Abnormalities of left ventricular filling in patients with coronary artery disease: assessment by colour M-mode Doppler technique

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1 European Heart Journal (1994) 15, Abnormalities of left ventricular filling in patients with coronary artery disease: assessment by colour M-mode Doppler technique M. STUGAARD*, U. BRODAHLf, H. TORPj AND H. IHLEN* * Medical Department B and ^Department of Radiology, Rikshospitalet, The National Hospital, Oslo, Norway, and %Institute of Biomedical Engineering, University of Trondheim, Trondheim, Norway KEY WORDS: Computer analysis, diastole, echocardiography, filling delay, peak velocity. In 54 healthy individuals and 107 patients with coronary artery disease, intraventricular early filling velocities were recorded by colour M-mode Doppler. The time difference between the occurrence of peak velocity in the apical region and at the mitral tip was calculated, and normalized by dividing it by the mitral to apical distance. Transmitral velocities were determined by the single pulsed Doppler technique. The patients were divided into groups according to systolic function as assessed by left ventriculography. The normalized time difference was similar in the reference group (12 ±8 ms. cm~') and the patient group with no electrocardiographical signs of previous infarction and normal ventriculography (16 ± 16 ms. cm~'). It increased significantly in the group with infarction andlor regional systolic dysfunction (43 ±21 ms. cm~'), and a further increase was present in the group with severely impaired ventricles (53 ±14 ms. cm~'). The ratio between peak early and late transmitral velocity fell significantly in the group with infarction andlor regional systolic dysfunction, but was normalized in the group with severely impaired ventricles. Colour M-mode Doppler shows that apical filling is delayed in patients with injured left ventricles due to coronary artery disease. This delay increases with progression of ventricular injury. The technique may be an important addition to transmitral pulsed Doppler in assessing left ventricular filling. Introduction Diastolic dysfunction of the left ventricle (LV) is commonly accepted as an important mechanism for clinical signs and symptoms in coronary artery disease (CAD)' 1 ' 21. Several authors have suggested that such dysfunction may precede systolic dysfunction' 3 ' 41. However, diastolic function is a complex process which cannot be described by a single variable and is therefore difficult to measure Several non-invasive methods have been used for clinical assessment of diastolic function, including radionuclide angiography, digitized M-mode echocardiography and Doppler echocardiography. These techniques have significant limitations, and new improved methods are needed. Recently, colour M-mode Doppler has been used for assessment of LV filling 17 " 101. This technique determines velocities simultaneously at multiple sites along a line, with a high repetition frequency, and can therefore detect regional differences in intraventricular filling velocity. The aim of the present study was to characterize intraventricular early diastolic filling in normal ven- Submitted for publication on 7 June 1993, and in revised form 7 October Marie Stugaard has received a research fellowship from the Norwegian Council on Cardiovascular Diseases. Oslo. Norway. Correspondence: Dr Marie Stugaard, Medical Department B, Rikshospilalet, The National Hospital, N-OO27 Oslo. Norway tricles by the colour M-mode Doppler technique, and to examine ventricular filling in patients with CAD and different degrees of LV injury. Furthermore, colour M-mode Doppler findings were compared with transmitral pulsed Doppler results obtained in these subjects. Methods MATERIAL Reference group Fifty-seven healthy individuals, recruited mostly from the hospital staff, were examined by colour M-mode Doppler. Due to technically inadequate recordings, three had to be excluded. The ages of the remaining 54 (26 females and 28 males) ranged from 24 to 73 (mean 47) years. Selection by age was made so that each decade between 20 and 70 years comprised about 10 individuals. No subject had a history of cardiovascular disease or hypertension, and no medication was taken. One third of these subjects were moderate smokers. None were active athletes. Physical examination, electrocardiogram (ECG) and echocardiogram including Doppler examination of the valves were normal in all persons. Regular sinus rhythm was present in all. Patient groups One-hundred and eleven patients who had severe stable angina pectoris due to angiographically proven CAD were examined by colour M-mode Doppler. Four X/94/ SOS.OQW 1994 The European Society of Cardiology

