Doppler echocardiographic estimation of left ventricular end-diastolic pressure after MI in rats

¹ Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 460, Faculté de Médecine Xavier Bichat; ² AP-HP, Department of Physiology, Hôpital Bichat; and ³ INSERM Unité 426, Institut Fédératif de Recherche 02, Faculté de Médecine Xavier Bichat, 75018 Paris, France

	ABSTRACT

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The spectral Doppler mitral flow pattern, alone or combined with tissue Doppler mitral annulus velocity, can be used to predict left ventricular (LV) filling pressure in humans, whereas invasive hemodynamic measurements are still required in the rat. This study was undertaken to assess whether LV end-diastolic pressure (LVEDP) can be estimated using Doppler echocardiography in the rat after myocardial infarction (MI). Thirty-seven rats (23 rats with MI after left coronary artery ligation and 14 sham-operated rats) were evaluated 3 mo after surgery with echo-Doppler and invasive hemodynamic measurements. Pulse wave spectral Doppler at the mitral valve tip was used to measure the E wave, the E wave deceleration time (DT), and the A wave; spectral Doppler tissue imaging was used to measure the early diastolic lateral mitral annulus velocity (E_a). We found weak correlations between LVEDP and the peak velocity of the early mitral inflow (E), E/peak velocity of the late mitral inflow, and DT, and strong correlations with E_a and especially with E/E_a [R² = 0.89, LVEDP (in mmHg) = 0.987E/E_a  4.229]. Longitudinal followup of a subgroup of rats with MI revealed a marked rise of E/E_a between days 7 and 21 in rats with heart failure only. We conclude that Doppler echocardiography can be used for serial assessment of LV diastolic function in rats with MI.

myocardial infarction; echocardiography; heart failure; tissue Doppler imaging

	INTRODUCTION

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HEART FAILURE (HF) is a major cause of morbidity and mortality in Western countries and remains a serious outcome of myocardial infarction (MI). Animal models of MI have been used extensively to study the pathophysiology of heart failure. Although large mammalian species are probably more relevant to the human situation, rats are commonly used for economic reasons. Left ventricular (LV) end-diastolic pressure (LVEDP) is often used to assess the degree of cardiac dysfunction and the effect of various drugs on LV function in rats (12, 23). However, measuring the LVEDP in rats requires invasive techniques that may affect LVEDP and are unsuitable for repeated measurements in the same animal. Echocardiography is routinely used in humans and is emerging as a noninvasive method for evaluating global systolic cardiac function, LV dimensions, and hypertrophy in rats (3, 5, 14, 21, 22, 26-29, 32). In humans, Doppler echocardiography is the reference noninvasive technique for evaluating diastolic LV function (2, 10, 30). Transmitral spectral Doppler and mitral annulus Doppler tissue imaging (DTI) have been validated as estimators of LV filling pressure in humans (8, 11, 15-18, 24, 31). In rats, the transmitral flow velocity pattern has been reported in a few studies (28, 29, 32). However, owing to the high physiological heart rate in rats, it is often impossible to distinguish E from A waves and thus to measure parameters used in clinical medicine, such as the peak velocities of each wave and the E wave deceleration time (DT). Likewise, the value of using mitral annulus DTI for estimating LV diastolic function in rats has not yet been evaluated.

In an attempt to facilitate longitudinal studies of cardiac function after MI in the rat, we assessed the feasibility and accuracy of transmitral inflow Doppler and mitral annular DTI for the estimation of LVEDP in this species.

	METHODS

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Experimental Design

All procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No. 85-23, Revised 1996). Male Wistar rats (Charles River) weighing 200 g at the time of surgery were used. LV infarction was obtained by ligating the left coronary artery under anesthesia, as previously described (9). The left descending anterior coronary artery was ligated proximally to obtain a moderate or large infarct, leading to compensated or decompensated heart failure (23). Control rats were sham operated without coronary artery ligation. Echocardiography was performed 3 mo later, 1 or 2 days before invasive hemodynamic studies. Echocardiographic and hemodynamic measurements were made under light anesthesia with 1-2% isoflurane in oxygen, with spontaneous ventilation without intubation. Rats were killed after the hemodynamic study, the pleural effusion was collected by needle aspiration, and its volume was measured by gravimetry. The heart was excised and weighed, and the LV was dissected free and weighed. Overt congestive HF (CHF) was defined as the presence of pleural effusion. Rats were thus classified in three groups: sham operated (sham; n = 14), nonfailing MI (NF-MI; n = 11), and CHF (CHF-MI; n = 12). In a subgroup of 10 rats with MI, echocardiography was performed 2, 7, and 21 days and 3 mo after infarction to assess LVEDP changes with time.

