CLINICAL STUDY: MYOCARDIAL INFARCTION
Pseudonormal and restrictive filling patterns predict left ventricular dilation and cardiac death after a first myocardial infarction: a serial color M-mode doppler echocardiographic study
Jacob E. Møller, MDa,
Eva Søndergaard, MDa,
Steen H. Poulsen, MD, PhDb and
Kenneth Egstrup, MD, DmSci, FESCa
a Department of Medicine, Svendborg Hospital, Svendborg,Denmark
b Department of Cardiology, Aarhus University Hospital, Skejby, Denmark
Manuscript received March 21, 2000;
revised manuscript received June 13, 2000,
accepted July 20, 2000.
Reprint requests and correspondence: Dr. Jacob E. Møller, Department of Medicine, Svendborg Hospital, 5700 Svendborg, Denmark
jam{at}shf.fyns-amt.dk
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Abstract
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OBJECTIVES
We sought to assess the prognostic value of left ventricular (LV) filling patterns, as determined by mitral E-wave deceleration time (DT) and color M-mode flow propagation velocity (Vp), on cardiac death and serial changes in LV volumes after a first myocardial infarction (MI).
BACKGROUND
Combined assessment of DT and Vp allows separation of the effects of compliance and relaxation on LV filling, thereby allowing identification of pseudonormal filling. This may be valuable after MI, where abnormal LV filling is frequently present.
METHODS
Echocardiography was performed within 24 h, five days and one and three months after MI in 125 unselected consecutive patients. Normal filling was defined as DT 140 to 240 ms and Vp  45 cm/s; impaired relaxation as DT 240 ms; pseudonormal filling as DT 140 to 240 ms and Vp <45 cm/s; and restrictive filling as DT <140 ms.
RESULTS
Left ventricular filling was normal in 38 patients; impaired relaxation in 38; pseudonormal in 23; and restrictive in 26. End-systolic and end-diastolic volume indexes were significantly increased during the first three months after MI in patients with pseudonormal or restrictive filling (37 ± 15 vs. 47 ± 19 ml/m2, p < 0.0005 and 71 ± 20 vs. 88 ± 24 ml/m2, p < 0.0005, respectively). During a follow-up period of 12 ± 7 months, 33 patients died. Mortality was significantly higher in patients with impaired relaxation (p = 0.02), pseudonormal filling (p < 0.00005) and restrictive filling (p < 0.00005), compared with patients with normal filling. On Cox analysis, restrictive filling (p = 0.003), pseudonormal filling (p = 0.006) and Killip class II (p = 0.008) independently predicted cardiac death, compared with clinical and echocardiographic variables.
CONCLUSIONS
Pseudonormal or restrictive filling patterns are related to progressive LV dilation and predict cardiac death after a first MI.
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Abbreviations and Acronyms
| | DT | = (mitral E-wave) deceleration time | | ECG | = electrocardiogram or electrocardiographic | | EF | = ejection fraction | | LV | = left ventricle or ventricular | | MI | = myocardial infarction | | Vp | = (color M-mode flow) propagation velocity | | WMSI | = wall motion score index |
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Despite major improvements in the management of patients with acute myocardial infarction (MI), the mortality rate in unselected populations remains high (1–3). Therefore, it is of great importance that patients with an increased risk of an adverse outcome are identified early for therapeutic interventions that may improve their outcome. Left ventricular (LV) diastolic function can noninvasively be assessed with Doppler echocardiography. Development of a restrictive filling pattern after MI, characterized by shortening of the mitral E-wave deceleration time (DT), has been shown to be a strong, independent predictor of an adverse outcome (4–6) and to be predictive of LV remodeling after anterior MI (7). However, because of the confounding effects of LV relaxation and LV compliance on transmitral Doppler measurements, an apparently normal filling pattern may be seen in patients with advanced diastolic dysfunction. Recent studies have shown that color M-mode flow propagation velocity (Vp) is a preload-independent index of LV relaxation (8–12), which allows identification of a pseudonormal filling pattern (10,12,13) and may provide prognostic information after MI (14). Therefore, combined assessment of DT and Vp may allow separation of the effects of relaxation and compliance on LV filling, which may be used to identify patients with severe diastolic dysfunction (restrictive filling) and moderate diastolic dysfunction (pseudonormal filling). This may be important after MI, when abnormal LV filling is frequently seen (4–7). So, the objective of the study was to assess the prognostic value of LV filling patterns, as determined by DT and Vp, on cardiac death and serial changes in LV volumes after a first MI.