2 LVfilling abnormalities in CAD 319 had to be excluded due to technically inadequate recordings. Further exclusion criteria were concomitant valvular heart disease, congenital heart disease, or cardiomyopathy. The age range of the remaining 107 (17 females and 90 males) was 33 to 75 (mean 55) years. Eighteen patients had moderate hypertension without electrocardiographic hypertrophy. Regular sinus rhythm without conduction abnormalities was present in all, and all patients were treated with one or more cardioactive drugs (beta-adrenergic blocking drugs, 66%; nitrates, 64%; calcium channel blocking drugs, 32%; or angiotensin converting enzyme inhibitors, 7%). The patients were divided into three groups: Group 1 (n=47) comprised patients with no ECG evidence of previous myocardial infarction and angiographically normal LV; Group 2 (n=42) comprised patients with ECG signs of previous infarction, and/or regional systolic hypokinesia or akinesia of the LV with normal left ventricular ejection fraction (LVEF) above 50%; Group 3 (n=18) comprised patients with angiographically large regions of systolic hypokinesia or akinesia of the ventricle without aneurysm and with a LVEF below 50%. All patients in this group had had a previous infarction. All individuals gave their informed consent to participate in the study, and the institutional ethical committee on human research approved the study protocol. HEART CATHETERIZAT1ON Standard left heart catheterization with coronary angiography was performed in the patient groups before echocardiographic examination. Left ventricular minimal (LVminP) and end-diastolic pressures (LVEDP) were measured before angiography. The ventricular angiogram was obtained in the right anterior oblique projection by injecting 45 ml Omnipaque 300/350 (Nycomed, Oslo, Norway) at a flow rate of 15 ml. s~'. The angiograms were assessed by two observers who worked independently of each other and were unaware of the echocardiographic results. Systolic dysfunction was assessed by visual inspection and described as systolic hypokinesia or akinesia. LVEF was calculated using a single plane ellipsoidal formula'"' l21. ECHOCARDIOGRAPHY A Vingmed CFM 700 cardiac ultrasound machine (Vingmed Sound, Horten, Norway) with a mechanical sector duplex transducer was used. The scanner utilizes the same annular array element for tissue and Doppler imaging; the excitation frequency is 3-75 MHz for tissue recordings and 2-5 MHz for Doppler recordings. Signals from the last 10 s are stored in an internal replay memory from where they can be recalled or transferred to external computers. The individuals were examined in the lateral recumbent position after 15 min of rest using the transthoracic apical long axis view to visualize the inflow of the LV 1 ' 31, and to avoid disturbing signals from the aortic outflow. The depth of the tip of the mitral valve was determined, and the transmitral diastolic velocities were measured at this site by the pulsed Doppler technique. LV inflow was then imaged by the two-dimensional (2-D) colour flow mode with flow data mapped on tissue data. The cursor line was placed centrally in the diastolic inflow to include both mitral and apical flow, and colour M-mode velocities were measured along this line. The velocity filter was set at 12 cm. s~' and the gain setting adjusted to avoid noise interference. The transducer position was carefully adjusted so that early filling was depicted as a column of blood flow from the mitral tip to the apex, and a continuous 'zone' of peak velocities was seen through the entire column (Fig. 1). Recordings with lack of continuity in the flow column were considered technically inadequate. When technically adequate recordings were obtained, the digital colour velocity data were transferred to an external computer (Macintosh, Apple Computer, Inc., Cupertino, California, U.S.A.) for further analysis. The ultrasonic examination included the standard procedure using echocardiography and Doppler ultrasound. In the reference group, LVEF was measured by M-mode echocardiography. ANALYSIS OF DOPPLER DATA Pulsed Doppler measurements Transmitral peak velocities during early (E) flow and flow induced by the atrial contraction (A) were measured, and the peak velocity ratio (E/A ratio) was calculated. The deceleration time was measured as the time from peak to zero velocity of the early flow wave. Coefficients of variation including, inter-observer, intraobserver, day-to-day, and random variation, vary between 0-4 and 22% for these transmitral flow parameters in our laboratory 14 ' 151. Colour M-mode measurements We utilized a tool-box of image processing routines (Echoprograms, Vingmed Sound, Horten, Norway), developed for this purpose, and a spreadsheet program for image calculations and presentation. Each picture element (pixel) in the colour M-mode picture represented a velocity averaged over a 2-3 mm distance along the vertical axis and over 5 ms along the horizontal axis. The velocities (ranging from -l-4m.s~' to m. s~') were digitized into 36 levels, which were colour coded by a rainbow colour system allowing good visual identification of the peak velocities. Early diastolic filling was defined by drawing an area of interest using the tools in the program. The velocity colour data in this area were decoded into numerical data, which were displayed in a spreadsheet, together with the corresponding time data along the horizontal axis and the depth data along the vertical axis. To reduce the problem of velocity 'dropouts' and noise in the flow recording, mean filtering was performed 1 ' 61 ; the velocity of each pixel was replaced by the mean of the velocities in an area of three pixels in the vertical axis and three pixels in the horizontal axis around that pixel.