Echocardiography

We used a commercially available echocardiograph (Toshiba Powervision 6000, SSA 370A) equipped with a 8- to 14-MHz linear transducer. The chest was shaved, and the animal was placed in the supine position on a heating pad. A single channel electrocardiogram was obtained on the imaging system. Data were transferred on-line to a computer for subsequent analysis (Ultrasound Image Workstation-300A, Toshiba). The LV was imaged in both parasternal long-axis and short-axis views at a frame rate of 120 Hz, and data were transferred on-line to a computer as dynamic loops of 50 frames. The end-diastolic area was defined as the largest LV area, and the end-systolic area was defined as the smallest LV area. The ejection fraction was measured off-line by a modified version of Simpson's biplane analysis (25). LV internal diameters were measured as recommended by the American Society of Echocardiography (25).

Doppler measurements. Pulsed wave Doppler spectra of mitral inflow were recorded from the apical four-chamber view. The sample volume was placed at the tip of the mitral leaflets and adjusted to the position at which velocity was maximal. The sample volume was set at the smallest size available (1 mm). All Doppler spectra were recorded for 5-10 cardiac cycles at a sweep speed of 100 mm/s.

Mitral annular velocity measurement by DTI. Pulse wave DTI was performed using the same probe with low filter and gain settings. From the apical four-chamber view, the smallest sample volume was placed at the lateral corner of the mitral annulus. Off-line measurements were made by two observers blinded to the animals' hemodynamic status. The peak velocity of early (E) and late filling waves (A), the E wave DT, and the isovolumic relaxation time (IVRT) were measured from the mitral inflow recording as previously described (15). Peak early diastolic velocity (E_a) was measured from the DTI recording as previously described (18). Within-observer and between-observer reproductivity of echographic parameters were assessed in all rats. Variability was expressed as the mean percent error (absolute difference between the two measurements divided by the mean of the measurements).

LV Pressure Measurements

A 3-Fr Mikro-Tip pressure transducer catheter (SPR-524, Millar Instruments) was introduced into the LV through the right carotid artery. The transducer was connected via a PowerLab/4s unit (ADInstruments) to a computer running MacLab (Chart 4.1 software). LVEDP was read directly from the pressure curve as being the diastolic pressure immediately preceding the pressure rise associated with LV contraction. The measurement was done in 10 consecutive cardiac cycles, and values were then averaged.

Statistical Analysis

All values were expressed as means ± SD. One-way ANOVA followed by Scheffé's F-test was used for group comparisons. The heart rates of each animal during echocardiography and hemodynamic studies were compared using Student's paired t-test. E/E_a values at 2, 7, and 21 days and 3 mo after MI were compared using ANOVA for repeated measures. Linear regression curves and correlation coefficients were obtained by using the least-squares method (Statview software). Agreement between Doppler-estimated and catheter-measured LVEDP was assessed according to Bland and Altman (4). A value of P < 0.05 was considered statistically significant.

	RESULTS

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Animal Characteristics

Thirty-seven rats (14 sham, 11 NF-MI, and 12 CHF-MI) were studied 3 mo after surgery. At the time of death, there were no differences in body weight among the three groups (Table 1). The heart weight index (ratio of heart weight to body weight) was higher in CHF-MI than in NF-MI or sham rats (P < 0.0001). Because of chronic hemodynamic overload due to increased LV diastolic pressures, the myocardium hemodynamically upstream of the infarcted LV (the atria and right ventricle) was hypertrophic in CHF-MI rats. This was indicated by a marked increase in heart weight minus the LV weight-to-body weight ratio (P < 0.0001), whereas this index was not significantly increased in NF-MI rats (Table 1).