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Methods
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The study group consisted of 130 unselected, consecutive patients with an enzymatically confirmed first MI (transient elevation of creatine kinase >210 U/liter and creatine kinase B >20 U/liter). Five patients were excluded from the study owing to an implanted pacemaker (n = 2), aortic stenosis (n = 2) and dementia (n = 1), leaving a total of 125 patients (96%). The protocol was approved by the regional Scientific Ethical Committee, and all enrolled patients gave written, informed consent.
Echocardiography.
Echocardiography was performed within 24 h of hospital admission on a Sonos 5500 ultrasound machine (Hewlett Packard, Andover, Massachusetts) with a 2.5-MHz transducer, and repeated five days and one and three months after MI. Echocardiograms were stored digitally, and analyses were done with no knowledge of the clinical data. Analyses of color M-mode recordings were done separately and with no knowledge of two-dimensional and pulsed Doppler recordings. For patients in sinus rhythm, five consecutive beats obtained during quiet respiration were measured and averaged for each Doppler variable, and for patients in atrial fibrillation, 10 consecutive beats were measured (15,16). If present, the severity of mitral regurgitation was graded by calculating the fraction of regurgitation using quantitative Doppler echocardiography (17).
The wall motion score index (WMSI) was obtained semiquantitatively using a 16-segment division of the LV (18). Left ventricular volumes and ejection fraction (EF) were estimated using Simpson’s modified biplane method (18) and corrected for body surface area. Endocardial border detection was enhanced using second harmonic imaging.
Pulsed Doppler measurements were obtained with the transducer in the apical four-chamber view, with the Doppler beam aligned perpendicular to the plane of the mitral annulus. The Doppler sample volume was placed between the tips of the mitral leaflets during diastole. Color M-mode Doppler echocardiography was done in the apical four-chamber view, with the M-mode cursor aligned parallel with LV inflow. Adjustments were made to obtain the longest column of flow from the mitral annulus to the apex of the LV. The M-mode cursor was positioned through the center of inflow, avoiding boundary regions. The Vp was measured as the slope of the first aliasing velocity (45 cm/s) from the mitral annulus in early diastole to 4 cm distally into the LV cavity. In patients with a low mitral E-wave velocity where no aliasing was seen, baseline shift was adjusted to aliase at  75% of the mitral E-wave velocity.
Patients were classified into four groups on the basis of their echocardiogram on hospital admission: DT 140 ms and <240 ms was considered normal; DT 240 ms was suggestive of impaired relaxation; and DT <140 ms was suggestive of a restrictive filling pattern. Patients with a normal-appearing DT were considered to have normal filling if Vp was 45 cm/s, and pseudonormal filling if Vp was <45 cm/s (Fig. 1). The cut points chosen were based on recent clinical studies and recommendations (4–7,19–21).
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Figure 1 Pulsed Doppler recordings of transmitral filling (top) and color M-mode Doppler echocardiography (bottom). A, Normal filling pattern (DT 165 ms, Vp 63 cm/s). B, Impaired relaxation (DT 296 ms, Vp 39 cm/s). C, Pseudonormal filling pattern (DT 205 ms, Vp 33 cm/s). D, Restrictive filling (DT 110 ms, Vp 43 cm/s).
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After thrombolytic therapy, a decrease of 50% from peak ST segment elevation on the electrocardiogram (ECG) 60 min after therapy was considered suggestive of successful reperfusion (22).
Reproducibility.
Intraobserver and interobserver variabilities of Vp were 7 ± 5% and 8 ± 6% and those of DT were 3 ± 4% and 4 ± 5% (absolute difference divided by mean value of measurements).
Statistical analysis.
Continuous data are expressed as the mean ± SD. Comparisons between groups of discrete variables were performed using the chi-square test, and continuous variables were tested with one-way analysis of variance, with the unpaired or paired t test, as appropriate. Mortality was calculated using the product limit method and was plotted according to the Kaplan-Meier method. Comparisons of death rates between subgroups were tested with the log-rank test. Multivariate Cox proportional hazards analysis was performed to identify independent predictors of cardiac death. A priori, we chose to include age, use of thrombolytic therapy, Killip class II, peak creatine kinase, WMSI, LVEF, end-systolic volume index and LV filling pattern in the multivariate models. A p value <0.05 was considered significant. Statistical analysis was performed using SPSS for Windows version 8.0 (SPSS Inc., Chicago, Illinois).
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Results
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Echocardiography was performed within 6 ± 5 h of hospital admission in 125 patients. At baseline, DT was apparently normal (140 to 240 ms) in 61 patients, prolonged (240 ms) in 38 and shortened (<140 ms) in 26 patients. In patients with a normal-appearing DT, Vp was 45 cm/s, suggestive of normal filling in 38; and in 23 patients, Vp was <45 cm/s, suggestive of pseudonormal filling. Table 1 summarizes patient characteristics, and Table 2 shows the echocardiographic variables.