3 320 M. Stugaard et al. cm J Mitral tip --> 300 ms Figure 1 Early and atrial-induced diastolic inflow recorded by colour M-mode Doppler technique in two normal individuals. Apical velocities are recorded in the upper part of the picture and transmitral velocities in the middle. The vertical axis represents the distance from the tip of the mitral valve towards the apex in early diastole. Blood velocities are coded by the rainbow colour system. The highest velocities are depicted as deep blue at mitral level due to velocity aliasing, turning gradually brighter and changing to bright yellow towards the apical region. Black: or white dots indicate peak velocities at the mitral tip and in the apical region determined by computer analysis. The timing of the velocity can be read from the horizontal time axis. Panel A: early inflow is shown as a single column of velocities; peak velocities at the mitral tip and at the apex occur almost simultaneously. Panel B: two phases of early inflow are present in the apical region. Peak velocity is included in the second phase. An algorithm was used to locate peak velocity of the LV inflow at the mitral tip, defined as the starting point zero, and at every fourth pixel depth (i.e. every 0-92 cm) towards the apex. If peak velocity at a given depth was found in several adjacent pixels, the most centrally located pixel was chosen. If the flow column was divided into two phases in the apical region, the algorithm was constructed to determine peak velocity in the phase with the highest velocity at the dividing site. The time difference of peak filling velocity (TD) was defined as the time difference between occurrence of peak velocity in the apical region and at the mitral tip (Fig. 2). Because the distance between the mitral tip and the apex varied between the patients, the time difference was normalized by dividing by the distance. The data are presented as normalized time difference of peak filling velocity (ntd) for the purpose of this study. All recordings and analysis were performed by the same observer (M.S.). Data were averaged from three consecutive heart beats. REPRODUCIBILITY ANALYSIS The reproducibility of recording and assessment of the colour M-mode images were examined in 12 individuals Distance from mitral tip (cm) A B Figure 2 Panel A: schematic illustration of the levels used for analysis of left ventricular filling. The heart is shown in the apical long axis view. M, mitral tip. Panel B: schematic example of computer analysis of a colour M-mode Doppler recording. The timing of peak velocity at the different depths from the mitral tip towards apex and the time difference of peak filling velocity between the apical region and the mitral tip (TD) can be read from the horizontal axis.

4 LV filling abnormalities in CAD 321 selected at random from the patient groups: five patients from group 1,fivefrom group 2, and two from group 3. Each individual was examined at the same time of day on two different days with an interval of 7-14 days. At the first examination two independent observers (M.S. and H.I.) recorded colour M-mode flow within 20 min. At the second examination, observer M.S. performed two separate recordings within 20 min. Assessment of the data was done twice by each of the two observers, with a time interval of days. ai'e (beai -H -H 3 I 3 V 1^ a o STATISTICAL ANALYSIS The data in the reference and patient groups are presented as means ± 1 standard deviation. Comparisons were by univariate analysis of variance and by simple linear regression analysis. R and r-squared values are given together with 95% confidence intervals (ci) of mean (x,y) and standard error (SE) of the slope. Significant P values were adjusted for number of comparisons made (Bonferroni adjustment). Random variation and systematic differences due to different recording conditions and assessment of the colour M-mode data were calculated by analysis of variance using the BMDP3V computer analysis package. P values below 005 were considered to be statistically significant, except when Bonferroni adjustment was appropriate. Results HAEMODYNAMIC RESULTS Haemodynamic data from the reference group and each of the patient groups are presented in Table 1. LVminP was elevated (^5mmHg) in eight (17%), 13 (31%), and 11 (61%) patients in groups 1, 2, and 3, respectively. LVEDP was elevated (>12mmHg) in 20 (43%), 25 (60%), and 14 (78%) patients in groups 1, 2, and 3, respectively. COLOUR M-MODE DOPPLER Reference group Early diastolic inflow was depicted as an almost vertical column, showing that flow at the mitral tip and in the apical region started almost simultaneously (Fig. 1A). Occasionally, apical peak velocity was seen simultaneously with, or even preceding, the transmitral peak velocity. In 37% of the normal individuals, the early diastolic filling of the apical part of the ventricle consisted of two phases (Fig. IB). At the dividing site, peak velocities were always found in the second phase, and therefore the algorithm used this phase to calculate the time difference of peak filling velocity. Sometimes the initial phase was found closer to the apex and had higher distal velocities than the second phase, despite lower velocities at the dividing site. The normalized time difference of peak filling velocity (ntd) in the whole group was 12 ± 8 ms. cm" 1. No age-related differences were observed, and ntd did not s. s a. $. c 5 fin s 3 c " ' C ^5 ( co "2,_ 3 mbei ber ient E a 3 O. Z a. 3 O O Jo -H a: - Q ^S 5-1 o Z o * g I I <0..s- It 2 * u 1 I ^ 3 n E S3 a E l.s c > II O 73 '5 O. Q on u c >1 s-g. e e c 53 g 1. a: X