View this table: [in this window] [in a new window]   Table 1.   Animal characteristics

Echocardiography

Echocardiography was successful in every case. The heart rate was similar in the three groups. Figure 1 shows typical transmitral flow velocity and DTI mitral annulus velocity patterns in each group: the E wave increased from sham to NF-MI to CHF-MI rats, whereas the E wave DT fell and the A wave decreased and even disappeared in some CHF-MI rats. At the mitral annulus, the E_a wave was similar to that of the shams in NF-MI rats and lower in CHF-MI rats. The mean data for the three groups are summarized in Table 2. CHF-MI and NF-MI rats had a dilated LV, as indicated by the increased LV end-diastolic diameter. Global systolic function, as assessed by the ejection fraction, was altered in CHF-MI rats and to a lesser extent in NF-MI rats. Diastolic function, as assessed by E, E/A, DT, and IVRT, was clearly altered in CHF-MI rats compared with the sham controls. In NF-MI rats, only E and IVRT differed from sham control values. Moreover, these two mitral inflow parameters did not distinguish failing from nonfailing hearts. In contrast, the DTI parameter E_a and E/E_a were significantly different in CHF-MI compared with NF-MI rats. E_a was decreased in CHF-MI rats and unchanged in NF-MI rats relative to shams.

View larger version (34K): [in this window] [in a new window]   Fig. 1.   Representative transmitral flow velocity (A) and Doppler tissue imaging (DTI) mitral annulus velocity patterns (B) from sham-operated (sham) rats, nonfailing myocardial infarction (NF-MI) rats, and congestive heart failure MI (CHF-MI) rats. E, early mitral diastolic wave; A, late mitral diastolic wave; Ea, early diastolic mitral annulus wave.

View this table: [in this window] [in a new window]   Table 2.   Echocardiographic data

Feasibility of Doppler measurements. The feasibility of Doppler measurements is shown Table 3. Because the heart rate was greater than 300 beats/min in most rats, it was difficult to clearly identify the A wave on transmitral flow velocity spectra. For this reason, measurement of the peak velocity of the A wave and DT was much less feasible than E wave measurement in all three groups (Table 2). Early diastolic mitral annulus velocity was measurable in all but two rats (1 sham and 1 CHF-MI rat). Within-observer and between-observer reproductivity ranged from 8.4% to 19.6% for A, DT, and IVRT (Table 3). Variability was much smaller for E, E_a, and E/E_a, ranging from 0.2% to 3.7%.

View this table: [in this window] [in a new window]   Table 3.   Within-observer and between-observer reproductivity of Doppler parameters

Hemodynamic Data

Hemodynamic measurement failed in four rats (2 sham and 2 NF-MI rats), including one that died during the procedure. The heart rate was similar during invasive hemodynamic study and echocardiography (Tables 2 and 4). As expected in this model, mean aortic pressure was decreased in CHF-MI rats and unchanged in NF-MI rats (Table 4). In contrast, NF-MI rats exhibited a moderate increase in LVEDP compared with shams. LVEDP was much higher in CHF-MI rats, and the minimal and maximal of the first derivative of LV pressure (+dP/dt and dP/dt) were markedly decreased compared with NF-MI and shams (Table 4), thus confirming the severe HF of rats with pleural effusion.

View this table: [in this window] [in a new window]   Table 4.   Invasive hemodynamic data

Relationship Between Doppler Parameters and LVEDP

Significant correlations were found between the measured LVEDP and several echographic parameters (A, E/A, E, DT, E_a, and E/E_a). No correlation was found with IVRT. The correlations with E, E_a, and E/E_a are presented in Fig. 2. The correlation with E/E_a was highly significant (R² = 0.89, P < 0.0001), suggesting that this parameter can be used to estimate LVEDP. The difference between catheter-measured and E/E_a-estimated LVEDP ranged from 0.5 to 7.8 mmHg. Bland-Altman analysis of the agreement between Doppler-estimated and catheter-measured LVEDP confirmed that E/E_a accurately reflects LVEDP (Fig. 3). A mean difference of 0.05 ± 3.8 mmHg was observed between invasive LVEDP measurement and Doppler estimates, using the regression equation LVEDP (in mmHg) = 0.987E/E_a  4.229. 

