppler measures of diastolic function. The abnormalities of Doppler indexes of early ventricular filling in the healthy aged are therefore likely not due to changes in LAP but rather the result of impairments in myocardial relaxation. The exact mechanisms have yet to be determined. A detailed analysis of diastolic function in the elderly, with particular attention to dynamic relaxation and myocardial compliance, is needed before this question can be fully answered.
Acknowledgments
This study was supported by NIH grant AG17479-02, the S. Finley Ewing Jr. Chair for Wellness at Presbyterian Hospital, and the Harry S. Moss Heart Foundation. We gratefully acknowledge L. David Hillis, MD, for his critical review of this manuscript; Joaquin Cigarroa, MD, for providing the supplemental clinical data used to validate the catheter system and approach; and Murugappan Ramanathan, PhD, and Kouresh Oufi, EE, for their valuable assistance with the frequency response measurement of our catheter system.
References
Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure, part I: diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002; 105: 1387–1393.
Spirito P, Maron BJ. Influence of aging on Doppler echocardiographic indices of left ventricular diastolic function. Br Heart J. 1988; 59: 672–679.
Gardin JM, Arnold AM, Bild DE, Smith VE, Lima JA, Klopfenstein HS, Kitzman DW. Left ventricular diastolic filling in the elderly: the Cardiovascular Health Study. Am J Cardiol. 1998; 82: 345–351.
Ohno M, Cheng C, Little B. Mechanism of altered patterns of ventricular filling during the development of congestive heart failure. Circulation. 1994; 89: 2241–2250.
Kitzman DW, Sheikh KH, Beere PA, Philips JL, Higginbotham MB. Age related alterations of Doppler left ventricular filling indexes in normal subjects are independent of left ventricular mass, heart rate, contractility and loading conditions. J Am Coll Cardiol. 1991; 18: 1243–1250.
Hees PS, Fleg JL, Dong S, Shapiro EP. MRI and echo assessment of the diastolic dysfunction of normal aging: altered LV pressure decline or load; Am J Physiol Heart Circ Physiol. 2004; 286: 782–788.
Zadeh AA, Dijk E, Prasad A, Torres PO, Fu Q, Zhang R, Thomas JD, Palmer D, Levine BD. Effect of aging and physical activity on left ventricular compliance. Circulation. 2004; 110: 1799–1805.
Carr J, Brown J. Introduction to Biomedical Equipment Technology. Englewood Cliffs, NJ: Prentice Hall; 2001: 92.
Batson GA, Chandrasekhar KP, Payas Y, Rickards DF. Measurement of pulmonary capillary wedge pressure by the flow directed Swan-Ganz catheter. Cardiovasc Res. 1972; 6: 748–752.
Connolly D, Kirklin J, Wood E. The relationship between pulmonary artery wedge pressure and left atrial pressure in man. Circulation Res. 1954; 2: 434–440.
Lange R, Moore D, Cigarroa R, Hillis LD. Use of pulmonary capillary wedge pressure to assess severity of mitral stenosis: is true left atrial pressure needed in this condition; J Am Coll Cardiol. 1989; 13: 825–829.
Werko L, Varnauskas E, Eliasch H, Lagerlof H, Senning A, Thomasson B. Further evidence that the pulmonary capillary venous pressure pulse in man reflects cyclic pressure changes in the left atrium. Circ Res. 1953; 1: 337–339.
Grossman W, Carabello B. Calculation of stenotic valve orifice area. In: Grossman‘s Cardiac Catheterization and Angiography. Philadelphia, Pa: Lea and Febiger; 1986: 143–154.
Firstenberg MS, Levine BD, Garcia MJ, Greenberg NL, Cardon L, Morehead AJ, Zuckerman J, Thomas JD. Relationship of echocardiographic indices to pulmonary capillary wedge pressures in healthy volunteers. J Am Coll Cardiol. 2000; 36: 1664–1669.
Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises, part III: cellular and molecular clues to heart and arterial aging. Circulation. 2003; 107: 490–497.
Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev. 1993; 73: 413–465.