5 322 M. Stugaard et al. Table 2 Colour M-mode and pulsed Doppler results of the reference group and the patient groups. P values represent significance between adjacent groups Number of patients ntd (ms. cm" 1 ) 54 12±8 in 47 16± ±21*f PI!# 53± 14*t Group Reference P value A (m.s" 1 ) P value E/A ratio 0-46 ± ± ± ± ± ± ± ± 1-35 ns ns P value ns ns 00O02 A=atrial induced transmitral peak velocity, E=early transmitral peak velocity; ns=not significant; ntd=normalized time difference of peak filling velocity between apical region and mitral tip; */*=00001 versus reference group; f^ooool versus group 1; /><001 versus reference group. correlate with heart rate or LVEF. ntd was significantly larger in individuals with two early phases compared to those with a single early phase (/><0001). Heart rate and LVEF did not differ significantly between the two groups. Patient groups In contrast to normal individuals, diastolic inflow velocities became progressively delayed as the filling wave front approached the apical region. In several patients peak apical flow velocities appeared clearly after mitral inflow had ceased (Fig. 3). Furthermore, two phases of early inflow were present in 43%, 74%, and 50% in groups 1, 2, and 3, respectively. Group 2 contained significantly more patients with two phases than the reference group. At the dividing site the highest filling velocities were always found in the second phase. The visual observation of delayed early inflow was quantified by the normalized time difference of peak filling velocity (ntd). Peak velocity in the apical region was detected significantly later in patient groups 2 and 3 than in the reference group and group 1 (Table 2, Figs 4 and 5). The largest increase between adjacent groups was observed from group 1 to 2 (,P=00001) whereas ntd increased moderately from group 2 to group 3 (NS). Patients with either angiographically anteroapical or inferior hypokinesia/akinesia and similar LVEF were compared. No significant difference in ntd was found Figure 3 Early diastolic inflow recorded by colour M-mode Doppler technique in three patient groups: group 1 (Panel A), group 2 (Panel B), and group 3 (Panel Q. Blood velocities are coded by the rainbow colour system. White dots indicate peak velocities at the mitral tip (M) and in the apical region determined by computer analysis. See Fig. 1 for further explanation. The patient in group 1 had a time difference of peakfillingvelocity between the apical region and the mitral tip (TD) of 53 ms. The patients in group 2 and 3 had TDs of 235 and 305 ms, respectively.

6 LVfilling abnormalities in CAD 323 Apex Reference group Apex Group Time (ma) Figure 4 Graphical analysis of the time difference of peak filling velocity at the different depths from the mitral tip towards the apex, given as mean ± 1 SD in the reference and patient groups. Zero time is occurrence of peak mitral velocity. The time difference is generally smaller at all depths in the reference group and group 1 than in groups 2 and 3, which show a considerable increase in time difference towards the apex. Ref Group Figure 5 Column chart showing the normalized time difference of peak filling velocity (ntd) and the transmitral peak early to peak atrial velocity ratio (E/A ratio) in the different groups. This figure summarises our main findings; the colour M-mode index increases with progression of ventricular injury, in contrast to a pulsed Doppler E/A ratio which shows a normalization in severely injured ventricles, and thus cannot be distinguished from the normal ventricles. between these two groups of patients with different localization of LV dysfunction. Linear regression analysis showed a negative correlation between ntd and LVEF (r=0-55, r^o-30, ci=29-37, SE=012,.P=0-0001). Positive correlations were found between ntd and LVminP (r=0-26, 1^=007, ci=28-37, SE=0-60, P<001), and between ntd and LVEDP (r=0-20, 1^=004, ci=28-37, SE=033, P<005). The regression plots revealed a wide scattering of the data for all three comparisons. TRANSMITRAL VELOCITIES A slight and gradual increase in peak velocity, induced by atrial contraction was found on comparison of the reference group to patient groups 1 and 2 (Table 2), but the increase was significant only between the reference group and group 2 (P=0000\). The peak early to late transmitral velocity ratio (E/A ratio) fell significantly on comparison of the reference group to group 2 (P<00l) (Fig. 5). This trend was reversed when groups