View larger version (15K): [in this window] [in a new window]   Fig. 2.   Relation between Doppler transmitral E wave (E; A) or DTI-derived Ea (B) or combined spectral and tissue Doppler parameters (E/Ea; C) with left ventricular end-diastolic pressure (LVEDP). , Sham-operated rats, , NF-MI rats; , CHF-MI rats. The best correlation was obtained with E/Ea.

View larger version (17K): [in this window] [in a new window]   Fig. 3.   Agreement between Doppler-estimated and catheter-measured LVEDP. Dotted line, average difference between the two methods; outer solid lines, 2 SD (95% confidence limits of agreement). , Sham-operated rats; , NF-MI rats; , CHF-MI rats.

In a subgroup of 10 rats, we performed echocardiography 2, 7, and 21 days and 3 mo after MI. At 3 mo, six rats were classified in the NF-MI group and four rats in the CHF-MI group. As shown in Fig. 4, echocardiography showed stability of E/E_a (<30) with time in the NF-MI group, whereas it increased by 48% between days 7 and 21 (P < 0.01) with no further increase at 3 mo in the CHF-MI group.

View larger version (19K): [in this window] [in a new window]   Fig. 4.   Doppler-estimated LVEDP at 2 (D2), 7 (D7), and 21 days (D21) and 3 mo (M3) after MI in 6 nonfailing rats (NF-MI) and 4 rats with overt CHF (CHF-MI) at the time of death. ** P < 0.01.

	DISCUSSION

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This study shows that combined Doppler transmitral inflow and mitral annular velocity measurements allow for accurate noninvasive estimation of LVEDP in rats after MI. This is of special interest for longitudinal studies in rats.

Transmitral Doppler Flow Velocity

Conventional Doppler parameters of diastolic LV function are related to the transmitral pressure gradient and have been used to estimate LV filling pressure in patients with LV systolic dysfunction (2, 11, 17, 24, 31). Three abnormal transmitral Doppler patterns have been described reflecting progressive impairment of diastolic function. First, the "delayed relaxation" pattern is characterized by a diminished early filling wave (E), an increased late diastolic atrial contraction wave (A), an E/A < 1, an increased IVRT, and a prolonged E wave DT. Such an inflow pattern results from impaired LV relaxation, in which LV early diastolic pressure is abnormally elevated; consequently, the transmitral pressure gradient is low, resulting in slow early diastolic filling. Vigorous atrial contraction compensates for reduced early filling and maintains normal mean left atrial pressure. Second, the "pseudonormal" filling pattern, characterized by E/A > 1 and a short E wave DT, results from an increase in left atrial pressure itself compensating for the slowed rate of LV relaxation (2) and increased LV diastolic chamber stiffness (30). Finally, the "restrictive" filling pattern, with increased peak E velocity, decreased peak A velocity (or no A wave at all), an increased E/A (usually >2), and rapid E wave deceleration, results from a markedly elevated left atrial pressure that offsets the slowing of LV relaxation. Such patterns are seen in patients with marked increases in LVEDP and severe pulmonary congestion.

In our study, the restrictive filling pattern was observed in all CHF-MI rats, indicating an elevated LV filling pressure confirmed by invasive LV catheterization and by the presence of pleural effusion. Normal, pseudonormal, and restrictive filling patterns were observed in NF-MI rats, depending on the degree of myocardial damage. Because of the deterioration of global contractile performance and the increase in LVEDP, the increase in E and E/A, and the decrease in A and DT, were more pronounced in rats with CHF as already described (14).

Transmitral flow-derived parameters are not entirely suited to the estimation of LV filling pressure because they are oppositely modified by impaired LV relaxation and elevated LV filling pressure. Furthermore, they are influenced by several factors, including preload, afterload, heart rate, and age (6, 7, 13, 17). Although we found a correlation between E and LVEDP, a large dispersion of E values was observed for similar levels of LVEDP, especially in NF-MI rats. This may have been caused by the influence of various degrees of relaxation alteration on the E wave.