Yamakado T, Takagi E, Okubo S, Imanaka-Yoshida K, Tarumi T, Nakamura M, Nakano T. Effects of aging on left ventricular relaxation in humans: analysis of left ventricular isovolumic pressure decay. Circulation. 1997; 95: 917–923.(Anand Prasad, MD; Kazunob)
Department of Integrative Physiology, University Medical Center, Nijmegen, the Netherlands (E.D.)
Cleveland Clinic Foundation, Cleveland, Ohio (J.D.T.).
Abstract
Background— Normal healthy aging results in changes in Doppler indexes of diastolic function. One widely accepted explanation for these alterations that is based on animal data is an age-associated impairment of myocardial relaxation resulting from abnormal myocyte calcium handling. However, an alternative theory based on altered left atrial compliance with aging has been proposed in which early left atrial pressure could be low in the aged heart but rise rapidly during atrial diastole, resulting in a higher late atrial pressure and thus a normal mean pressure. We sought to explore this issue directly by performing a detailed analysis of the pulmonary capillary wedge pressure waveform obtained by right-heart catheterization during 5 different loading conditions.
Methods and Results— Twelve healthy elderly sedentary subjects (mean age, 69.8±3 years) were recruited for the seniors group. An additional 12 young sedentary subjects (mean age, 35±8 years) made up the young group. All subjects were rigorously screened for comorbidities. All subjects underwent transthoracic echocardiography to determine Doppler variables of early and late transmitral filling (E and A velocities) and isovolumetric relaxation time. Each subject also underwent pulmonary artery catheterization with measurement of pulmonary capillary wedge pressure waveform during 5 different loading conditions: baseline, lower-body negative pressures of –15 and –30 mm Hg, and rapid saline infusions of 10 to 15 and 20 to 30 mL/kg. Pressure was measured at 6 points of the waveform: point 1, peak of the atrial contraction (a wave); point 2, the left atrial pressure during the start of ventricular systole; point 3, peak of atrial filling (v wave); point 4, earliest left atrial pressure during ventricular filling; and the line between points 5 and 6, pressure during diastasis. Aging resulted in a decrease in the E/A ratio (P<0.001) and a prolongation of the isovolumetric relaxation time (P<0.001) as assessed by echocardiography, but there was no effect of age on pulmonary capillary wedge pressure at any point throughout the cardiac cycle (P=0.290). Specifically, at no measured point at any level of cardiac filling volume was the pulmonary capillary wedge pressure of the seniors lower than that of the young subjects.
Conclusions— We conclude that the age-related echocardiographic change of decreasing E/A ratio is not the result of a lowering of early diastolic left atrial pressure.
Key Words: aging ; diastole ; heart diseases ; heart failure ; pulmonary wedge pressure
Introduction
Normal healthy aging results in changes in Doppler indexes of diastolic function, including a prolongation of the isovolumetric relaxation time (IVRT), a reduction in the E-wave velocity of early mitral inflow compared with the late atrial wave (A), and a slower deceleration time of early mitral filling.1–3 These parameters depend, in part, on the relationship between left atrial pressure (LAP) and the ventricular properties of relaxation and compliance.4
Although elevation of mean LAP can be seen in patients with congestive heart failure, normal healthy aging does not lead to an increase in mean LAP.5 Furthermore, mean LAP is normal in the elderly, despite marked alterations of mitral inflow velocities. These findings suggest that the origin of abnormal Doppler indexes of diastolic function in the aged population lies in the ventricle, not the atrium. Recently, however, Hees et al,6 extrapolating from indirect, noninvasive Doppler measurements, suggested that early diastolic LAP might be lower in the elderly compared with young subjects and then rise rapidly during late diastole, resulting in a normal mean pressure. A low early diastolic LAP would result in a smaller driving force for early mitral filling, which would then manifest as abnormal Doppler filling indexes.
Our own studies have not demonstrated a significant difference in mean LAP in aged subjects compared with young control subjects.7 In the present study, we sought to determine whether LAP is altered with aging, at any point in diastole, by performing a detailed, point-by-point analysis of the pulmonary capillary wedge pressure (PCWP) waveform obtained by right-heart catheterization in healthy young and senior subjects during 5 different loading conditions.