7 324 M. Stugaard et al. 2 and 3 were compared; a significant increase in E/A ratio occurred, and group 3 was thus not significantly different from the reference group. Peak early velocity or deceleration time were not significantly different between the groups. Linear regression analysis showed no correlations between the transmitral velocities and the colour M-mode variable. A negative correlation was present between the E/A ratio and LVEF (r=0-33, 1^=0-11, ci= , SE=001, 7»<0-01). No correlations were observed between the transmitral velocities and LVminP or LVEDP. REPRODUCIBILITY The values included in the analysis varied from 0 to 127 ms. cm" 1. The estimate of mean normalized time difference of peak filling velocity was 31 ms. cm~'. The inter-observer difference of recording and of the day-today difference were both statistically significant (P<00001). Observer M.S. recorded higher values than H.I., and the difference was 13 ms. cm" 1. The systematic difference between recordings on different days was 12 ms. cm"'; the recordings from the first day were highest. The other differences between pairs of measurements of each factor in the statistical model were 5 ms. cm" 1 or less and not significant, except from a borderline significance on inter-observer difference on assessment (.P=0039). The standard deviation of the differences between all pairs of measurements in each patient reflects random variation, and was calculated as the square root of the error variance, which was 12 ms. cm" 1. Reproducibility analysis was also performed only with the factors contributing to statistical significance; the result was similar to the analysis including all factors. Discussion The present study shows that colour M-mode Doppler detects abnormal intraventricular filling patterns in patients with injured ventricles due to CAT). Apical filling is progressively delayed with increasing injury of the LV. This new technique also reveals abnormal filling in the patients with severely impaired systolic function and with a transmitral velocity pattern which cannot be distinguished from that found in normal individuals. Comparing the different groups of patients, however, the largest increase in apical filling delay was present in the group with moderately impaired systolic function. This finding is in accordance with the assumption that diastolic dysfunction precedes systolic dysfunction. PULSED DOPPLER Measurement of transmitral filling velocities by pulsed Doppler has been the commonly used ultrasonic method for assessing diastolic dysfunction of the LV. The Doppler technique has shown that ventricular filling in patients with CAD is delayed to late diastole due to slow myocardial relaxation With increasing injury of the ventricle and higher filling pressure transmitral blood flow shows a relative shift from late to early diastole, resulting in normalization of the transmitral flow pattern' 181. Similar results were present in this study, showing a significant shift in filling to early diastole in patients with severe dysfunction of the ventricle. Thus, the transmitral filling pattern in patients with severely injured ventricles was not significantly different from the pattern in apparently normal persons. Several studies have shown that the transmitral velocity pattern is very sensitive to loading conditions of the LV, and is also influenced by several other factors, including heart rate and age 119 " 2 ' 1. In recent years the enthusiasm for assessing diastolic function by measurements of transmitral velocities has therefore declined considerably. COLOUR M-MODE DOPPLER Using the multigated colour M-mode Doppler technique, we recently showed that apical filling is delayed during acute myocardial ischaemia' 8 " 101. We used an algorithm for automatic detection of peak velocity in the signal at different levels from the mitral valve towards the apex. Brun el al. measured the slope of the flow wave front in the colour M-mode recording and demonstrated that LV flow propagation during early filling was delayed in patients with various myocardial diseases' 91. We preferred to measure peak velocity for several reasons. The start flow consists of Doppler signals with low velocities and intensities, which may lead to misinterpreting noise artefacts as blood flow. This was avoided by using the peak velocity profiles. Unpublished results from our institution have shown that the propagation velocity is less reproducible than ntd. In cases with two phases of early apical flow, measurements of the slope of the flow wave front would miss the second phase. This can be seen from the colour M-mode figures which also shows that the linearity of the flow wave front was usually lost in the apical region, whereas peak velocities at this site could easily be determined. Measurements from the front of the flow wave depicts delay of filling in the more basal part of the ventricle. Measurements of peak velocity, however, also include retardation of filling in the apical region. The pulsed Doppler technique might have been used for measuring the timing of intraventricular filling velocities. This technique displays the velocity spectrum, whereas colour M-mode measures mean spectral velocity. Pulsed Doppler therefore may have a higher level of precision in determining the exact timing of peak velocity. However, if pulsed Doppler were to be used, the normalized time difference would have to be calculated from different heart beats, thus introducing an additional factor of variability. The reproducibility analysis showed that only small errors were introduced by the same observer repeating the recording and by one or more observers repeating the assessment. Differences were found between the recordings of the two observers, and between the 2 days of recording. The differences, however, were in the same

