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European Journal of Heart Failure 2008 10(7):689-695; doi:10.1016/j.ejheart.2008.05.007
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© 2008 European Society of Cardiology

Prognostic importance of a short deceleration time in symptomatic congestive heart failure

Dilek Akkana, Jesper Kjærgaarda, Jacob Eifer Møllera,*, Christian Hassagera, Christian Torp-Pedersenb, Lars Købera EchoCardiography and Heart Outcome Study (ECHOS) investigators

a The Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
b Department of Cardiology, Copenhagen University Hospital, Gentofte Hospital Copenhagen, Denmark

* Corresponding author. The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej, DK 2100 Copenhagen Ø, Denmark. E-mail address: jem{at}dadlnet.dk (J.E. Møller).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: A restrictive transmitral filling (RF) pattern predicts increased mortality in heart failure (HF) with reduced left ventricular (LV) systolic function. We performed a combined evaluation of LV function and RF for prognosis in patients with HF with and without systolic dysfunction.

Methods and results: Doppler echocardiography was performed in 972 patients with symptomatic HF. RF was considered present when deceleration time (DT) was ≤140 ms and non-RF when > 140 ms. A DT >240 ms was defined as delayed relaxation. During a median of 51 months the unadjusted all-cause mortality rates were significantly increased among patients with RF vs. the non-RF group (1- and 4-year mortality was 25% and 54% vs. 17% and 43%). In a multivariable model, RF was a significant predictor of all-cause mortality (hazard ratio (HR)=2.0, 95% confidence interval (CI):1.5–2.6) whereas delayed relaxation was without prognostic importance (HR=0.9, CI:0.5–1.6). Repeating the multivariable model in subgroups of wall motion index (WMI) showed that RF was a strong predictor of mortality independent of WMI. For patients with LVEF of at least 50%, HR for RF was 2.0 (CI:1.1–3.4; p=0.02) and interaction between LVEF and RF was not significant.

Conclusion: In a heterogeneous population hospitalised for symptomatic HF a restrictive transmitral filling pattern, defined as shortened deceleration time, during hospitalisation is an ominous prognostic sign independent of LV systolic function.

Key Words: Heart failure • Deceleration time • Prognosis

Received January 5, 2008; Revised April 10, 2008; Accepted May 15, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Left ventricular ejection fraction (LVEF) is conventionally used to stratify heart failure (HF) patients according to the presence of preserved or decreased LVEF. Although LVEF is a universally approved marker for the evaluation of systolic dysfunction, it is limited by only reflecting systolic performance and several studies have failed to identify LVEF as a strong predictor of mortality in chronic HF [1-3]. Recognition of the complex interplay between systolic and diastolic function, combined with the increasing prevalence and grave prognosis of HF, highlights the need for clinically useful risk markers in order to evaluate and establish prognosis in HF patients.