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Table 2 Baseline Echocardiographic Variables in 125 Patients Classified According to Left Ventricular Filling Pattern
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Thrombolytic therapy was given to 64 patients, 44 of whom showed signs of successful reperfusion based on ECG criteria. There were no differences in the use of thrombolytic therapy between the groups (p = 0.31). Forty-eight patients were referred for coronary arteriography, and accordingly, coronary artery bypass graft surgery was performed in 24 and angioplasty in 20. At hospital discharge, all patients were treated with aspirin, 79% with beta-blockers, 26% with an angiotensin-converting enzyme inhibitor, 42% with a diuretic agent, 23% with long-acting nitrates and 53% with a lipid-lowering agent, evenly distributed between the groups.
Left ventricular volumes and diastolic filling pattern.
Changes in LV volumes were assessed in 100 three-month survivors, excluding patients undergoing bypass surgery. During follow-up, both end-systolic and end-diastolic volume indexes decreased in patients with normal or impaired relaxation; however, the changes were not significant (Fig. 2). In contrast, patients with pseudonormal filling showed progressive dilation during follow-up, leaving both the end-systolic volume index (31 ± 10 vs. 44 ± 19, p < 0.0005) and the end-diastolic volume index (63 ± 13 vs. 82 ± 21, p < 0.0005) significantly higher after three months of follow-up (Fig. 2). Patients with restrictive filling also showed a progressive increase in the end-systolic volume index (45 ± 19 vs. 57 ± 17 ml/m2, p < 0.0005), as well as in the end-diastolic volume index (79 ± 21 vs. 103 ± 24 ml/m2, p < 0.0005) (Fig. 2).
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Figure 2 Serial changes in end-systolic volume index (top) and end-diastolic volume index (bottom) in 100 three-month survivors after MI. Data are presented as the mean value ± SEM. *p < 0.001, compared with baseline (paired sample t test). Triangles = normal filling; squares = impaired relaxation; diamonds = pseudonormal filling; circles = restrictive filling. See text for definitions of groups.
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Predictors of cardiac death.
During a follow-up period of 12 ± 7 months, 33 patients died: progressive heart failure in 9, sudden death in 15, papillary muscle rupture in 2, myocardial reinfarction in 3, postinfarction ventricular septal defect in 3 and LV free wall rupture in 1.
No patients with a normal filling pattern died during follow-up; in contrast, five patients with impaired relaxation (log-rank statistic 5.3, p = 0.02, compared with patients with a normal filling pattern), 11 patients with pseudonormal filling (log-rank statistic 24.1, p < 0.00005) and 17 patients with restrictive filling (log-rank statistic 37.3, p < 0.00005) died during follow-up (Fig. 3). Univariate predictors of cardiac death are summarized in Table 3. On multivariate Cox analysis, the variables listed in Table 4 were tested initially, without including the LV filling pattern. In this model, WMSI (p = 0.009), age (p = 0.02) and Killip class II (p = 0.01) were independently related to cardiac death. The overall chi-square statistic of the model was 45.5 (p < 0.00005). Also, the end-systolic volume index (p = 0.01) and LVEF (p = 0.01) were independent predictors of outcome when tested separately. However, when the filling pattern was included in the model, a pseudonormal filling pattern (p = 0.006), a restrictive filling pattern (p = 0.003) and Killip class II (p = 0.008) proved to be independent predictors of cardiac death, and the overall chi-square statistic of the model was increased to 79.3 (p < 0.00005) (Table 4). The end-systolic volume index, WMSI and LVEF were tested in separate models, but did not provide independent prognostic information after the LV filling pattern was included in the model.
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Figure 3 The effect of LV filling patterns on survival. Mortality was significantly higher in patients with impaired relaxation (p = 0.02), pseudonormal filling (p < 0.00005) or restrictive filling (p < 0.00005) than in patients with a normal filling pattern. Short-hatch/dotted line (top) = normal filling pattern; dotted line = impaired relaxation; long-hatch line = pseudonormal filling; solid line (bottom) = restrictive filling.
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Discussion
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Transmitral and color M-mode Doppler echocardiography.