8 LVfilling abnormalities in CAD 325 range as the random variation. Our findings signify that the variability of the parameter normalized time difference of peak filling velocity was small in the present study because the same observer performed all recordings and assessments. NORMAL DIASTOLIC FILLING Diastolic filling of the LV is determined by the atrioventricular pressure gradient and the impedance of the mitral valve During the early phase of diastolic filling, active myocardial relaxation and elastic recoil are the major factors influencing the gradient. Recent studies have demonstrated intraventricular pressure gradients with a faster fall in pressure to a lower value in the apical region than in the mid ventricle Several authors have therefore proposed that the normal heart acts as a dynamic suction pump Rumberger et al. [25] showed, by the use of ultrafast computed tomography, that peak diastolic filling occurs almost simultaneously at different levels in the normal LV. Similar results were found in the present study by the use of colour M-mode Doppler; in some of our normal individuals, peak filling velocity occurred almost simultaneously at the mitral tip and in the apical region, whereas, in others, peak velocity occurred slightly later in the apical region than at the mitral tip. In fact, a slightly retarded propagation of blood flow towards the apex can also be read from the tomography data of Rumberger et al. l2s] and is of the same magnitude as in the present study. However, about 40% of the normal subjects showed two phases of early diastolic filling in the apical region. Our technique of measuring the peak velocity profile in the ventricular inflow ignores the first phase, and one might speculate that the two phases have different physiological significance. It is possible that the initial phase of apical filling is caused by an intraventricular gradient which induces suction of blood towards the apex. The second phase might be caused by blood entering from the atrium, suggesting regional differences in diastolic filling. DIASTOLIC FILLING IN CORONARY ARTERY DISEASE Myocardial ischaemia and infarction induce regional hypokinesia or akinesia in systole and delayed active relaxation in diastole. These haemodynamic changes lead to reduced regional compliance of the ventricle with elevated diastolic pressure, and ventricular filling is thus impaired. The present study support previous studies using pulsed Doppler 1261 and colour M-mode Doppler techniques' 7 l0] and shows that there is a delayed propagation of the velocity profile of ventricular inflow from the mitral valve towards the apex in patients with severely injured LV. However, our finding that the largest increase in filling delay was seen between patients with and patients without moderate systolic dysfunction is a new observation. Nevertheless, we showed that the delay of apical filling progressively increased with increasing severity of ventricular injury. This finding does not exclude the possibility that different loading conditions might have influenced the results. In recent experimental work, however, we have shown that this method of measuring filling delay is not affected by changes in loading condition or heart rate 1 ' 01. The use of drug was similar in the different groups of patients, and thus it is unlikely that the differences in apical filling delay between the patient groups could be attributed to drug effects. It is therefore possible that the differences in filling delay between groups express differences in diastolic function. MECHANISMS In the present study we found that apical filling occurred almost simultaneously with mitral inflow in normal ventricles, suggesting that the filling of the LV occurs without loss of energy due to an almost ideal matching of rate of relaxation and rate of filling. Our findings of delayed apical filling may be caused by a delayed propagation of blood flow towards the apex due to regional delayed relaxation or diastolic dysfunction, suggesting that energy is lost during early filling. These observations are supported by our own studies during experimental ischaemia and another study on patients with dilated cardiomyopathy showing significant correlations between filling parameters and time constant of isovolumic relaxation' 9 ' 10 '. We observed that apical filling occurred after mitral inflow had ended in several patients. This finding suggests that the colour M-mode flow pattern may reflect intraventricular redistribution of blood. Courtois et al. l27] showed that the early diastolic regional pressure gradient decreased after coronary artery occlusion in dogs. Our findings of rapid apical filling in the normal LV and delayed apical filling in the injured ventricles might reflect such a change in intraventricular pressure gradients. Two phases of early apical inflow were present significantly more often in patients with regional systolic dysfunction than in normal individuals. One might speculate that this observation reflects different waves of apical inflow. The first wave might be due to the suction effect or filling of normal ventricular regions, whereas the second wave might be retarded due to impaired relaxation in regions with myocardial infarction. Several authors 17 " have proposed that the altered inflow patterns in dilated ventricles in patients with infarction or cardiomyopathy may be due to the existence of eddy currents. The delayed filling of the apical region in our study might be due to formation of such currents. In patients with dilated ventricles and low LVEF, a low stroke volume would be expected to result in delayed apical filling. However, these mechanisms could not explain the filling pattern in a majority of our patients because their ventricles were not dilated and had normal LVEF.

