Author + information
- Received October 20, 1997
- Revision received January 20, 1998
- Accepted February 19, 1998
- Published online June 1, 1998.
- Pier L Temporelli, MDa,* (, )
- Ugo Corrà, MDa,
- Alessandro Imparato, MDa,
- Enzo Bosimini, MDa,
- Francesco Scapellato, MDa and
- Pantaleo Giannuzzi, MDa
- ↵*Address for correspondence: Dr. Pier L. Temporelli, Centro Medico di Riabilitazione, Divisione di Cardiologia, 28010 Veruno (NO), Italy
Objectives. We sought to assess whether in clinically stable patients with chronic heart failure (CHF) the prolongation (i.e., increase) of an initially short (≤125 ms) Doppler transmitral deceleration time (DT) of early filling obtained with long-term optimal oral therapy predicts a more favorable prognosis.
Background. It has been recently demonstrated that transmitral early DT is a powerful independent predictor of poor prognosis in patients with left ventricular dysfunction. However, DT may change over time according to loading conditions and medical treatment.
Method. One hundred forty-four patients with CHF and a short DT (≤125 ms) underwent repeat Doppler echocardiographic study 6 months after the initial examination, while clinically stable with optimal oral therapy, and were then followed up for a mean period of 26 ± 7 months.
Results. After 6 months, DT had not changed in 80 patients (group 1), whereas it was significantly prolonged (>125 ms) in the remaining 64 patients (group 2). Baseline Doppler echocardiographic features were similar in the two groups. No changes were found after 6 months in group 1, whereas group 2 showed a slight but significant (p < 0.01) reduction in end-systolic volume, an improvement in left ventricular ejection fraction (p < 0.01) and a decrease (p < 0.01) in the degree of tricuspid regurgitation. During follow-up, 37% of patients in group 1 experienced cardiac death versus 11% in group 2 (p < 0.0005). By Cox model analysis, prolongation of a short DT emerged as the single best predictor of survival (chi-square 15.70).
Conclusions. The prolongation of an initially short DT obtained with long-term optimal oral therapy predicts a more favorable outcome in clinically stable patients with CHF.
It is now well recognized that Doppler echocardiography of mitral flow is a useful tool for assessing left ventricular (LV) filling abnormalities in various cardiac diseases (1–7). In patients with LV dysfunction the mitral flow velocity pattern has been shown (1,5–15)to correlate with symptoms, central hemodynamic variables and prognosis. In particular, the so-called restrictive pattern, characterized by a shortened isovolumetric relaxation time and deceleration time (DT) of early filling, together with an increased ratio of peak flow velocity in early to late diastole, is associated with elevated LV filling pressures, more severe functional status and poor exercise capacity. In recent years, it has been demonstrated (13)that Doppler-derived mitral DT of early filling, as an index of restrictive LV diastolic filling irrespective of the filling pattern, provides a simple and noninvasive method of estimating and monitoring pulmonary capillary wedge pressure in patients with severe LV systolic dysfunction. More recently still, a short (≤125 ms) mitral DT has also been proved to be a powerful independent predictor of poor prognosis in both symptomatic and asymptomatic patients with LV systolic dysfunction (16). However, in view of the dynamic nature of LV filling, DT together with the restrictive pattern may change over time after loading manipulations as a function of variations in LV filling pressures. In other words, an optimal therapeutic regimen may reverse a restrictive pattern and normalize a short DT; but to date, the prognostic value of these changes has been only poorly investigated.
Accordingly, the aim of the present study was to assess whether an increase in an initially short (≤125 ms) early DT, as an expression of reversible restrictive physiology, obtained with long-term optimal oral therapy could predict a more favorable prognosis in patients with chronic heart failure (CHF).
Patients with LV systolic dysfunction (echocardiographic LV ejection fraction ≤35%) and CHF due to either ischemic or nonischemic dilated cardiomyopathy, in clinically stable condition for at least 3 weeks with oral therapy and with a short DT (≤125 ms) of early filling on Doppler echocardiography irrespective of the ratio of early (E) to late (A) diastolic filling (E/A ratio) were eligible for the study. Patients were ineligible if they were >75 years old or if they had any of the following: echocardiographic images and transmitral Doppler tracings of inadequate quality for analysis, atrial fibrillation, severe valvular stenosis, unstable angina pectoris or myocardial ischemia requiring revascularization, myocardial infarction during the previous 3 months, severe pulmonary diseases, coronary artery bypass graft procedures during the previous 6 months, cancer or other systemic disease affecting survival. From December 1992 through December 1995, 265 patients were consecutively evaluated in our heart failure unit for possible enrollment. Of these 265 patients, 185 met the entry criteria for the study. All patients gave their written informed consent to participate in this prospective study, which had been approved by the science and ethics committee of our institution.
The study consisted of two parts: clinical evaluation and Doppler echocardiography at rest, both at entry and 6 months later, and follow-up. Patients enrolled underwent clinical examination and a complete Doppler echocardiographic study at rest; a second evaluation was scheduled for 6 months later, provided that patients were clinically stable. In the interim, patients were to receive an optimal oral therapeutic regimen. Angiotensin-converting enzyme inhibitors and beta-adrenergic blocking agents were gradually increased to the target or the maximal tolerated dosage. The target dosage for enalapril and captopril were 10 mg twice a day and 50 mg three times/day, respectively. The target dosage for metoprolol and carvedilol were 50 mg twice a day and 25 mg twice a day, respectively. Diuretic drugs were administered in flexible dosages on the basis of body weight and daily diuresis. Digitalis was titrated to reach a serum concentration between 0.8 and 2 ng/ml. Of the 185 patients initially enrolled, 41 experienced severe adverse events (hospital admission for heart failure or death) before the second evaluation; the remaining 144 patients, clinically stable in the absence of cardiac events, underwent the repeat Doppler echocardiographic study after 6 months and were then followed up for a mean (±SD) period of 26 ± 7 months. During follow-up, the therapeutic regimen was not influenced by Doppler DT results at the second evaluation. Stable clinical conditionwas defined as stable body weight and fluid balance and the absence of signs of pulmonary or peripheral congestion.
The functional status of patients at the time of the Doppler echocardiographic study was determined according to New York Heart Association class. Asymptomatic patients were assigned to functional class I, mildly symptomatic patients to class II, those moderately symptomatic to class III and those very symptomatic at minimal activity or rest to class IV.
A complete two-dimensional echocardiographic and Doppler ultrasound examination was performed in all patients at the entry evaluation and after 6 months by means of a Hewlett-Packard ultrasound system (model 77729-A or 77622-A) with 2.5- and 3.5-MHz probes. Images were stored on a Panasonic videotape recorder (AG-7330E) for further analysis.
LV volumes were calculated from orthogonal apical views using the area–length method. LV ejection fraction was derived from the standard equation. Maximal atrial area and right ventricular end-diastolic diameter 1 cm below the tricuspid annulus were also measured from the apical four-chamber view. Mitral regurgitation was diagnosed and semiquantitatively graded by color-flow Doppler as none, mild, moderate or severe according to previously reported criteria (17). Mitral flow velocity was assessed by pulsed-wave Doppler echocardiography in the apical four-chamber view with the sample volume positioned between the tip of the mitral leaflets, where maximal flow velocity was recorded (1,5). Care was taken to obtain the smallest possible angle between the presumed direction of the diastolic blood flow and the orientation of the ultrasound beam. Traces of five to eight consecutive cycles were analyzed using a microcomputer-based digitizing system, and the following variables were measured: maximal early diastolic velocity (peak E), maximal late diastolic velocity (peak A), their ratio (peak E/A) and the DT of early filling. DT was measured as previously described (1,13). Cardiac cycles with nonlinear deceleration slopes and fusion of early and late mitral flow velocity were excluded from the analysis.
After the second examination, patients were seen in our outpatient clinic at regular intervals (on average every 6 months). Patients who did not attend the scheduled appointments were followed up by chart review or contact with the treating physician, telephone interview with the patient conducted by trained personnel or review of the patient’s hospital record. Outcome eventswere cardiovascular mortality, heart transplantation while in critical condition (status 1), hospital admission for worsening heart failure and cumulative events (death, transplantation or hospital admission for heart failure). Only one event was considered in each patient, and any event occurring after the initial event was not considered.
All descriptive data are given as mean value ± SD. Differences between patients were compared by unpaired ttesting and frequency of variables and events by the chi-square test with the Yates correction. Differences between groups and changes over time within each group, as well as any interaction (different trends between groups), were assessed by multivariate repeated measures analysis of variance. Those variables that showed a significant association with the outcome were included in the multivariate Cox model in stepwise fashion. Survival was estimated by the product-limit Kaplan-Meier method. Differences between survival curves were tested with the log-rank chi-square statistic. A p value <0.05 was considered statistically significant.
The study included 144 patients (118 men, 26 women; mean age 57 ± 9 years) with CHF and a short (≤125 ms) early DT. All patients had had at least one unequivocal episode of clinical heart failure. The etiology of heart failure was coronary artery disease in 75% of patients and idiopathic dilated cardiomyopathy in the remaining 25%. Mean left ventricular ejection fraction was 22 ± 6%. Forty-nine patients (44%) were in functional class III or IV; the other 95 (66%) were in functional class II.
Mitral flow velocity pattern changes
At the second evaluation (6 months after initial examination), the DT of early filling had not changed in 80 patients (group 1, persistent short DT); the remaining 64 patients showed a significant prolongation (>125 ms) of DT (group 2, prolonged DT). Baseline clinical characteristics of the two study groups are shown in Table 1. More patients in group 1 were in functional class III or IV (p = 0.03) and had been given digitalis (82% vs. 66%, p = 0.02); all other clinical variables were well comparable between the two groups. Of significance, when treatment was optimized after the first evaluation, medical therapy between the two studies was similar in both groups (Table 2).
Table 3shows Doppler echocardiographic variables at baseline and after 6 months in the two groups. At baseline, all echocardiographic and transmitral Doppler variables considered were similar in the two groups. After 6 months, no significant changes could be seen in patients with persistent short (≤125 ms) DT of early filling (group 1), whereas DT had increased from 107 ± 14 to 165 ± 33 ms (p < 0.001) in those with a significant prolongation of DT (group 2); moreover, in group 2 the E/A ratio was lower (p < 0.001), end-systolic volumes had slightly decreased (p < 0.01), LV ejection fraction had improved (p < 0.001), and the number of patients with moderate to severe tricuspid regurgitation had also decreased (p < 0.001).
Follow-up data were available for 141 (98%) of the 144 patients enrolled. During a mean follow-up period of 26 ± 7 months, 37 patients (26%) died of cardiovascular causes, 7 (5%) underwent transplantation while in critical condition, and 49 (34%) were admitted to the hospital for worsening heart failure. Overall, there were 75 hard events (52%). No patient died of noncardiac causes. Of the 37 patients with cardiac death, 21 died of progressive heart failure and 16 of sudden death. The two patients who underwent elective transplantation while their clinical condition was stable were excluded from the analysis at the date of the transplantation.
There were 30 cardiac deaths (37%) in group 1 (persistently short DT) as opposed to 7 (11%) in group 2 (prolonged DT) (p < 0.0005). Fewer patients (7 [11%]) were admitted to the hospital for worsening heart failure in group 2 than in group 1 (42 [54%]) (p < 0.0000). Moreover, fewer patients underwent urgent transplantation while in critical condition in group 2 (1 [1.5%]) than in group 1 (6 [7.5%]), although the difference was not statistically significant (p < 0.2). Overall, cumulative cardiovascular events (defined as cardiac death, urgent transplantation and hospital admission for worsening heart failure) were significantly lower in group 2 than in group 1 (24% vs. 77%, p < 0.0001).
On univariate analysis, several echocardiographic and mitral Doppler variables, including changes between baseline and 6-month evaluation, together with functional status were found to be predictive of fatal outcome (Table 4). Of note, no specific medication at baseline or during the 6-month period of optimized therapy emerged as significantly associated with prognosis. When multivariate analysis in a forward stepwise regression procedure was performed (including in the model baseline echocardiographic and mitral Doppler variables with their changes at 6 months and the use of medications both at entry and between the two evaluations), only prolongation of an initially short DT, LV end-systolic volume and tricuspid regurgitation at entry and changes in LV ejection fraction between baseline and late evaluation emerged as independent predictors of survival (Table 5). Prolongation of a short DT proved to be the single best predictor (chi-square 15.7%). Furthermore, when survival without hospital admission for CHF and survival without any cardiovascular events (hospital admission for heart failure, urgent transplantation or death) were analyzed, prolongation of a short DT still emerged as the most powerful independent predictor (Table 5). Survival free of death, survival free of hospital admission for heart failure and event-free survival according to the evolution of DT are reported in Figure 1. The 4-year cumulative mortality rate was 48% in patients with a persistent short DT and 14% in those with a prolonged DT (p < 0.0005). Moreover, the cumulative 4-year incidence rate of all hard events was 86% in patients with a persistent short DT and 36% in those with a prolonged DT (p < 0.0001).
The present study demonstrates that in clinically stable patients with CHF, significant prolongation of an initially short (≤125 ms) DT of early filling may be obtained after 6 months of optimized oral therapy and clearly identifies patients with more favorable outcome.
Conversely, a higher risk for fatal outcome can be predicted by a group of noninvasive variables, including a persistently short DT, the presence of moderate to severe tricuspid regurgitation, lack of change in LV ejection fraction over time and LV end-systolic volume at entry. All these variables are independent prognostic indicators, persistent short DT being the single best predictor of cardiac mortality. Over a 4-year follow-up period, cardiac death occurred in 48% of patients with DT persistently ≤125 ms after 6 months of optimized medical therapy but in only 14% of patients showing a significant prolongation of a short DT after such therapy (Fig. 1A). Furthermore, a persistently short DT proved the most important predictor of hospital admission for worsening heart failure and cumulative cardiac events (death, urgent transplantation and hospital admission for heart failure).
Comparison with previous studies
Several studies (1,2,4, 13,14,18–20)have shown that a restrictive transmitral flow pattern is strongly related to LV filling pressure and the severity of clinical symptoms of various cardiovascular disorders. More recent studies (8–12,15)have also clearly demonstrated the prognostic value of the restrictive pattern and, more recently still, of a short DT (≤125 ms) of early filling (16)in patients with LV dysfunction. However, in those studies mitral flow pattern was assessed only once, which could be a limitation because we know that the transmitral filling pattern may change over time according to loading conditions and medical treatment. To date, few studies (and featuring only small groups of patients with a short follow-up period) have investigated the prognostic power of a favorable evolution of the restrictive pattern (21–24), namely, its normalization by means of a reduction of the E/A ratio or prolongation of a short early DT, or both.
Of these latter studies, Klein et al. (21)and Werner et al. (22), investigating patients with cardiac amyloidosis and with dilated cardiomyopathy, indicated that changes in transmitral flow pattern occur during serial Doppler echocardiographic evaluations and that they are closely related to changes in clinical condition and course of the disease. Still more recent data by Traversi et al. (23)and Pozzoli et al. (24), in a group of patients with CHF closely comparable to our study cohort, showed that changes in transmitral flow pattern after loading manipulations or long-term optimized therapy are correlated with changes in central hemodynamic variables and functional capacity and provide relevant independent prognostic information. However, in those studies focusing on the evolution of the LV diastolic filling, the restrictive pattern was defined by an E/A ratio ≥2 or by the combination of an E/A ratio between 1 and 2 and a DT ≤140 ms.
In the present study—on the basis of the recent demonstration of the independent predictive power of a short (≤125 ms) Doppler transmitral early DT in patients with CHF irrespective of the filling pattern as defined by the E/A ratio (16)—we enrolled patients purely on the basis of a short DT (≤125 ms) as an index of restrictive LV diastolic filling, and to our knowledge, investigated for the first time the prognostic contribution of changes over time of this transmitral Doppler variable. In agreement with our previous experience (16), we confirmed here that in patients with CHF, a short early DT (≤125 ms) is associated with a very high event rate: 41 of the 185 patients initially enrolled experienced an adverse cardiac event (death or hospital admission for worsening heart failure) before the second evaluation at 6 months and were excluded from the study; in the remaining 144 patients who completed the study protocol, with a second Doppler echocardiographic evaluation after 6 months of clinical stability under optimized therapy, there were a further 44 hard events (31%) (death or urgent transplantation while in critical condition) and 49 hospital admissions for worsening CHF (35%). Nevertheless, in this cohort we also found that up to 44% of patients showed a significant prolongation of their initially short early DT (i.e., reversible restrictive LV diastolic filling) after 6 months of clinical stability with optimal oral therapy (group 2), and these patients had a substantially better outcome. Thus, we believe that our study is the first to clearly demonstrate that, irrespective of E/A ratio changes, prolongation of an initially short DT, which may occur in a sizeable number of patients with CHF with long-term optimal therapy, predicts a more favorable prognosis.
Of note, although at univariate analysis an E/A ratio >2 and its variation over time were significantly associated with a worse outcome, at multivariate analysis these variables did not prove to be independent prognostic indicators. On the contrary, a persistently short early DT (≤125 ms) (which was associated with an E/A ratio <2 in 26% of patients) was found to be the single most powerful indicator of poor prognosis, whereas a prolongation of an initially short DT, which was usually accompanied by a significant reduction in E/A ratio, was associated with a 66% risk reduction of cardiac mortality.
How can this different evolution in transmitral flow be explained in patients with comparable clinical and Doppler echocardiographic features, and why are these changes related to progression of heart failure and prognosis? In fact, more patients with a persistent short DT were in NYHA class III to IV at entry and were receiving digitalis, even though during the 6-month period of optimized therapy between the two Doppler echocardiographic studies, medications became equally distributed between the two groups, and no specific therapeutic intervention was found predictive of subsequent conversion to a nonrestrictive pattern. Moreover, at multivariate analysis, medications both at baseline and during the 6 months between baseline and late evaluation were not independently related to survival, and a persistently short DT proved the best independent predictor of fatal outcome over other variables, including functional class.
Although the duration of heart failure was similar in the two groups, patients who showed a significant prolongation of an initially short DT at entry had slightly less enlarged, although not significantly, LV volumes and a slightly higher LV ejection fraction. Thus, it could be hypothesized that patients with a reversible short DT had a lesser extent of fibrosis and probably some residual contractile reserve, as confirmed by the significant decrease in end-systolic volume and the small but significant improvement in LV ejection fraction at 6 months. A favorable evolution of the restrictive LV filling as a function of reduction in elevated filling pressures with optimized long-term therapy may have facilitated or at least paralleled this modest functional improvement and may also have exerted a positive influence on the progression of heart failure and prognosis. On the contrary, patients with persistent restrictive LV diastolic filling, as documented by a persistent short DT and, consequently, elevated filling pressures, could have had more extensive fibrosis refractory even to optimized long-term unloading therapy, although this possibility could not have been predicted by traditional echocardiographic markers of LV dimension and function.
Therefore, in light of the well known correlations between mitral Doppler variables (1–4,18–20), particularly DT of early filling (13), and central hemodynamic variables (i.e., the shorter the DT the higher the pulmonary wedge pressure) in patients with LV dysfunction and CHF, it is reasonable to speculate that prolongation of an initially short DT (namely, the reduction in pulmonary wedge pressure) may result in a beneficial effect on the long-term outcome. The results of the present study strongly support this hypothesis.
We studied patients with CHF with sinus rhythm and restrictive LV diastolic filling, as indicated by a short DT irrespective of the filling pattern. Patients underwent a second Doppler echocardiographic study after 6 months of optimized oral therapy following well established therapeutic protocols. Although medical treatment was unblinded, Doppler DT results at the late evaluation did not influence subsequent selection of therapy, and no specific therapeutic regimen was independently related to survival.
In the present study we excluded patients with atrial fibrillation. However, in light of the recent evidence of similar hemodynamic correlations of early mitral DT in patients either in sinus rhythm or with atrial fibrillation (25), we can speculate that our results are reliably applicable also to patients with atrial fibrillation. Further studies are warranted in this subset of patients.
The increase of an initially short DT of early filling obtained with long-term optimal oral therapy predicts a more favorable prognosis in clinically stable patients with CHF due to LV systolic dysfunction. Our results indicate that in these patients, serial evaluations of Doppler transmitral flow may be useful in monitoring the progression of the disease and the effects of long-term medical treatment. We believe that the reversibility of restrictive LV diastolic filling in response to optimized therapy, as evidenced by the prolongation of a short DT by mitral Doppler echocardiography, easy to obtain and reliable, should be included in the noninvasive prognostication of all patients with CHF.
We are grateful to Fabio Comazzi for computer and statistical help. We also thank Rosemary Allpress for English language assistance in the preparation of the manuscript.
This study was presented in part at the 69th Annual Scientific Sessions of the American Heart Association, New Orleans, Louisiana, November 1996.
- chronic heart failure
- deceleration time
- E/A ratio
- ratio of early to late diastolic filling
- left ventricular
- Received October 20, 1997.
- Revision received January 20, 1998.
- Accepted February 19, 1998.
- by the American College of Cardiology
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