Methods
Subject Population
Twelve healthy seniors subjects (mean age, 69.8±3 years; 6 men, 6 women) and 12 young subjects (mean age, 35±8 years; 9 men, 3 women) were recruited as previously described.7 All participants were sedentary and were excluded if they engaged in endurance exercise for >30 minutes 3 times a week. Both groups had similar resting blood pressures (mean blood pressure, 123/73 mm Hg in the seniors, 114/74 mm Hg in the young) and heart rates (62±9 bpm in the seniors, 66±3 bpm in the young).
All subjects were screened for comorbidities, including systemic hypertension, obstructive coronary artery disease, and structural heart disease, through 24-hour ambulatory blood pressure measurements, exercise ECG testing, and transthoracic resting and postexercise echocardiograms. Exclusion criteria included mean daytime blood pressure >140/90 mm Hg, ECG changes suggestive of ischemic heart disease, left bundle-branch block, atrial flutter/fibrillation, AV block more than first degree, depressed systolic function, baseline or exercise-induced wall motion abnormalities, valvular heart disease other than mild valvular insufficiency, right or left ventricular hypertrophy, untreated thyroid disease, chronic lung disease, cigarette smoking within the past 10 years, body mass index >30 kg/m2, cardiovascular medications, and anticoagulation with warfarin. All subjects signed an informed consent approved by the institutional review boards of the University of Texas Southwestern Medical Center and Presbyterian Hospital of Dallas.
Experimental Protocol
Catheterization
The subjects were studied in the resting, supine position. A 6F balloon-tipped fluid-filled catheter (Edwards Lifesciences) was placed under fluoroscopic guidance through an antecubital vein into the pulmonary artery. The catheter was connected to a physiological pressure transducer with the zero reference point set at 5.0 cm below the sternal angle. The wedge position of the catheter tip was confirmed by fluoroscopy and the presence of an appropriate PCWP waveform. The balloon was inflated briefly, and the baseline pressure waveform was recorded at end expiration.
Testing Protocol
Cardiac filling was decreased by applying lower-body negative pressure as has been previously described.7 The PCWP waveform was recorded after 5 minutes each of –15 and –30 mm Hg lower-body negative pressure. The negative pressure was then released. After baseline measurements were repeated to confirm a return to a hemodynamic steady state, cardiac filling was increased by rapid infusion (100 mL/min) of warm (37°C) isotonic saline. The PCWP waveform was then recorded after 10 to 15 and 20 to 30 mL/kg had been infused.
Frequency Response Determination of Catheter-Pressure Transducer System
A catheter-pressure transducer setup, which was identical to the one used in the testing protocol, was assembled with the tip of the catheter connected via a 3-way stopcock to a column of water that generated a pressure of 25 mm Hg. The stopcock was then rapidly switched from atmospheric pressure (0 mm Hg) to the column pressure to generate a step input of 25 mm Hg. The resulting output signal was recorded by a computer program (Acknowledge, Biopac) at a sampling rate of 1 kHz. A fast-Fourier transform was then applied to the first derivative of the output signal, assuming a step input, and the gain was calculated in decibels. The frequency at which the output gain fell by 3 dB was considered the maximum frequency response of the catheter system.8 This procedure was repeated 5 times, and the results were averaged. Figure 2 shows a typical frequency-response curve, with the 3-dB level evident at 8 Hz.
In addition, we acquired true LAP recordings using a large (7.5F), stiff (Goodale-Lubin) catheter in a 60-year-old patient undergoing percutaneous closure of an atrial septal defect. In this same patient, we also measured PCWP using a Swan-Ganz catheter and assessed the frequency characteristics of both waveforms. First, we applied a fast-Fourier transform, followed by spectral analysis of the LAP signal (mean pressure, 8 mm Hg; minimum y descent, 5 mm Hg), which showed that the peak power was present at 1.70 Hz, with smaller degrees of power (one-fifth magnitude) at 2.45 and 3.40 Hz. There was virtually no power contained in this signal at frequencies >4 Hz. For the PCWP waveform (mean pressure, 7 mm Hg; minimum y descent, 6 mm Hg), the peak power was present at 1.68 Hz, with a smaller degree (one-fifth magnitude) of power at 2.46. As with the true LAP waveform, there was no substantive power in this signal >4 Hz.