Systolic and diastolic dysfunction coexist in a wide spectrum of different HF severities [4,5] and diastolic dysfunction is an important contributor to HF regardless of LVEF [6]. Using Doppler echocardiography, distinctive diastolic transmitral filling patterns have been identified which relate to functional status and diminished exercise tolerance [7-11]. In advanced cases where filling pressures are high and LV chamber stiffness is often increased, the mitral filling pattern is characterized by a short deceleration time (DT) of the early diastolic filling wave and an increased ratio of peak flow velocity of early to late diastole, this has been termed a restrictive filling pattern [7,8,12-14]. Restrictive filling is associated with clinical severity of heart failure and poor prognosis in patients with LV systolic dysfunction, dilated cardiomyopathy and amyloidosis [8,15-21]. However, our understanding of the importance of restrictive filling as a prognostic marker is based on selected populations often with low power, and almost exclusively in patients with poor systolic function. Accordingly, the aim of the present study was to evaluate the long-term prognostic importance of restrictive filling, defined as a deceleration time ≤140 ms, in a large group of prospectively enrolled patients with symptomatic HF irrespective of LVEF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
This study was based on a consecutively recruited subpopulation of patients participating in the Echocardiography and Heart Outcome Study (ECHOS) [22]. ECHOS was a prospective, double-blind, randomised, placebo-controlled, Scandinavian multi-centre trial, to evaluate the effect of a selective agonist of the pre-synaptic DA2- and {alpha}2-receptors in patients with moderate to severe New York Heart Association (NYHA) functional class II-IV congestive heart failure. The study drug had no effect on overall mortality [22]. In the study centres, all consecutive patients ≥18 years of age hospitalised with symptomatic HF, estimated as current NYHA II-IV, requiring treatment with diuretic and at least one episode of dyspnoea or fatigue at rest or during slight exertion within the last month corresponding to at least NYHA class III, were screened for entry into the study. Patients with acute coronary syndrome or acute myocardial infarction were not eligible for the study. In addition, patients with atrioventricular block grade II and III were excluded. The diagnosis of congestive heart failure was supported by the presence of rales on auscultation, cardiomegaly and/or pulmonary congestion on chest X-ray, and presence of peripheral oedema and or jugular venous distension. Furthermore other causes of dyspnoea including acute coronary syndrome, ongoing infection, or arrhythmia were evaluated along with other comorbidities as COPD and chronic renal failure. The study was carried out in accordance with the standards for clinical studies in the Declaration of Helsinki II. The Danish Board of Health and the Central Danish Ethics Committee approved the protocol and guidelines for Good Clinical Practice were followed. Since there was no effect of the study treatment on overall mortality [22], the present analysis is performed without making any distinction between the study treatment groups. To ensure complete follow-up, only Danish patients were included in the present study. Hence, the population of this study consists of screened Danish patients with symptomatic HF.

2.2. Echocardiography and data analysis
Echocardiography was performed within the first 7 days after admission. A total of 3078 patients were screened and underwent 2-dimensional baseline transthoracic echocardiography in order to determine LV ejection fraction. In addition to standard 2-dimensional echocardiography the centres were also encouraged to perform Doppler ultrasound and M-mode examinations, but this was optional. Thus, Doppler flow recordings of sufficient quality were only available for 972 patients. Echocardiograms were digitized and subsequently analyzed by two experienced investigators (D.A. and J.K.) who were blinded to all clinical data. Analyses of wall motion index (WMI) were evaluated separately in a core lab. LVEF was assessed semi-quantitatively from WMI using a 16 segment model [23]. Using a reverse scoring system, each of the 16 LV segments were assigned a descending score from 3 to –1, according to myocardial function (hyperkinesis = 3, normokinesis = 2, hypokinesis = 1, akinesis = 0, paradoxical motion =–1). WMI was calculated by dividing the sum of the scores by the number of segments analyzed. A satisfactory approximation of LVEF in percent can be derived by multiplying WMI by 30 [24].

LV filling pattern was obtained by measuring the diastolic flow velocities across the mitral valve in the apical 4-chamber view. Effort was made to detect maximal flow velocities during diastole with the sample volume placed at the tips of the mitral leaflets as parallel with inflow as possible. Deceleration time of early filling (DT), peak flow velocity in early diastole (E velocity) and peak flow velocity at atrial contraction (A velocity) were measured as the averages of five consecutive cardiac cycles. DT was measured similarly in patients with atrial fibrillation/-flutter, but was based on averages of 5 to 10 consecutive cardiac cycles. Cardiac cycles with fusion of early and late velocities or with nonlinear deceleration slope were excluded. RF was considered when deceleration time was ≤140 ms and non-RF when >140 ms [25,26]. A filling pattern of delayed relaxation was considered if DT was >240 ms.

2.3. Clinical data
Demographic data, medical history, NYHA class and medication at admission and discharge as well as in-hospital complications were recorded for all patients.

2.4. Follow-up
The main outcome was all-cause death. Survival status was obtained from the Danish Central Person Register where all deaths in Denmark are registered within 2 weeks. No patients were lost to follow-up. The register was interrogated in July 2006, giving a follow-up time of up to 5 years.

2.5. Statistical analysis
Continuous baseline variables are summarized as medians with 5th and 95th percentiles and group comparisons assessed by Wilcoxon rank sum test. Categorical variables are expressed as number and percentage of the group total and comparative analysis was done using the {chi}2-test. Survival curves used Kaplan-Meier estimators and comparisons used the log rank test. Multivariable analysis was performed using Cox proportional hazard models. The assumptions (proportional hazard assumption, linearity of continuous variables and lack of interaction) were tested and found valid. All variables apart from medication in Table 1 were included in multivariable analyses. The final model included filling pattern and those variables that had independent contribution in the univariable models. Left atrial size was omitted from multivariable analyses since it was only available in 357 cases. Filling pattern was prospectively divided into 3 groups: restrictive FP, normal FP and delayed relaxation. Since the prognostic value of normal filling pattern and delayed relaxation were similar we have reported a dichotomisation of filling pattern in RFP and non-RFP. In addition a post-hoc analysis was performed to assess the optimal cut-off for DT. We performed separate Cox analyses with forced entry of fixed variables using different cut-offs for DT (110 to 150 ms with increments of 5 ms). By comparing the overall log likelihood ratio of the models the optimal cut-off proved to be 135-140 ms. Calculations used the Statistical Analysis System (SAS version 9.1). Results were considered significant at p-value<0.05.


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  		Table 1 Clinical baseline characteristics of 972 patients hospitalised with symptomatic heart failure according to the presence or absence of a restrictive filling pattern

 

   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Clinical baseline characteristics of the 972 patients in whom Doppler recordings were available are summarized in Table 1. There were no differences regarding all-cause mortality, LV ejection fraction or the rest of the variables shown in Table 1 between patients with and without transmitral filling measurements (data not shown). As mentioned, the study drug had no effect on the overall mortality and it similarly had no effect on DT. In Table 1 the patients are divided into two groups according to non-RF (n=503) and RF (n=469). The groups were not statistically different with respect to age, sex, body mass index (BMI) or S-creatinine. There were more smokers in the RF group compared to the non-RF group. More patients with non-RF had chronic obstructive pulmonary disease (COPD). Regarding medication at discharge, more patients with non-RF were prescribed calcium channel blockers, while more patients in the RF group were treated with digitalis. Table 2 summarizes echocardiographic findings. Patients with shortened DT had higher peak E velocity, lower peak A velocity and consequently higher E/A ratio. From the overall population 350 (36%) patients had LVEF>50% and they constituted 28% of the RF group. Patients with RF had lower WMI. There was no difference in left atrial size between the groups.


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  		Table 2 Echocardiographic characteristics at hospital admission according to the presence or absence of a restrictive filling pattern (n=972)

 
3.1. Outcome
During a median follow-up of 51 months (range 33.6-64.6 months) 482 patients died. The crude overall mortality in the whole population was 51%. Fig. 1 shows the probability of mortality among patients divided according to RF and non-RF. The unadjusted mortality rates were significantly (p<0.001) increased among patients with RF (1-year and 4-year mortality was 25% and 54%, respectively) compared to the group with non-RF (1-year and 4-year mortality was 17% and 43%, respectively). Univariable Cox proportional hazards analyses were performed to assess the impact of the transmitral filling pattern on all-cause mortality. Delayed relaxation was without prognostic importance (HR 0.9, 95% CI: 0.5-1.6) while RF was a significant predictor of all-cause mortality (HR 2.0, 95% CI: 1.5-2.6). The results of the multivariable analyses with the variables ranked in order are shown in Table 3. When the model was repeated, adding delayed relaxation and normal filling pattern into the non-RF group, the results were identical.


Figure 01
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  		Fig. 1 Kaplan-Meier analysis of the probability of mortality among 972 patients with symptomatic congestive heart failure divided according to restrictive and non-restrictive filling pattern.

 


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  		Table 3 Multivariable Cox proportional hazard analysis of Doppler echocardiographic and clinical variables predicting all-cause death

 
The multivariable model was repeated in subgroups according to left ventricular systolic function, Fig. 2. For patients with LVEF of at least 50% (n=350) HR for RF was 2.0 (95% CI: 1.1-3.3; p=0.02). Interaction between left ventricular systolic function and RF was not significant (p-value for interaction=0.96).


Figure 02
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  		Fig. 2 Restrictive filling pattern (RFP) as a predictor of mortality in relation to wall motion index (WMI).

 
Finally it was tested whether E/A flow velocity ratio added prognostic information to DT. When DT was in the model E/A ratio provided no additional information (p=0.47).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present large study demonstrates in a heterogeneous population hospitalised for symptomatic heart failure that a restrictive mitral filling is a powerful independent predictor of all-cause mortality. This finding was independent of LVEF, thus, RF was a significant predictor of mortality in patients with heart failure and preserved LVEF.

Several recent studies have highlighted the apparent paradox that as many as 50% of patients admitted with signs and symptoms of congestive heart failure only have mildly depressed or even normal LV ejection fraction [27]. Despite a high mortality in this large group of patients, risk stratification is challenging as LVEF offers little prognostic information. Furthermore, in many HF patients considerable discrepancy exists between the magnitude of systolic dysfunction and functional impairment [28,29]. This may be at least partly explained by differences in filling pressure and ventricular compliance hence differences in LV diastolic function. Even though exact assessment of intrinsic diastolic function requires cardiac catheterization, important information about the pressure-volume relationship may be obtained from 2-dimensional- and Doppler echocardiography [30].

In vitro, experimental animal and human studies have suggested that with increasing LV chamber stiffness (low operating compliance) the transmitral DT will be shortened [13,14,31]. With low operating compliance, filling will occur on the steep portion of the diastolic pressure-volume relationship. Thus, the ventricle will only fill at very high pressures.

Several previous studies have demonstrated the prognostic potential of shortened DT in patients with systolic dysfunction. In 1996, Giannuzzi demonstrated that a restrictive filling pattern was an independent predictor of all-cause mortality in a large population with ischaemic cardiomyopathy [17]. However, data are mixed and there are some controversies regarding the predictive role of DT. Nijland and Møller found restrictive filling pattern predictive of cardiac death after acute myocardial infarction, when defining RF as a combination of DT and E/A ratio and colour M-mode flow velocity, respectively [26,32]. In a retrospective study of patients with idiopathic dilated cardiomyopathy, Rihal showed that systolic indices were stronger predictors of survival, though DT<130 ms had an additive prognostic role when analysing subgroups with EF≤25% [21]. Shen concluded that only increased early to late velocity ratio and NYHA class were significant independent predictors of outcome in a group of patients with dilated cardiomyopathy of variable origin [33]. Some studies in small groups of heart failure patients with decreased LVEF have indicated that restrictive filling pattern, as defined by the combination of E/A ratio and DT, was a better predictor of outcome than a single Doppler parameter [20,34,35]. The highly selected nature of the studied populations, [19,21,33,36,37] the often small sample sizes with overall low numbers of events [18,21,33,36,37] combined with differences in the definition of a restrictive filling pattern [17-19,33,34,36,37] and studies which almost exclusively included patients with concomitant LV systolic dysfunction, has limited the impact of DT in everyday clinical practice. We therefore sought to evaluate the prognostic impact of a short deceleration time obtained by conventional Doppler echocardiography in a large heterogeneous group of patients with symptomatic CHF. Our results demonstrate that restrictive filling, defined as a mitral deceleration time≤140 ms, was a powerful long-term predictor of mortality. The result is strengthened by our inclusion of a wide range of aetiologies and severities of heart failure, as our patient population was selected based on symptomatic HF and not on echocardiographically verified or predetermined HF. This makes the present results applicable to many patients presenting with clinical heart failure.

Importantly, this effect on outcome was also seen when LVEF appeared mildly depressed or even normal. The presence of heart failure in patients with preserved systolic function remains an area of much controversy. Some have attributed this condition to abnormal diastolic function, but others have challenged this theory. The present study suggests that restrictive filling may also be seen in non-systolic heart failure where it is associated with excess mortality. Although speculative, it also seems likely that in patients with preserved systolic function, shortening of deceleration time is attributed to a non-compliant ventricle and high filling pressures and is thus linked to the excess mortality in this population. From our results it could seem that in advanced systolic heart failure with an ejection fraction of less than 25%, restrictive filling is of less importance. In cases of severely depressed LVEF a normal filling pattern is highly unlikely, and thus an apparently normal deceleration time in fact suggests a pseudonormal filling pattern with high filling pressures. Thus, the reference group in the multivariable model in case of severely depressed LVEF is likely moderately abnormal whereas in case of normal LVEF a truly normal filling pattern is more likely.

In our study, we found that LVEF estimated from regional wall motion analyses had only a borderline predictive value in multivariable models that included shortened DT. This may be a reflection that systolic function was preserved in many patients in the present study and additionally that the prognostic information obtained from depressed systolic function could also be obtained from other covariates included in the multivariable model.

Finally, we found in the present study that the morality rate was high and much higher than what is seen in most randomised heart failure trails. We made no selection based on age, symptoms, comorbidity or LVEF. As opposed to many randomised trails our population is therefore elderly with considerable comorbidity thus representing an everyday scenario. This likely explains the high mortality.

4.1. Limitations
It is likely that many patients with an apparently normal deceleration time in the present study actually has a pseudonormalized deceleration time due to coexisting delayed relaxation and increased filling pressure. As there was no tissue Doppler assessment of mitral annular diastolic motion or data on pulmonary venous flow, colour M-mode or valsalva manoeuvre, we were not able to differentiate a normal from a pseudonormal filling pattern. It is likely that additional prognostic information could be obtained from further grading of the LV filling pattern and assessment of diastolic E/e' ratio. Mitral DT is not only affected by effective chamber compliance, but also by mitral regurgitation, tachycardia, and ongoing ischaemia. As these conditions per se are associated with poorer outcome, this may have influenced the apparent prognostic importance of a shortened DT in some patients. Although the majority of studies were performed between days 2 and 4 after admission, differences in timing of the echo may have been a confounder. However, timing of the echo had no long-term prognostic impact. Stress testing/coronary angiography was not mandatory for this study, thus heart failure may have been caused by undetected coronary artery disease in some patients. However, almost half of the population had a history of coronary artery disease and we were unable to detect an interaction between deceleration time and aetiology, thus a restrictive filling pattern was associated with the same hazard ratio, irrespective of whether the aetiology was ischaemic or not. We therefore believe that unrecognised coronary artery disease did not significantly affect the conclusions of the present study.

The present study represents a heterogeneous heart failure population with a high prevalence of comorbidities. Although in all patients it was judged that dyspnoea on admission was caused by heart failure, we cannot rule out the fact that dyspnoea may have been due to other conditions such as COPD or obesity in some patients. Despite this, a shortened deceleration time was still a powerful predictor of outcome.

4.2. Conclusion
In a heterogeneous population hospitalised for symptomatic heart failure, restrictive transmitral filling as defined by shortened deceleration time on echocardiography during hospitalisation, is an ominous prognostic sign. This was even the case in patients with apparently preserved LVEF and supports the theory that abnormalities in ventricular compliance and filling pressure are associated with the development of heart failure in these patients.


   Acknowledgements
 
The ECHOS study was supported by unrestricted grants from Chiesi Pharmaceutical Company.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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