Left ventricular filling depends on multiple factors, most importantly relaxation and compliance. Left ventricular relaxation is an energy-dependent process during which the contractile elements are deactivated in the sarcomere, whereas LV compliance describes the passive properties of the LV during filling (19,20). Impaired relaxation decreases early filling, leading to prolongation of DT. When LV compliance decreases, LV filling pressure rises, which has the opposite effect on transmitral filling, leading to shortening of DT (19–21). Therefore, a normal-appearing filling pattern may be seen despite coexisting abnormalities in LV relaxation and compliance. Combined hemodynamic and color M-mode Doppler studies have shown a strong correlation between flow propagation and invasive indexes of LV relaxation (8–10,12). Furthermore, Vp has been shown to be independent of changes in preload (8–12). These results strongly suggest that Vp allows a noninvasive estimation of LV relaxation. The combined use of mitral pulsed wave and color M-mode Doppler echocardiography may therefore be used to separate the effects of relaxation and compliance on LV filling, and thereby separate patients with normal filling (normal DT and normal Vp) from those with pseudonormal filling (normal DT and reduced Vp).
Left ventricular volumes and diastolic filling pattern.
Left ventricular remodeling, as characterized by LV dilation, scar expansion and hypertrophy, is an important determinant of long-term outcome after MI (23). Previously, enzymatic infarct size, anterior MI and patency of the infarct-related artery have been shown to be related to the remodeling process (24,25). Furthermore, restrictive filling has recently been shown to predict LV dilation after reperfused anterior MI (7), which was confirmed by the present study in a more heterogeneous group of patients. Interestingly, we also found LV dilation in patients with normal DT but decreased Vp. At baseline, LV volumes, enzymatic infarct size, anterior MI, Q wave MI and patency rates, based on ECG criteria in this group, were not different from those variables of patients with normal LV filling. This suggests a true relation between LV filling pattern and LV remodeling, possibly mediated through increased LV filling pressures and increased wall stress.
Predictors of cardiac death.
As in previous studies (4–6), patients with a restrictive transmitral filling pattern were characterized by large anterior infarctions with moderate to severe LV systolic dysfunction, as well as a high risk of fatal and nonfatal cardiovascular events. However, a group of patients with apparently normal transmitral filling and with preserved LV systolic function (mean LVEF 0.50) was identified by decreased Vp suggestive of a pseudonormal filling pattern. The mortality in this group was considerably higher than that of the group of patients with normal filling or impaired relaxation, and pseudonormal filling was identified as an independent predictor of cardiac death. On Cox analysis, excluding the LV filling pattern, indexes of systolic function proved to be importantly related to cardiac death. However, when the filling pattern was added to the model, systolic functional variables did not provide additional prognostic information. These results, indicating that assessment of LV filling patterns provides superior prognostic information, compared with systolic variables, may be related to the fact that patients with restrictive filling were characterized by poor LV systolic function and by a poor prognosis, whereas patients with pseudonormal filling had preserved LV systolic function but a poor prognosis.
In a recent study of a similar group of patients with MI, we have reported that the ratio of peak E wave velocity to Vp >1.5 was a predictor of outcome after MI (14). Using this method, no data on filling patterns are obtained, and the method has the potential risk of misclassifying patients with impaired relaxation where Vp is markedly reduced in the "high risk group."
Study limitations.
The older age profile, high frequency of in-hospital heart failure and relatively low use of revascularization in the present study may indicate an increased risk profile for our group. This may exaggerate the predictive value of any prognostic indicator. However, after controlling for age and heart failure, the LV filling pattern still proved to be importantly related to outcome. In addition, the age profile and rate of in-hospital heart failure of our study group closely resemble those previously reported from studies of patients with MI where no selection based on age or eligibility for thrombolytic therapy were done—studies which have reported one-year mortality rates of 20% to 23% (1–3).
Nitroglycerin is known to increase DT by lowering preload (19,20). This may have led to the misclassification of some patients as having impaired relaxation who in fact had a normal LV filling pattern. Because of the low event rates in these groups, this is considered less important. Achievement of successful reperfusion is important for recovery of systolic function and survival, and may potentially influence the recovery of diastolic function. Routine angiographic assessments of artery patency were not performed. This may have confounded the results indicating LV remodeling in patients with pseudonormal filling; however, no differences in noninvasive assessment of patency were seen between the groups.
Conclusions.
Left ventricular filling pattern, as characterized by either normalized DT and decreased Vp or shortening of DT, effectively identifies patients at increased risk of LV dilation and cardiac death after a first MI.
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Footnotes
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This study has been supported by a grant from the Danish Heart Foundation.
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G. A. Whalley, R. N. Doughty, G. D. Gamble, S. P. Wright, H. J. Walsh, S. A. Muncaster, and N. Sharpe
Pseudonormal mitral filling pattern predicts hospital re-admission in patients with congestive heart failure
J. Am. Coll. Cardiol.,
June 5, 2002;
39(11):
1787 - 1795.
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G.-Y. Xie and M. D. Smith
Pseudonormal or intermediate pattern?
J. Am. Coll. Cardiol.,
June 5, 2002;
39(11):
1796 - 1798.
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