9 326 M. Stugaard et al. LIMITATIONS OF THE STUDY LV pressures were measured by a fluid-filled catheter system. Therefore, the ventricular minimal pressure must be considered with particular caution due to problems with low resonant frequency and excessive damping resulting in undershoot of pressure in early diastole. Manometer-tipped catheters would have been preferable, but were not possible to use in our laboratory for routine examination of a large number of patients. The ventricular angiogram was obtained in a single plane, and LVEF was calculated using a single plane ellipsoidal formula. We may thus have underestimated the frequency of regional systolic dysfunction. However, the ECG was used as an additional method for detecting injury of the ventricle. Furthermore, the main objective of the study was to compare the colour M-mode Doppler with another method measuring diastolic filling, namely the validated transmitral pulsed Doppler technique. A major problem with the colour M-mode Doppler technique is that the ultrasonic beam investigates only a small part of the ventricle. Since spatial resolution is very limited, care should be exerted when conclusions are drawn regarding global filling of the LV. We did not study the isovolumic relaxation phase, which could have been easily done non-invasively. Timing of events during this phase might have revealed important information about early diastole However, our primary aim was to study the early inflow phase. Most patients used beta-adrenergic blockers or calcium channel blockers which may have modified LV diastolic filling and the measurements of normalized time difference of peak velocity. The use of these drugs probably affected the cardiac function of all patient groups similarly and was not important for the main results. CLINICAL IMPLICATIONS Colour M-mode Doppler recordings of left ventricular diastolic inflow were easily obtained in the majority of patients. Apical delay of peak filling velocity was measured using an algorithm which reduced observer interaction considerably. The post-processing work was easily performed, and thus the filling delay was quickly determined, even if it had to be done off-line. However, the software package used is not commercially available at the moment. If a colour coding system with high resolution is used as in the present study, our impression is that peak velocities in the inflow image may be localized visually. Thus, this method of measuring delayed apical filling should be easily applicable in future clinical work. Conclusions Colour M-mode Doppler technique shows that peak filling velocity during the early filling phase of the normal LV occurs almost simultaneously at the mitral tip and in the apical region. The filling of the apical region is delayed in impaired ventricles due to CAD. The delay increases with progression of LV injury, in contrast to transmitral filling velocities which are normalized in severely injured ventricles. Colour M-mode Doppler is therefore an important addition to transmitral pulsed Doppler technique for the detection of abnormal ventricular filling in patients with CAD. We are grateful to Dr Arvid Lundervold, MD, BSc, Norwegian Computing Center, Oslo, Norway, for advice concerning the statistical image analysis techniques. Professor Lars Wallooe, PhD, MD, Institute of Physiology, University of Oslo, Norway, is gratefully acknowledged for statistical advice and help during reproducibility analysis. References [1] Grossman W, McLaurin LP. Diastolic properties of the left ventricle. Ann Intern Med 1976; 84: [2] Little WC, Downes TR. Clinical evaluation of left ventricular diastolic performance. Prog Cardiovasc Dis 1990; 32: [3] LabovitzAJ, Lewen MK, Kern M, Vandormael M, Deligonal U, Kennedy HL. Evaluation of left ventricular systolic and diastolic dysfunction during transient myocardial ischemia produced by angioplasty. J Am Col! Cardiol 1987; 10: [4] Bonow RO, Vitale DF, Bacharach SL, Frederick TM, Kent KM, Green MV. Asynchronous left ventricular regional function and impaired global diastolic filling in patients with coronary artery disease: reversal after coronary angioplasty. Circulation 1985; 71: [5] Lew WYW. Evaluation of left ventricular diastolic function. Circulation 1989; 79: [6] Labovitz AJ, Pearson AC. Evaluation of left