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Circulation. 1996;94:673-682

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(Circulation. 1996;94:673-682.)
© 1996 American Heart Association, Inc.

Articles

Changes in Early and Late Diastolic Filling Patterns Induced by Long-term Adrenergic ß-Blockade in Patients With Idiopathic Dilated Cardiomyopathy

Bert Andersson, MD, PhD; Kenneth Caidahl, MD, PhD; Andrea di Lenarda, MD; Sanford E. Warren, MD; Franz Goss, MD; Anders Waldenstrom, MD, PhD; Stig Persson, MD, PhD; Ingemar Wallentin, MD, PhD; Åke Hjalmarson, MD, PhD; Finn Waagstein, MD, PhD

the Divisions of Cardiology (B.A., A°.H., F.W.) and Clinical Physiology (K.C., I.W.), Sahlgrenska University Hospital, Goteborg, Sweden; the Department of Cardiology (A.d.L.), Ospedale Maggiore and University, Trieste, Italy; the Division of Cardiology (S.E.W.), Beth Israel Hospital, Boston, Mass; the Department of Medicine (F.G.), Zentralklinikum, Augsburg, Germany; the Department of Medicine (A.W.), Norrland University Hospital, Umea°, Sweden; and the Department of Medicine (S.P.), University of Lund (Sweden).

Correspondence to Dr Bert Andersson, Kardiologdivisionen, Sahlgrenska Sjukhuset, S-413 45 Goteborg, Sweden. E-mail bert.andersson@hjl.gu.se.


*    Abstract
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 *Abstract
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Background ß-Blockers have been used in patients with idiopathic dilated cardiomyopathy to improve cardiac performance and theoretically would be beneficial to diastolic function. However, there are few reports on changes in diastolic function during chronic pharmacological treatment of congestive heart failure.

Methods and Results The present study was a substudy in the international Metoprolol in Dilated Cardiomyopathy Trial. Transmitral Doppler echocardiography was used to evaluate diastolic function in 77 patients randomly assigned to placebo (n=37) or metoprolol (n=40). The patients were treated for 12 months. Changes in Doppler flow variables in the metoprolol group implied a less restrictive filling pattern, expressed as an increase in E-wave deceleration time (placebo, 185±126 to 181±64 ms; metoprolol, 152±63 to 216±78 ms; P=.01, placebo versus metoprolol). Maximal increase in deceleration time had occurred by 3 months, whereas systolic recovery was achieved gradually and maximal effect was seen by 12 months of treatment. Although deceleration time was correlated to heart rate at baseline, changes in deceleration time were not significantly correlated to changes in heart rate during treatment.

Conclusions During the first 3 months of treatment, maximal effects on diastolic variables were reached, whereas the most prominent effect on systolic function was seen late in the study. It is suggested that effects on diastolic filling account for subsequent later myocardial systolic recovery. The E-wave deceleration time, which in recent studies has been shown to be a powerful predictor of survival, was significantly improved in the metoprolol-treated patients.


Key Words: heart failure • cardiomyopathy • systole • diastole • echocardiography • receptors, adrenergic, beta


*    Introduction
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 up arrowAbstract
 *Introduction
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Diastolic heart failure has been addressed in several studies in recent years. Because of its sensitivity to loading conditions, alteration in diastolic function is not easy to evaluate in the clinical setting.1 Besides improvement in hypertensive patients after unloading therapy,2 there have been no reports on isolated diastolic improvement in congestive heart failure. Adrenergic ß-blockade has the potential of being beneficial to diastolic function by lengthening of the diastolic period and improving subendocardial perfusion.3 4 5 6 7 8 9 ß-Blockers have, in numerous publications, been shown to exert a beneficial effect on systolic function in patients with congestive heart failure and in particular in patients with idiopathic dilated cardiomyopathy (IDC),10 11 12 13 14 whereas there has been less attention to the possible beneficial effect on diastolic function.15 16 However, in the first publications from our group, an early positive effect of ß-blockers on diastolic function was suggested on the basis of the reduction of a phonocardiographically recorded third heart sound and rapid filling wave from the apex cardiogram recordings.17 18 19 Later, we demonstrated a parallel reduction of the rapid filling wave and the left ventricular filling pressure after long-term ß-blocker treatment. It was suggested on the basis of findings in serially recorded apex cardiograms that improvement of diastolic function occurred as early as 2 weeks after treatment and preceding improvement in systolic function measured as an increase in ejection fraction (EF).20 All these studies were uncontrolled, open studies that used older techniques for evaluating diastolic function than those used today. The present investigation was therefore aimed at studying serial changes in left ventricular diastolic function in a prospective, randomized, double-blind, placebo-controlled trial with metoprolol in patients with IDC. Pulsed-wave Doppler echocardiography is a noninvasive method for evaluating diastolic function that is suitable for repeated measurements during a long-term study.

Study objectives were to evaluate the influence of long-term ß-blockade on diastolic function in patients with IDC. It was hypothesized that ß-blockade would improve diastolic function and that the improvement should precede improvement in systolic function.


*    Methods
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 up arrowAbstract
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 *Methods
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 down arrowDiscussion
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As the largest randomized, controlled trial of its kind on the use of ß-blockade in chronic heart failure, the Metoprolol in Dilated Cardiomyopathy Trial enrolled 383 patients in 33 centers in Europe and North America.11 The study was a double-blind, randomized, placebo-controlled trial, stratified according to center and to EF (<0.20 or 0.20 to 0.39, respectively).

Patients
Patients with symptomatic IDC and EF <0.40 were eligible for the study. Exclusion criteria included coronary artery disease confirmed by coronary arteriography, systemic disease, insulin-dependent diabetes mellitus, excessive alcohol consumption, hypertension, signs of active myocarditis, or other serious disease that might influence the prognosis of the patient. In the present study we report the results from an optional substudy on diastolic function, which recruited 78 patients from eight centers. Baseline characteristics for the 78 participating patients are given in Table 1Down.


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  		Table 1. Baseline Characteristics in 79 Patients With Idiopathic Dilated Cardiomyopathy

Protocol
Before entering the study, the patient received a test dose of 5 mg metoprolol twice daily for a minimum of 2 days. If this dose was tolerated, the patient was included in the study. Treatment was continued with slowly increasing doses according to the following schedule: week one, 5 mg twice daily; week two, 5 mg three times daily; week three, 10 mg three times daily; week four, 25 mg twice daily; week five, 25 mg three times daily; week six, 50 mg twice daily; and week seven and onward, 50 mg three times daily.

The period of treatment was 12 months, and investigations were performed at baseline and after 3, 6, and 12 months of treatment. To avoid the direct pharmacological effect of ß-blockade, the study drug was withheld for 24 hours before investigation. All other medications were continued during the investigation. Thirty-eight patients were assigned to placebo and 40 patients were assigned to metoprolol. There were 28 patients with EF <0.20 and 50 patients with EF 0.20 to 0.39.

Investigations
A right heart catheterization was performed in the morning with the patient in a fasting state and without premedication. A triple-lumen Swan-Ganz pulmonary artery catheter was introduced percutaneously through the internal jugular vein. An arterial line was obtained in the radial artery. Pressures, flows, and blood samples were obtained at rest. The invasive protocol with follow-up at 6 and 12 months was optional in the study and was available in 26 placebo patients and 27 metoprolol patients.

Radionuclide Investigation
An equilibrium radionuclide angiography was performed. Red blood cells were labeled with 925 MBq of 99mTc with the use of standard in vivo–in vitro labeling techniques. Imaging was performed with a small-field-of-view, single-crystal gamma camera in the left anterior oblique position that best separated the right and left ventricles, with 20 degree caudal tilt. Studies were conducted with the patient in semisupine position. We collected data by using 32 frames per RR interval with ECG gate tolerance ±10% of the cardiac cycle with exclusion of extrasystolic and postextrasystolic cycles. The acquisition was stopped when the left ventricular region of interest contained approximately 150 counts per pixel. The radionuclide investigation with follow-up at 6 and 12 months was optional in the study and was available in 28 placebo patients and 29 metoprolol patients.

Echocardiographic Investigation
M-mode, two-dimensional, pulsed-wave Doppler, continuous Doppler, and color Doppler echocardiographic examinations were performed with the patient in the left lateral position. All echocardiographic recordings were obtained during relaxed end-expiration apnea. Mitral flow velocities were measured by the pulsed-wave Doppler technique in the four-chamber view under two-dimensional guidance. The sampling volume was placed at mid position between the annulus level and the tips of the mitral valve. Mitral and tricuspid regurgitations were measured by continuous and color Doppler flow registrations and graded on a four-grade scale.20 Echocardiographic measurements were recorded on strip charts and videotape for further analysis.

Measurements
Functional status was assessed according to the New York Heart Association functional classification. Cardiac output was measured by a thermodilution technique. The radionuclide investigations were evaluated by investigators who were unaware of patient identity, treatment, or time of investigation. EF was calculated from left ventricular time-activity curves.

The diastolic transmitral flow was evaluated by digitization of the spectral flow curves. All recordings were analyzed at the coordinating center. The investigator was blinded to patient data. The mean value of three beats was used unless irregular heart rhythm was present, in which case five representative beats were used. Analyzed variables were calculated by a specially designed software program (Mednet, Sahlgrenska University Hospital, Goteborg). Interobserver and intra-observer variabilities (variation coefficient) in our laboratory were as follows: deceleration time, 8.3% and 6.1%; E-wave peak velocity, 1.7% and 1.5%; A-wave peak velocity, 1.2% and 0.9%; E-wave velocity time integral (VTI), 5.1% and 3.5%; and A-wave VTI, 3.7% and 3.9%. The following variables were analyzed in the study: E- and A-wave peak velocity; E- and A-wave VTI; VTI of total diastolic flow; first one-third VTI/last two-thirds VTI ratio; E-wave deceleration time; first derivative of the E-wave deceleration period (maximum negative dV/dt); slope of first one third of E-wave deceleration phase; and total diastolic time (Fig 1Down). Further, diastolic Doppler variables were analyzed by adjusting for heart rate (HR), by dividing by the square root of the RR interval. Normal age-matched values in our laboratory were (n=98) E-wave peak velocity, 55±15 cm/s; A-wave peak velocity, 51±11 cm/s; E-wave VTI, 6.95±2.1 cm; A-wave VTI, 4.56±1.0 cm; total diastolic VTI, 12.9±2.6 cm; E-wave deceleration time, 183±36 ms; E-wave max neg dV/dt, -3.8±1.7 m/s2; slope of first one third of E-wave deceleration, -3.5±1.3 m/s2; and E/A height ratio, 1.17±0.49.



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  		Figure 1. Schematics of mitral flow velocities with the use of pulsed-wave Doppler. Top depicts total diastolic flow. Bottom shows measurements of the E-wave deceleration process. Measured variables include peak mitral flow velocity in early diastole (E), peak mitral flow velocity at atrial contraction (A), E-wave velocity time integral (E VTI), A-wave velocity time integral (A VTI), E-wave deceleration time (EDT), E-wave slope maximal negative dV/dt (Max neg dV/dt), and first one-third slope of E-wave deceleration period (First 1/3 slope).

The time constant of isovolumic relaxation ({tau}) was measured from the continuous mitral Doppler flow curve in patients with mitral insufficiency, according to the method of Chen et al21 and Nishimura et al.22 The pulmonary capillary wedge pressure (PCWP) from the corresponding catheterization was added to the pressures, calculated with use of the Bernoulli formula. In 24 investigations there was no corresponding invasive investigation, and the interpolated mean PCWP from the previous and subsequent investigations was used.

The study was approved by the Ethics Committee of the Medical Faculty, Goteborg University. Participating patients gave informed consent before inclusion in the study.

Statistical Methods
Data were analyzed on an IBM 3081 minicomputer-based SAS statistical software. ANOVA was used to test differences over time between the two treatment groups.23 Correlation between variables was performed by the Spearman rank correlation test. The association between changes from baseline to follow-up in different variables (here denoted as {Delta}) were compared by the Spearman rank correlation test. The influence of HR, PCWP, and EF on diastolic Doppler variables at baseline was tested by univariate and multiple regression stepwise correlations. The variable with significant correlation to E-wave deceleration time in the multivariate analysis was entered in a regression formula to predict values of the deceleration time at the follow-up investigations and compare these to the actually measured values in a measured-to-predicted quotient. These quotients were subsequently compared by ANOVA. All probability values are expressed as mean±SD and in figures as mean±SEM.


*    Results
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Compliance
There were four deaths during the study. One placebo patient was investigated at baseline only and died suddenly at 47 days of follow-up. This patient is not included in the follow-up analysis. One metoprolol patient died suddenly after 6 months of treatment, and two placebo patients (sudden death in one and progressive congestive heart failure in one) died after 6 months of treatment. There were three permanent withdrawals before the end of the study because of noncompliance in one (metoprolol) and because of stroke (metoprolol) and preeclampsia during pregnancy (placebo) in one.

Baseline Correlations
Linear correlation analysis was applied between baseline Doppler variables and HR, EF, and PCWP, respectively. All Doppler variables were significantly correlated to HR. EF and PCWP were less strongly correlated to diastolic variables. See Table 2Down.


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  		Table 2. Univariate Correlations Between Diastolic and Hemodynamic Variables at Baseline

Invasive Hemodynamics
Although there was a minor decrease in PCWP in the placebo group (NS), PCWP had decreased significantly more in the metoprolol group than in the placebo group at 6 months of follow-up. There were no significant changes in PCWP between 6 and 12 months of follow-up (Fig 2Down). Systemic vascular resistance was not significantly changed during the study, placebo from 1323±482 to 1155±393 (6 months) and 1194±449 (12 months) dyne·s-1·cm-5; metoprolol from 1333±496 to 1160±484 (6 months) and 1139±441 (12 months) dyne·s-1·cm-5 (placebo versus metoprolol; NS).



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  		Figure 2. Effects on pulmonary capillary wedge pressure. Probability values denote intergroup comparison by ANOVA from baseline (BL) to 6 and 12 months of follow-up. Data are mean±SEM values. Filled circles represent metoprolol; unfilled squares, placebo.

Radionuclide Investigation
Radionuclide investigation in the total group of patients showed a significant improvement in EF in the metoprolol group compared with the placebo group by 12 months of treatment and trends by 3 or 6 months, although there also was minor improvement in the placebo group (Fig 3Down).



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  		Figure 3. Effects on radionuclide ejection fraction. Probability values denote intergroup comparison by ANOVA from baseline (BL) to 6 and 12 months of follow-up. Data are mean±SEM values. Filled circles represent metoprolol; unfilled squares, placebo.

Doppler
HR decreased significantly in the metoprolol group, and the maximal HR reduction was achieved by 3 months (Fig 4Down). Total diastolic time was prolonged in the metoprolol group, whereas the total diastolic VTI was unaltered during the study. Also see Table 3Down.



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  		Figure 4. Effects on heart rate. Probability values denote intergroup comparison by ANOVA from baseline (BL) to 6 and 12 months of follow-up. Data are mean±SEM values. Filled circles represent metoprolol; unfilled squares, placebo.


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  		Table 3. Doppler Echocardiography Data at Baseline and Follow-up Investigations

At baseline the E/A ratios were elevated in both groups compared with normal subjects (1.36 in the placebo group, 1.55 in the metoprolol group), suggesting a "pseudonormal" or a restrictive filling pattern in both groups. The baseline data indicated a tendency toward worse diastolic function in the metoprolol group, although there were no statistically significant differences between the two groups. During the study, there were signs of a less restrictive filling pattern in the metoprolol group as expressed in terms of changes in several indices of the deceleration part of the E wave (Table 3Up). The height of the E wave and the E/A ratio decreased compared with the placebo group, and the deceleration time of the E wave increased (Fig 5Down). Because most Doppler variables were closely correlated to HR at baseline, we adjusted for HR by dividing by the square root of the RR interval (Table 4Down). The analysis of the adjusted values revealed similar results as the native data.



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  		Figure 5. Effects on transmitral Doppler E-wave deceleration time. Probability values denote intergroup comparison by ANOVA from baseline (BL) to 6 and 12 months of follow-up. Data are mean±SEM values. Filled circles represent metoprolol; unfilled squares, placebo.


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  		Table 4. Doppler Echocardiography Data Adjusted for Heart Rate by Dividing by the Square Root of the RR Interval

There was a significant correlation between {Delta}E-wave deceleration time and {Delta}HR in the total study group at 3 months of follow up (r=-.32; P=.012), whereas the corresponding correlation coefficient was -.34 (P=.07) in the placebo group and -.14 (NS) in the metoprolol group. The correlation between {Delta}deceleration time and {Delta}HR at 12 months of follow-up was placebo, r=.00 (NS), and metoprolol, r=-.22 (NS). When the correlation was corrected for PCWP changes, the association by 12 months was placebo, r=.10 (NS), and metoprolol, r=-.16 (NS). With baseline deceleration time as the dependent variable and with HR, PCWP, and EF as the independent variables, the stepwise regression formula revealed only HR (P=.003) to be significantly correlated to deceleration time, giving the regression formula Deceleration time=368-(2.36xHR) (ANOVA; P=.0003). The measured-to-predicted quotients using the regression formula are shown in Fig 6Down. There were no significant intergroup differences by ANOVA during the study period, although there was a trend toward an increased quotient in the metoprolol group, with an intragroup significant increase from baseline to 12 months of investigation (P=.04).



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  		Figure 6. Measured-to-predicted quotients of deceleration time with use of the regression formula Deceleration time=368–(2.36xheart rate). There were no intergroup differences during follow-up. *P<.05, within-group difference between baseline and follow-up. Data are mean±SEM values. Filled circles represent metoprolol; unfilled squares, placebo.

There were 11 placebo patients and 12 metoprolol patients who showed a very short deceleration time (less than 111 ms, which is 2 SD below the mean value of the control group). Two of these 11 placebo patients died during the study, 2 were permanently withdrawn, whereas 1 patient increased deceleration time >2 SD. One of 12 metoprolol patients with deceleration time <111 ms died, while 8 patients had an increase in deceleration time >2 SD during follow up.

At baseline, 8 placebo patients and 10 metoprolol patients exhibited a single diastolic filling wave. Owing to the impaired systolic function and restrictive filling pattern, it was decided to evaluate this single filling wave as an E wave in the total analysis. During follow-up, 2 placebo patients and 6 metoprolol patients regained separate E and A waves (Fig 7Down). In the patients with discernible A wave at baseline, neither the A-wave height nor the A-wave VTI differed between the two treatment groups during the study. Further, the first one-third VTI/last two-thirds VTI ratio, which takes into account the entire diastolic VTI, also was significantly reduced in the metoprolol group and remained unchanged in the placebo group. An analysis in which the patients with a single diastolic filling wave were excluded revealed a similar trend in the remaining patients on the effects on diastolic variables as for the whole group, although with less statistical significance (Table 5Down). Examples of Doppler flow recordings in 2 patients with an isolated diastolic filling wave at baseline are shown in Fig 8Down. The placebo and metoprolol patients had similar filling patterns at baseline. At 12 months of treatment, the metoprolol patient had a prolongation of diastolic filling and a separation into a short E wave and a considerably taller A wave, whereas the placebo patient had an identical filling profile compared with the baseline investigation. The prolonged E-wave deceleration time is clearly visible in the recording from the metoprolol patient.



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  		Figure 7. Individual data points expressing late diastolic transmitral A-wave velocity time integral in placebo (left) and metoprolol (right) patients with an isolated diastolic filling wave at baseline (BL).


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  		Table 5. Doppler Echocardiography Data in the 60 Patients With a Separate E Wave and A Wave at Baseline






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  		Figure 8. Diastolic transmitral flows from a placebo group patient (top) and a metoprolol group patient (bottom) at baseline (left) and at 12 months' follow-up (right).

At baseline, 10 of 36 (28%) placebo patients and 20 of 40 (50%) metoprolol patients exhibited significant mitral regurgitation (grade >=2). At 12 months of follow-up, the fraction of placebo patients who showed mitral insufficiency was 8 of 30 (27%; NS), whereas the number of metoprolol patients with mitral insufficiency had been reduced to 11 of 36 (31%; P=.01). There was no significant difference between the two groups in intergroup comparison.

Individual data on {tau} constant generated from continuous mitral Doppler recordings are shown in Fig 9Down. There were no significant differences in intergroup or intragroup comparisons.



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  		Figure 9. Individual data points expressing {tau} constant of isovolumic relaxation derived from continuous Doppler recordings of mitral regurgitation in placebo patients (left) and metoprolol patients (right).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The results of the present study confirm earlier reported findings that signs of disturbed diastolic function were reversed early after initiation of ß-blocker treatment. Although diastolic function partly appears to improve parallel to systolic function, some diastolic indices reached maximal change by 3 months, whereas EF continued to increase at 6 and 12 months. It is therefore suggested that diastolic effects might be important in the early phase of ß-blockade treatment and that they also might be responsible for the paradoxically good initial tolerance.

Early Diastole
The findings in the present study confirm our earlier observations of a reduction in rapid filling wave and reduction in the phonocardiographically recorded third heart sound, which may be explained by the displacement of filling from the early to the late diastolic phase. A rapid early diastolic filling has previously been considered a sign of adequate diastolic function. However, during the last decade it has become obvious that in the case of severe ventricular dysfunction, there is a simultaneous rapid early diastolic filling accompanied with a restrictive filling pattern.24 25 Thus, in these patients, a prolongation of the early filling period might be beneficial to diastolic function and allow a less restrictive filling pattern. It would be expected that this could be accomplished by HR reduction, although it has not been shown in any previous long-term study.

In a previous study on the short-term effects of intravenous ß-blockade, we demonstrated a shift of diastolic volumes from early diastole to late diastole parallel to a decrease in HR in patients with severe heart failure.15 Reductions in peak filling rate were significantly correlated to changes in HR but were unchanged when HR was held constant by atrial pacing. This was accomplished with unchanged end-diastolic, end-systolic, and stroke volumes. Haber et al16 have presented results in accordance with these data. They showed a decrease in peak left ventricular filling rate after intravenous ß-blockade, as our studies have shown. Although the authors concluded that there were no changes in passive diastolic function (PCWP and chamber elastic stiffness), the interpretation of changes in peak filling rate differs if derived in severe heart failure or in hearts with normal systolic function. A reduction in peak filling rate actually may be a sign of improvement in diastolic function and left ventricular stiffness.26 Furthermore, a recent publication reported that deceleration time showed a close positive correlation with chamber stiffness, and the investigators provided a regression formula for calculation of chamber stiffness.27 Passive chamber stiffness is not constant during the diastolic period, and the pressure-volume relation shows a curvilinear relationship. The authors showed that the early diastolic transmitral pressure gradient was constant at lower filling pressures but tended to increase during later diastole in left ventricular dysfunction. We evaluated the very early portion of the deceleration phase (first one third of the E-wave deceleration slope), and similar to the total deceleration phase, this first one-third slope was significantly less steep after 3 months of metoprolol treatment (Table 3Up).

The time constant of left ventricular pressure decay is considered representative of myocardial relaxation properties. Previous studies on ß-blockade in congestive heart failure do not suggest an improvement of internal myocardial relaxation at spontaneous HR.16 28 The limited data on the mitral Doppler-generated {tau} constant in this study did not reveal any change in the two treatment groups during the study. The present results may indicate that the early myocardial relaxation process was not improved per se but was facilitated rather by allowing a prolonged period for myocardial relaxation. However, the lack of effect on {tau} may be biased because the calculations required the presence of a significant mitral regurgitation. As part of cardiac improvement, more metoprolol patients lost mitral regurgitation during follow-up.

Late Diastole
In the present study, diastolic flow appeared to be redistributed to late diastole, as expressed by a decrease in the E wave and the mitral flow E/A ratio. Some study patients had total diastolic filling that occurred during a very short diastolic time, as expressed by the absence of an A wave or fused E and A waves. During metoprolol treatment, the E and A waves were restored in most of these patients. By the term "diastolic function," one is referring mainly to the early myocardial relaxation process. However, the diastolic period consists of different phases, all of which may be important for ventricular filling. Filling during late diastole accomplished by atrial contraction would benefit from a prolonged diastolic time, separating early from late diastolic events.

Short-term Versus Long-term Effects
In this study, the first follow-up measurements were performed at 3 months. Our data suggest that all changes in diastolic variables had already occurred by 3 months of treatment. These findings confirm earlier observations in an open study with metoprolol in IDC,20 in which significant improvement of the diastolic variable rapid filling wave of the apex cardiogram, reflecting the same diastolic period as the deceleration phase of the Doppler E wave, already was evident after 1 month of treatment, with no further improvement over the following 11 months. In that study, no effect on ejection fraction was seen until after 3 months, with marked further improvement over the next 9 months. Withdrawal of ß-blockers after long-term treatment was followed by an abrupt increase in rapid filling wave of the apex cardiogram, whereas the decrease in EF occurred more slowly over several months, again suggesting that the increased metabolic load secondary to withdrawal of ß-blockade caused deterioration of the diastolic function. In the present study, a trend toward improvement in EF was seen after 3 months, but additional improvement was noted by 6- and 12-month follow-up. In the main study11 in which EF was studied at 6 and 12 months, further improvement was observed between these two investigations. These data strongly suggest that there is a time lag between the onset of improvement of diastolic and systolic functions. Processes in early diastole may be a functional part of late systole. It could not be determined from the results of this study whether the early filling effects preceded any increase in EF. However, the prominent changes in diastolic variables at 3 months, when changes in EF were not significant, suggested that diastolic events preceded systolic recovery. In a small, open study, it has been suggested that diastolic improvement preceded systolic recovery, as expressed by a reduction in PCWP, before any increase in EF was detected.7 Furthermore, during the initiation of ß-blockade, we have shown a reduction in peak filling rate without changes in EF,15 which implies that a slower early diastolic filling may be a prerequisite for subsequent myocardial recovery.

The Importance of Loading Conditions and HR for the Interpretation of Changes in Diastolic Function
The observations of changes in diastolic function may be explained partially by a reduction in HR and partially by a decrease in left ventricular filling pressure (PCWP), which may improve early filling. At baseline, the diastolic function was more closely correlated to HR than to EF or PCWP. In accordance with previous studies,29 30 31 we found significant correlations at baseline between raised filling pressure and predominant early diastolic filling. An improvement in systolic function seen after 3 months of treatment, leading to more effective emptying of the left ventricle, may account for the reduced filling pressure. During long-term metoprolol treatment, the systemic vascular resistance is unchanged. Systolic blood pressure tends to increase32 33 simultaneously with an increase in stroke work index, which would tend to increase afterload. In contrast to this, a reduction in left ventricular volumes,34 which has been observed after long-term metoprolol treatment,35 36 is associated with lower afterload. However, it it suggested that these alterations in load are not primary events but are secondary to myocardial recovery, first observed as an amelioration of the restrictive filling pattern.

Few studies have reported on isolated diastolic improvement unaccompanied by systolic improvement. In this study, the improvement in diastolic and systolic functions was parallel to some extent. Normally, inotropic drugs produce an increase in systolic as well as diastolic velocities.37 38 With metoprolol we found signs of a less rapid early filling together with signs of systolic improvement, as expressed by EF. Previous experimental studies have shown that an optimal force-frequency relation was present at a considerably lower HR in the failing myocardium compared with the normal myocardium.39 Therefore, not only diastolic but also systolic function as well as coronary circulation may be improved by HR reduction in the failing heart.

Although diastolic Doppler variables were significantly correlated to HR at baseline as well as during follow-up, the alterations in deceleration time were not significantly correlated to changes in HR or PCWP. These findings are in accordance with the prognostic studies that found a short Doppler deceleration time to be a marker of poor long-term survival independent from other conventional prognostic variables such as HR, EF, or PCWP.40 41 42 43 The overall clinical improvement of the patients on metoprolol treatment compared with the placebo-treated patients11 and the improvement (increase) in deceleration time is in accordance with these observations. In addition, in normal hearts there is a reversed correlation between HR and diastolic Doppler indices compared with severe heart failure, which emphasizes that a short deceleration time reflects the disease process and not only an increase in HR.44 In our normal control population there was no significant correlation between E-wave deceleration time and HR (unpublished observations).

The analysis of the predicted quotient of deceleration time showed a minor increase in the metoprolol group, suggesting that the increase in deceleration time was partially independent from changes in HR. If ß-blockade ameliorates a restrictive filling pattern-and this is not only mediated by a prolongation of diastolic time or an improvement in systolic function-then what is the mechanism? Although the results of this study give such indications, we cannot at the present give the answer to that question. Our previous data suggest that ß-blockade administration alters myocardial metabolism in a favorable way, as expressed by improved lactate utilization32 33 and by a decrease in myocardial oxygen consumption, the latter of which was not merely dependent on HR reduction.15 Similar results have been reported by others.45 46 Increased inotropism may cause an inappropriate increase in myocardial oxygen consumption simultaneous with an increase in HR.38 47 A recent study suggested that intravenous ß-blockade also was capable of reducing myocardial oxygen consumption in the presence of inotropic drugs.48 The increase in myocardial performance caused by ß-blockade during long-term treatment is not accompanied by an increase in myocardial oxygen consumption.32 33 Furthermore, there might be an improvement in intracellular calcium handling and tissue pH.49 50 Improved myocardial energy utilization would favor the highly energy-dependent diastolic processes51 and may be partially unrelated to HR alterations.

Limitations of the Study
According to the protocol, the study drug had been withdrawn before investigations, producing a trough effect. With ongoing ß-blockade, the results might have been different. However, there were no signs of a rebound phenomenon such as an increase in HR. The data on systolic function were limited to EF recordings. Multiple invasive procedures are not suitable for clinical trials, and invasive follow-up data on left ventricular filling pressure were not available for all patients. Although the present study investigated changes 3 months after the initiation of ß-blocker treatment, information from parallel studies of left ventricular volumes and transmitral Doppler flow is lacking regarding acute administration of ß-blockers and the very early period after the start of peroral treatment. Such information should be of value for our understanding of the early effects of ß-blockers on diastolic function in patients with congestive heart failure.

Conclusions
In this long-term trial on adrenergic ß-blocker effects on diastolic function in patients with IDC, we present a unique series of follow-up investigations. Diastolic alterations displayed early beneficial effects of ß-blockade preceding changes in systolic function. These changes occurred parallel to the reduction in HR but were not significantly correlated to the decrease in HR. Improvement in EF continued for another 9 months after a plateau of the improvement in diastolic function was obtained. It is suggested that the improvement in diastolic function accounts for the excellent tolerability seen during the early phase after the initiation of ß-blocker therapy and may be of main importance in allowing subsequent systolic recovery. Early diastolic inflow deceleration time, which has been shown to be a powerful predictor of survival, was significantly improved by metoprolol treatment.


*    Acknowledgments
 
This study was supported by grants from Astra Hassle Pharmaceuticals, Molndal, Sweden, and the Goteborg Medical Society. Technical assistance was provided by Margareta Scharin Tang, Eva Lavik Olofsson, Gunilla Fritzon, and Ronny Wijk.

Received August 24, 1995; revision received February 8, 1996; accepted February 16, 1996.


*    References
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 *References
 

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