Echocardiography
A resting and postexercise transthoracic echocardiogram (HDI 2000, ATL) was performed to screen for depressed ventricular function, structural abnormalities, and ischemic heart disease. At baseline, immediately after measurement of the PCWP, apical 4-chamber views were obtained for analysis of Doppler signals. If necessary for image quality, the subjects were turned 15° to 20° in the left lateral decubitus position via a motorized table that rotated the subject around the long axis of the body. Every effort was made to ensure that the images were not foreshortened and that there was optimal endocardial definition. Pulse-waved Doppler, with a sample volume of 2.0 mm placed at the tips of the mitral valve leaflets, was used to determine the peak velocities of mitral inflow (E, A velocities). The time interval between aortic outflow during systole and the opening of the mitral valve (IVRT) was also determined after the sample volume had been increased to 4.0 mm. All images were evaluated offline by a blinded sonographer.
Statistical Analysis
Data are presented as mean±SD. Results for the young and senior subjects were compared by use of 2-way repeated-measures ANOVA for the pressure points (SigmaStat, SPSS). Echocardiographic data were compared by use of an unpaired t test. A value of P<0.05 was considered statistically significant.
Results
Echocardiographic Data
As expected, aging resulted in a decrement of the E/A ratio (0.821±0.21 in the senior versus 1.71±0.36 in the young; P<0.001). There was a prolongation of the IVRT with aging (146.8±19.7 in the seniors versus 107.7±19.7 in the young; P<0.001). The results are summarized in the Table.
Echocardiographic Data
Catheterization Data
The comparisons for each pressure point across filling conditions are shown in Figures 3 and 4. There was no significant effect of age on PCWP throughout the cardiac cycle at baseline (Figure 3) (P=0.290) or during any level of cardiac unloading (–15 mm Hg, P=0.137; –30 mm Hg, P=0.08) or loading (Figure 4) (10 to 15 mL/kg, P=0.726; 20 to 30 mL/kg, P=0.775). In particular, the pressure during early diastolic filling (point 4) was 10.8±1.9 mm Hg in the elderly versus 9.5±2.0 mm Hg in the young at baseline, and there was no difference in this point between the 2 groups during any cardiac filling condition.
Discussion
The primary new finding from this study is that there was no significant difference in LAP between healthy young adults and healthy elderly adults at any point in diastole. This relationship was maintained over a wide range of cardiac filling conditions. Therefore, the age-related echocardiographic change of decreasing E/A ratio is not the result of a low early diastolic LAP. Rather, this change may be the result of alterations of ventricular processes such as myocardial relaxation or ventricular compliance.
Technical Considerations
To use the PCPW waveform derived from a fluid-filled catheter to approximate LAP, the catheter-pressure transducer system must have an adequate frequency response to accurately detect the signal of interest. The PCWP waveform must not only provide an accurate representation of mean LAP but also should reflect the dynamic cyclical changes in the magnitude and contour of the LAP waveform.
Frequency Response Validation
As described in Methods, the 6F catheter system used in this experiment had a frequency response of 8.0 Hz. A resolution of 8.0 Hz allows the accurate sampling of signals occurring at a frequency of 4.0 Hz without an aliasing error. This frequency corresponds to a Nyquist limit of 250 ms. The baseline mean period of early diastolic filling in this study, as measured by the Doppler derived E-wave duration, was 285±29 ms; thus, it is unlikely that a pressure differential occurring during early diastolic filling that could alter the pattern of mitral inflow velocity would be missed by our catheter system.
However, a waveform occurring during IVRT (100 to 200 ms) would not be measured accurately. Thus, we cannot exclude the possibility that LAP was lower in the elderly subjects at the very onset of relaxation. However, we can conclude with confidence that LAP was not lower at the point of mitral valve opening or throughout the early diastolic filling period. Therefore, a significant sustained drop in LAP during early diastole cannot explain the E/A reversal observed in elderly individuals.
Can the PCWP Waveform Be Used as a Representation of Dynamic Changes of LAP;
The use of PCWP to estimate mean LAP has been well validated and is commonplace in clinical practice.9 Given an adequate frequency response of the measurement system, the PCWP waveform can also be used to accurately determine both the magnitude and contour of the LAP waveform. Several studies involving patients with atrial septal defects or stenotic mitral valves have documented the close relationship between PCWP and directly measured LAP.10–12 Moreover, in the context of this study, direct recording of LA pressure with a large, stiff, fluid-filled catheter confirmed that there is little power in the LAP waveform at frequencies >4 Hz and that the mean, phasic, and power spectra of the pressure oscillations were very similar in the LAP and PCWP waveforms. Of course, to overlap the 2 pressure waveforms, a time delay representing transmission of the LAP through the pulmonary venous and capillary system must be considered.13 However, this issue does not apply to the present study because our interest was only in the absolute early diastolic pressure and not in the phasic delay.
Early Diastolic LAP Does Not Decrease With Aging
Our results counter the low early diastolic LAP theory proposed by Hees et al.6 In such a paradigm, a low early diastolic LAP would increase the amount of time required for the ventricular pressure to fall low enough for the mitral valve to open. This time delay would be reflected as a prolongation of IVRT. Furthermore, once the mitral valve opened, early filling would be reduced as a consequence of a smaller AV pressure gradient, resulting in a diminished E wave.
This theory is predominantly based on echocardiographic estimates of mean LAP such as the ratio of the peak E-wave velocity to the propagation velocity of early mitral inflow (E/Vp) and to myocardial motion velocities (E/Em). Although regression analysis has identified reasonable correlations between Doppler indexes and mean PCWP for groups of subjects, these measures have not been shown to precisely estimate mean LAP for individuals.14 Furthermore, they have never been shown to have the precision necessary to estimate LAP at multiple time points. Our detailed evaluation of the PCWP waveform did not demonstrate a difference in the early diastolic LAP, emphasizing the pitfalls in using Doppler measurements to estimate filling pressures.
Alternative Explanations for Abnormal Mitral Inflow Velocities With Aging
Myocardial relaxation and ventricular compliance likely both play important roles in the establishment of the AV pressure gradient necessary for ventricular filling. A large amount of animal data suggests that as the heart ages, relaxation becomes impaired. The physiological explanation for this finding is likely multifactorial, involving, in part, alterations of key Ca2+ handling proteins, which regulate energy-dependent myocyte contraction and relaxation.15,16
Unfortunately, few human data examine the effects of aging on myocardial relaxation. One of the few studies in this area by Yamakado et al17 did not show a change in ventricular isovolumetric pressure decay with aging. However, this study was clouded by the fact that it had few elderly participants. Only 9 of 55 patients in the study were >65 years of age. Furthermore, the experiment was not performed on normal healthy subjects but rather on patients referred for cardiac catheterization. Certainly, more human data are needed before this issue can be resolved.
Although myocardial relaxation likely plays an important role in early diastolic filling, the role of ventricular compliance remains unclear. Our laboratory has previously demonstrated that left ventricular compliance decreases with healthy sedentary aging.7 Whether this loss in compliance contributes to the Doppler abnormalities of mitral filling in the elderly remains to be examined. Overall ventricular stiffness may not, in fact, affect early diastolic filling because the ventricle is likely to be relatively compliant at the time of early mitral inflow. Chamber stiffness may become important predominantly at higher filling volumes later in the diastolic filling period or in instances of pericardial constraint.
Clinical Implications
We have demonstrated for the first time in normal healthy subjects, across a broad range of physiological filling conditions at rest, that neither early diastolic nor mean LAP is different in the elderly compared with the young, despite marked differences in Doppler measures of diastolic function. The abnormalities of Doppler indexes of early ventricular filling in the healthy aged are therefore likely not due to changes in LAP but rather the result of impairments in myocardial relaxation. The exact mechanisms have yet to be determined. A detailed analysis of diastolic function in the elderly, with particular attention to dynamic relaxation and myocardial compliance, is needed before this question can be fully answered.
Acknowledgments
This study was supported by NIH grant AG17479-02, the S. Finley Ewing Jr. Chair for Wellness at Presbyterian Hospital, and the Harry S. Moss Heart Foundation. We gratefully acknowledge L. David Hillis, MD, for his critical review of this manuscript; Joaquin Cigarroa, MD, for providing the supplemental clinical data used to validate the catheter system and approach; and Murugappan Ramanathan, PhD, and Kouresh Oufi, EE, for their valuable assistance with the frequency response measurement of our catheter system.
References
Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure, part I: diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002; 105: 1387–1393.
Spirito P, Maron BJ. Influence of aging on Doppler echocardiographic indices of left ventricular diastolic function. Br Heart J. 1988; 59: 672–679.
Gardin JM, Arnold AM, Bild DE, Smith VE, Lima JA, Klopfenstein HS, Kitzman DW. Left ventricular diastolic filling in the elderly: the Cardiovascular Health Study. Am J Cardiol. 1998; 82: 345–351.
Ohno M, Cheng C, Little B. Mechanism of altered patterns of ventricular filling during the development of congestive heart failure. Circulation. 1994; 89: 2241–2250.
Kitzman DW, Sheikh KH, Beere PA, Philips JL, Higginbotham MB. Age related alterations of Doppler left ventricular filling indexes in normal subjects are independent of left ventricular mass, heart rate, contractility and loading conditions. J Am Coll Cardiol. 1991; 18: 1243–1250.
Hees PS, Fleg JL, Dong S, Shapiro EP. MRI and echo assessment of the diastolic dysfunction of normal aging: altered LV pressure decline or load; Am J Physiol Heart Circ Physiol. 2004; 286: 782–788.
Zadeh AA, Dijk E, Prasad A, Torres PO, Fu Q, Zhang R, Thomas JD, Palmer D, Levine BD. Effect of aging and physical activity on left ventricular compliance. Circulation. 2004; 110: 1799–1805.
Carr J, Brown J. Introduction to Biomedical Equipment Technology. Englewood Cliffs, NJ: Prentice Hall; 2001: 92.
Batson GA, Chandrasekhar KP, Payas Y, Rickards DF. Measurement of pulmonary capillary wedge pressure by the flow directed Swan-Ganz catheter. Cardiovasc Res. 1972; 6: 748–752.
Connolly D, Kirklin J, Wood E. The relationship between pulmonary artery wedge pressure and left atrial pressure in man. Circulation Res. 1954; 2: 434–440.
Lange R, Moore D, Cigarroa R, Hillis LD. Use of pulmonary capillary wedge pressure to assess severity of mitral stenosis: is true left atrial pressure needed in this condition; J Am Coll Cardiol. 1989; 13: 825–829.
Werko L, Varnauskas E, Eliasch H, Lagerlof H, Senning A, Thomasson B. Further evidence that the pulmonary capillary venous pressure pulse in man reflects cyclic pressure changes in the left atrium. Circ Res. 1953; 1: 337–339.
Grossman W, Carabello B. Calculation of stenotic valve orifice area. In: Grossman‘s Cardiac Catheterization and Angiography. Philadelphia, Pa: Lea and Febiger; 1986: 143–154.
Firstenberg MS, Levine BD, Garcia MJ, Greenberg NL, Cardon L, Morehead AJ, Zuckerman J, Thomas JD. Relationship of echocardiographic indices to pulmonary capillary wedge pressures in healthy volunteers. J Am Coll Cardiol. 2000; 36: 1664–1669.
Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises, part III: cellular and molecular clues to heart and arterial aging. Circulation. 2003; 107: 490–497.
Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev. 1993; 73: 413–465.
Yamakado T, Takagi E, Okubo S, Imanaka-Yoshida K, Tarumi T, Nakamura M, Nakano T. Effects of aging on left ventricular relaxation in humans: analysis of left ventricular isovolumic pressure decay. Circulation. 1997; 95: 917–923.(Anand Prasad, MD; Kazunob)