Mitral Annulus DTI

Mitral annulus motion recording by DTI has already been studied as a means of assessing human LV function. Transmitral velocities are dependent on both preload and relaxation (6, 7), whereas early diastolic mitral annulus velocity is dependent on LV relaxation and independent of LV filling pressure (18). To our knowledge, our study is the first to assess Doppler echocardiographic estimation of LV filling pressure in rats. The annular DTI pattern in rats is similar to that observed in humans. As in patients with MI, E_a was significantly decreased in rats with decompensated HF relative to sham-operated controls (1). Although E_a is thought to be independent of LV filling pressure, we found a correlation between E_a and LVEDP (Fig. 2). This may be due to the simultaneous slowing of LV relaxation and the increase in LVEDP after MI. To overcome the confounding effects of relaxation and preload changes on transmitral flow, it has been proposed to use a ratio of a relaxation- and preload-dependent index (E) to a relaxation-dependent, preload-independent index (E_a) (16, 18, 20). Nagueh et al. (18) have shown that E/E_a can yield a noninvasive estimate of pulmonary capillary wedge pressure in humans. In this study of rats, E/E_a correlated strongly with LVEDP, whereas transmitral velocity parameters (E, A, E/A, and DT) correlated weakly. The weak correlations might be caused by the confounding effects of impaired relaxation and increased filling pressure after MI. In contrast, E/E_a is the best Doppler parameter for assessing LVEDP, because dividing E by E_a eliminates the effects of relaxation on E. In the present study, E/E_a >30 (corresponding to LVEDP >25 mmHg) was observed only in CHF-MI rats. This could be an effective parameter for identifying the progression toward HF in rats. Indeed, only CHF-MI rats showed a marked rise (+48%) of E/E_a between days 7 and 21 in our longitudinal study. In addition, E_a and E/E_a measurements were feasible in 95% of rats compared with <70% of rats for A and DT determinations. The high frequency of E and A wave fusion resulting from the high rat heart rate (>300 beats/min) means that conventional Doppler parameters cannot be used to estimate LV diastolic function. This was overcome in previous studies by using cardiodepressive drugs to slow the heart rate, an approach that is hardly optimal for estimating cardiac function.

Limitations

The present study demonstrates that chronic changes in LV filling pressure can be detected in the rat using echo-Doppler technology. It does not demonstrate that this technique allows the assessment of acute changes in LV filling pressure. Others have shown that acute changes in LV filling pressure can be measured accurately in the dog using the same techniques (20). The physiological heart rate recorded in this study was 300-330 beats/min, i.e., near the limit above which the E and A waves fuse (29). Similarly, the early (E_a) and late (A_a) wave velocities of the mitral annulus often fused in our study. In theory, this wave fusion could have distorted the measurement of E and E_a. However, increased LVEDP is associated with increased E and decreased A, and the peak velocity of fused waves of transmitral flow may thus be composed principally of the E wave. In addition, it has been reported that increased LVEDP decreases A_a (20) and that the peak of the fused mitral annulus diastolic velocity waves may thus be mainly composed of E_a. Furthermore, E/E_a has been reported to accurately reflect LVEDP in humans with sinus tachycardia, even with complete merging of E and A waves (19). The estimation of LVEDP in rats with a physiological heart rate and thus a "fused" E/E_a needs to be validated in other experimental models in which impaired relaxation predominates.

Applications

The suitability of echocardiography for noninvasive assessment of LV morphology and systolic function in rats is well established (3, 22, 27, 28). Combined Doppler transmitral flow velocity and mitral annulus velocity provide the first noninvasive means of assessing LVEDP in rats. This should permit serial evaluation of LV function or the effect of various treatments aimed at reducing the postinfarction remodeling process. Further studies are needed to determine whether this method can be applied to other models of HF in rats.

	ACKNOWLEDGEMENTS

We thank David Young for help in restyling the manuscript.

	FOOTNOTES

This study was supported by Institut National de la Santé et de la Recherche Médicale and by grants from the Fondation de France and Association Française contre les Myopathies. F. Prunier was supported by the Fondation pour la Recherche Médicale.

Address for reprint requests and other correspondence: J.-J. Mercadier, INSERM U 460, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France (E-mail: jjmercadier{at}wanadoo.fr).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

First published March 28, 2002;10.1152/ajpheart.01050.2001

Received 30 November 2001; accepted in final form 12 March 2002.

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