ventricular diastolic function: clinical relevance and recent Doppler echocardiographic insights. Am Heart J 1987; 114: [7] Jacobs LE, Kotler MN, Parry WR. Flow patterns in dilated cardiomyopathy: a pulsed wave and colour flow Doppler study. J Am Soc Echo 1990; 3: [8] Stugaard M, Risoe C, Ihlen H, Smiseth OA. Color M-mode Doppler reflects diastolic dysfunction during regional myocardial ischaemia (abstr). Circulation 1991, 84 (Suppl II): [9] Brun P, Tribouilloy C, Duval AM et al. Left ventricular flow propagation during early filling is related to wall relaxation: a color M-mode Doppler analysis. J Am Coll Cardiol 1992; [10] Stugaard M, Smiseth OA, Risoe C, Ihlen H. Intraventricular early diastolic filling during acute myocardial ischemia: assessment by multigated color M-mode Doppler. Circulation 1993; 88: [11] Davila JC, Sanmarco ME. An analysis of the fit of mathematical models applicable to the measurement of left ventricular volume. Am J Cardiol 1966; 18: 31^2. [12] Arbogast R, Solignac A, Bourassa MG. Influence of aortocoronary saphenous vein bypass surgery on left ventricular volumes and ejection fraction. Comparison before and one year after surgery in 51 patients. Am J Med 1973; 54: [13] Hurst JW, Logue RB, Rackley CE. The heart. Arteries and veins, 6 edn. New York: McGraw-Hill, 1986: [14] Myreng Y, Ihlen H. Reproducibility of transmitral flow velocity parameters measured by pulsed Doppler Echocardiography. J Cardiovasc Ultrason 1988; 7: [15] Ihlen H, Endresen K, Myreng Y, Myhre E. Reproducibility of cardiac stroke volume estimated by Doppler echocardiography. Am J Cardiol 1987; 59: [16] Gonzales RC, Wintz P. Digital Image Processing, 2nd edn Reading, Massachusetts: Addison-Wesley Publishing Company, Inc., 1987:

10 LVfilling abnormalities in CAD 327 [17] de Bniyne B, Lerch R, Meier B, Schlaepfer H, Gabathuler J, Rutishauser W. Doppler assessment of left ventricular diastolkfillingduring brief coronary occlusion. Am Heart J 1989, 117: [18] Appleton CP, Hatle L, Popp RL. Relation of transmitral flow velocity patterns to left ventricular function: New insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988; 12: [19] Myreng Y, Smiseth OA. Assessment of left ventricular relaxation by Doppler echocardiography: a comparison of isovolumic relaxation time and transmitral flow velocities with the time constant of isovolumic relaxation. Circulation 1990; 81: [20] Choong CY, Abascal VM, Thomas JD, Guerrero JL, McGlew S, Weyman AE. Combined influence of ventricular loading and relaxation on the tranmitral flow velocity profile in dogs measured by Doppler echocardiography. Circulation 1988; 78: [21] Ishida Y, Meisner JS, Tsujioka et al. Left ventricular filling dynamics: Influence of left ventricular relaxation and left atrial pressure. Circulation 1986; 74: [22] Yellin EL, Nikolic S, Frater RWM. Left ventricular filling dynamics and diastolic function. Prog Cardiovasc Dis 1990; 32: [23] Courtois M, Kovacs SJ Jr., Ludbrook PA. Transmitral pressure-flow velocity relation. Importance of regional pressure gradients in the left ventricle during diastole. Circulation 1988; [24] Robinson TF, Factor SM, Sonnenblkk EH. The heart as a suction pump. Sci Am 1986; 254: [25] Rumberger JA, Weiss RM, Feiring AJ et al. Patterns of diastolic function in the normal human left ventricle: an ultrafast computed tomographic study. J Am Coll Cardiol 1989; 14: [26] Delemarre BJ, Bot H, Visser CA, Dunning AJ. Pulsed Doppler echocardiographic description of a circular flow pattern in spontaneous left ventricular contrast. J Am Soc Echo 1988; 1: [27] Courtois M, Sandor KJ, Ludbrook PA. Physiological early diastolic intraventricular pressure gradient is lost during acute myocardial ischemia. Circulation 1990; 81: [28] Beppu S, Izumi S, Miyatake K et al. Abnormal blood pathways in left ventricular cavity in acute myocardial infarction. Experimental observations with special reference to regional wall motion abnormality and hemostasis. Circulation 1988; 78: [29] Delemarre BJ, Visser CA, Bot H, de Koning HJ, Dunning AJ. Predictive value of pulsed Doppler echocardiography in acute myocardial infarction. J Am Soc Echo 1989; 2: [30] Brecker SJD, Lee CH, Gibson DG. Relation of left ventricular isovolumic relaxation time and incoordination to transmitral Doppler filling patterns. Br Heart J 1992; 68: