Download Doppler-derived dP/dt and −dP/dt predict survival in

Journal of the American College of Cardiology
© 2000 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 36, No. 5, 2000
ISSN 0735-1097/00/$20.00
PII S0735-1097(00)00908-6
Doppler-Derived dP/dt and ⫺dP/dt
Predict Survival in Congestive Heart Failure
Theodore J. Kolias, MD, Keith D. Aaronson, MD, William F. Armstrong, MD, FACC
Ann Arbor, Michigan
The purpose of this study was to evaluate the ability of novel Doppler indices of left
ventricular (LV) systolic and diastolic function to predict survival in patients with congestive
heart failure (CHF).
BACKGROUND Congestive heart failure is associated with an increased risk of death or cardiac transplantation, yet techniques to predict survival are limited.
METHODS
Doppler-derived dP/dt and ⫺dP/dt were determined prospectively from the continuous-wave
Doppler spectrum of the mitral regurgitation jet (dP/dt ⫽ 32/time between 1 and 3 m/s;
⫺dP/dt ⫽ 32/time between 3 and 1 m/s) in 56 patients with chronic CHF (age, 60 ⫾ 15
years; LV ejection fraction, 23 ⫾ 9%). Baseline clinical and echocardiographic variables were
also obtained, and clinical follow-up was performed in all patients.
RESULTS
Twenty-four patients experienced a primary event of cardiac death (n ⫽ 15), United Network
for Organ Sharing status I (inotrope-dependent) heart transplant (n ⫽ 3) or urgent
implantation of a LV assist device (n ⫽ 6). Doppler-derived dP/dt (dichotomized to ⱖ or
⬍600 mm Hg/s; p ⫽ 0.0002) and ⫺dP/dt (trichotomized to ⬍450, 450 to 550 and
⬎550 mm Hg/s; p ⫽ 0.0001) predicted event-free survival, as did Doppler-derived risk
groups determined by the combination of the two (low risk, dP/dt ⱖ 600; intermediate risk,
dP/dt ⬍ 600 and ⫺dP/dt ⱖ 450; high risk, dP/dt ⬍ 600 and ⫺dP/dt ⬍ 450; p ⫽ 0.0001).
Multivariable analysis revealed Doppler-derived risk groups, intravenous inotrope requirement and blood urea nitrogen as significant independent predictors of outcome.
CONCLUSION New Doppler indices of dP/dt, ⫺dP/dt and risk groups defined by the combination of dP/dt
and ⫺dP/dt predict event-free survival in patients with CHF. (J Am Coll Cardiol 2000;36:
1594 –9) © 2000 by the American College of Cardiology
OBJECTIVES
Severe congestive heart failure (CHF) is associated with a
marked increase in risk of death or need for cardiac
transplantation (1–3). The ability of current techniques to
predict which patients will die or require heart transplantation is limited. Identification of such patients is important
so that resources may be appropriately allocated and patients
may understand their prognosis.
Previous investigators have evaluated markers of left
ventricular (LV) systolic and diastolic function to predict
outcome in heart failure. These markers have included
ejection fraction (3–7) and transmitral inflow characteristics
(8 –12). One of the limitations of these markers, however, is
their load-dependence (13,14), which may confound accurate assessment of LV systolic or diastolic function and limit
their predictive value. By contrast, isovolumic phase indices
of LV function, such as dP/dt and ⫺dP/dt, are less
load-dependent (13,15,16) and are theoretically a more
accurate reflection of LV function. Their measure, however,
has required invasive cardiac catheterization using a high
fidelity micromanometer-tipped catheter, thus limiting
their widespread use. Recently, a noninvasive echocardiographic method has been proposed to determine the isovolumic phase indices of cardiac function dP/dt (17–19) and
⫺dP/dt (18 –21).
Doppler-derived dP/dt and ⫺dP/dt can be calculated
From the Division of Cardiology, University of Michigan Medical Center, Ann
Arbor, Michigan.
Manuscript received January 14, 2000; revised manuscript received April 25, 2000,
accepted June 26, 2000.
from the continuous-wave Doppler spectrum of the mitral
regurgitation (MR) jet obtained during transthoracic echocardiography. They have been shown to correlate with their
corresponding invasively derived parameters (17,21). This
method, however, has not been applied to heart failure
patients to determine if it predicts survival. The present
study was designed to test the hypothesis that Dopplerderived dP/dt and ⫺dP/dt predict survival in patients with
chronic CHF.
METHODS
Patients (n ⫽ 61) with chronic CHF and LV ejection
fraction (LVEF) ⬍50% were recruited for the study between March 1998 and November 1998. Five patients were
excluded secondary to inadequate MR signals (n ⫽ 3) or
mechanical valve prostheses (n ⫽ 2), leaving 56 patients
who were enrolled. Each patient underwent a baseline
history, physical examination and transthoracic echocardiogram, and clinical and echocardiographic variables were
recorded. In addition, the baseline serum sodium, blood
urea nitrogen and serum creatinine values were recorded.
The patients were then followed for the occurrence of
primary events, which were defined as cardiac death, United
Network for Organ Sharing (UNOS) status I heart transplantation or urgent implantation of a LV assist device.
Patients not experiencing a primary event were censored at
the time of UNOS status II heart transplant, noncardiac
death or last follow-up. Patient follow-up was conducted by
Kolias et al.
Doppler-Derived dP/dt and ⴚdP/dt in CHF
JACC Vol. 36, No. 5, 2000
November 1, 2000:1594–9
1595
Abbreviations and Acronyms
CHF ⫽ congestive heart failure
LV
⫽ left ventricular
LVEF ⫽ left ventricular ejection fraction
MR
⫽ mitral regurgitation
UNOS ⫽ United Network for Organ Sharing
phone interviews and/or review of the hospital records and
was complete in all patients. The study was approved by the
institutional review board of the University of Michigan,
and all patients provided informed consent.
Echocardiographic examination. A transthoracic twodimensional echocardiogram and Doppler examination
were performed in all patients using an echocardiography
system (Hewlett-Packard 2500, Hewlett-Packard 5500
[Hewlett-Packard; Andover, Massachusetts], Acuson Sequoia, or Acuson 128XP [Acuson Corporation; Mountain
View, California]). The MR jet was interrogated with
continuous-wave Doppler from an apical four-chamber or
two-chamber view, using a sweep speed of 100 mm/s, and
the baseline and scale were adjusted to maximize the
spectral signal. Care was taken to align the imaging beam
parallel to the direction of the regurgitant jet. Other
echocardiographic parameters obtained included LV dimensions from the parasternal long axis views and the E/A
ratio obtained using pulsed-wave Doppler from the apical
four-chamber view with the sample volume placed at the
mitral valve leaflet tips. The ejection fraction was calculated
at baseline for each patient using the modified Simpson
method from the apical four-chamber view.
Doppler-derived dP/dt and ⴚdP/dt measurements.
Continuous-wave Doppler spectra of the MR jet were
analyzed prospectively using an offline system (TomTec
Imaging; Boulder, Colorado). Doppler-derived dP/dt was
determined as follows: the two points on the MR spectrum
corresponding to 1 m/s and 3 m/s were identified. These
points corresponded to LV-left atrial pressure gradients of
4 mm Hg and 36 mm Hg using the modified Bernoulli
equation (P ⫽ 4v2). Doppler-derived dP/dt was defined as
⌬P/⌬t ⫽ 36-4/⌬t ⫽ 32 mm Hg/⌬t (Fig. 1). ⫺dP/dt was
determined from the diastolic slope of the MR spectrum,
using the time required to go from 3 m/s to 1 m/s. The
averages of three dP/dt measurements and three ⫺dP/dt
measurements were determined for each patient (five if they
were in atrial fibrillation), thus yielding an averaged dP/dt
and ⫺dP/dt for each patient.
Statistical analysis. Clinical and echocardiographic variables were evaluated as possible univariable predictors of
survival by the Kaplan-Meier method and log-rank testing
(categorical variables) or by univariable Cox proportional
hazards models (continuous variables). Continuous variables
were grouped into strata for Kaplan-Meier analysis. The
proportional hazards assumption was confirmed graphically
by log (⫺log survival) versus log time plots. Significant
univariable predictors of outcome (p ⬍ 0.1) were then
Figure 1. Determination of Doppler-derived dP/dt and Doppler-derived
⫺dP/dt from the continuous-wave Doppler spectrum of the MR jet. P ⫽
pressure; t ⫽ time; v ⫽ velocity.
analyzed with multivariable Cox proportional hazards regression models. Statistical testing was two-tailed, and
significance was defined as p ⬍ 0.05. Calculations were
performed using statistical analysis software (SAS version
6.12).
RESULTS
The baseline clinical and echocardiographic characteristics
of the patients in the study are summarized in Table 1.
During follow-up, 24 (43%) of the patients experienced a
primary event of cardiac death (n ⫽ 15), UNOS status I
heart transplantation (n ⫽ 3) or urgent implantation of a
LV assist device (n ⫽ 6). Of the 32 patients not experiencing a primary event, 29 were alive without transplant, 2
underwent UNOS status II heart transplantation and one
developed lung cancer and died during follow-up.
Univariable analysis demonstrated that several clinical
and echocardiographic variables significantly predicted the
occurrence of a primary event during follow-up (Table 2).
The strongest of these were intravenous inotrope requirement, Doppler-derived ⫺dP/dt and Doppler-derived
dP/dt. Of note, ejection fraction and E/A ratio ⬎2.0 were
not significant predictors of a primary event.
Evaluation of event-free survival for ranges of Dopplerderived dP/dt revealed two distinct strata: dP/dt ⬍ 600 and
dP/dt ⱖ 600. Patients with dP/dt ⬍ 600 mm Hg had worse
event-free survival compared with those with dP/dt ⱖ 600
(Fig. 2). Likewise, evaluation of event-free survival for
ranges of Doppler-derived ⫺dP/dt revealed three distinct
strata: ⫺dP/dt ⬍ 450, ⫺dP/dt ⫽ 450 –550 and ⫺dP/dt ⬎
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Kolias et al.
Doppler-Derived dP/dt and ⴚdP/dt in CHF
Table 1. Baseline Clinical and Echocardiographic Characteristics
of the Patients in the Study
Age (yr)
Gender (female)
Etiology (ischemic)
NYHA class
I
II
III
IV
Medical therapy
ACEI or AIIB
Loop diuretic
Digoxin
Intravenous inotrope
Symptoms
Orthopnea
Paroxysmal nocturnal dyspnea
Dyspnea with exertion
Physical examination
Jugular venous distention
Rales
S3
Peripheral edema
Heart rate
Systolic blood pressure
Diastolic blood pressure
Ejection fraction
E/A ratio ⬎2.0
LVIDs
LVIDd
Doppler-derived dP/dt
Doppler-derived ⫺dP/dt
60 ⫾ 15 (range, 30–87)
18 (32%)
28 (50%)
1 (2%)
3 (5%)
31 (55%)
21 (38%)
41 (73%)
48 (86%)
42 (75%)
16 (29%)
37 (66%)
36 (64%)
55 (98%)
41 (73%)
20 (36%)
27 (48%)
15 (27%)
83 ⫾ 16 beats/min
106 ⫾ 18 mm Hg
65 ⫾ 10 mm Hg
23 ⫾ 9%
25 (64%)*
58 ⫾ 11 mm
66 ⫾ 10 mm
676 ⫾ 297 mm Hg/s
564 ⫾ 161 mm Hg/s
Data presented are mean ⫾ SD or number of patients.
NYHA ⫽ New York Heart Association; ACEI ⫽ angiotensin-converting enzyme
inhibitor; AIIB ⫽ angiotensin II receptor blocker; LVIDs ⫽ left ventricular internal
dimension at end-systole; LVIDd ⫽ left ventricular internal dimension at enddiastole.
*E/A ratio was determined in 39 patients in whom it could be obtained. Primary
reasons for its absence were atrial fibrillation or ventricular pacing.
550, with a significant overall difference among the groups
(Fig. 3). The difference between ⫺dP/dt ⬍ 450 and
⫺dP/dt ⫽ 450 –550 was also significant (p ⫽ 0.0428), as
was the difference between ⫺dP/dt ⬍ 450 and ⫺dP/dt ⬎
550 (p ⫽ 0.0001). The difference between ⫺dP/dt ⫽
450 –550 and ⫺dP/dt ⬎ 550, however, was not significant
(p ⫽ 0.1357).
We then combined information from both dP/dt and
⫺dP/dt to define three Doppler-derived risk groups based
on the following criteria: low risk (dP/dt ⱖ 600), intermediate risk (dP/dt ⬍ 600 plus ⫺dP/dt ⱖ 450) and high risk
(dP/dt ⬍ 600 plus ⫺dP/dt ⬍ 450). Survival analysis
revealed both a significant overall difference as well as
significant differences between the individual groups (Fig.
4). Using this risk stratification strategy, the 30-day eventfree survival estimate of the high-risk group is 0.21 ⫾ 0.11
(mean ⫾ SD); by contrast, the 180-day survival estimates of
the intermediate- and low-risk groups are 0.61 ⫾ 0.15 and
0.81 ⫾ 0.07, respectively. The sharp drop in survival of the
low-risk group near the end of the study occurred because
only a few patients remained at that point.
Multivariable proportional hazards regression modeling
JACC Vol. 36, No. 5, 2000
November 1, 2000:1594–9
Table 2. Predictive Value of Clinical and Echocardiographic
Variables on Event-Free Survival by Univariable Analysis
Variable
p Value
Requiring intravenous inotrope
Doppler-derived ⫺dP/dt
Doppler-derived dP/dt
Blood urea nitrogen
Serum sodium
NYHA class IV
Severe tricuspid regurgitation
S3 heart sound
Systolic blood pressure
Diastolic blood pressure
Severe mitral regurgitation
LVIDd
0.0001
0.0001†
0.0002‡
0.0008
0.0008
0.0012
0.0054
0.0082
0.0110
0.0216
0.0311
0.0453
Peripheral edema
LVIDs
E/A ratio ⬎ 2.0
Rales
Heart rate
Ejection fraction
Jugular venous distention
Orthopnea
Gender
Atrial fibrillation
Paroxysmal nocturnal dyspnea
Etiology
Age
Serum creatinine
0.0764
0.1031
0.1199*
0.1382
0.1697
0.1830
0.2151
0.2294
0.4629
0.4962
0.4966
0.6446
0.7617
0.7739
NYHA ⫽ New York Heart Association; LVIDs ⫽ left ventricular internal dimension
at end-systole; LVIDd ⫽ left ventricular internal dimension at end-diastole.
*E/A ratio was determined in 39 patients in whom it could be obtained. Trend was
for better event-free survival in patients with E/A ⬎ 2.0 (not significant).
†Trichotomized to ⬍450, 450 –550 or ⬎550 mm Hg/s.
‡Dichotomized to ⬍600 or ⱖ600 mm Hg/s.
was performed using Doppler-derived risk groups together
with other significant univariable clinical and echocardiographic predictors of outcome. This yielded only three
significant independent predictors of outcome: Dopplerderived risk group, the requirement for intravenous inotropes, and blood urea nitrogen (Table 3). Using ⫺dP/dt
and dP/dt individually in place of Doppler-derived risk
groups revealed ⫺dP/dt as a significant independent predictor of outcome (p ⫽ 0.0004). Finally, if dP/dt was
entered into the model in the absence of ⫺dP/dt and
Figure 2. Kaplan-Meier survival curves of patients dichotomized by
Doppler-derived dP/dt.
JACC Vol. 36, No. 5, 2000
November 1, 2000:1594–9
Kolias et al.
Doppler-Derived dP/dt and ⴚdP/dt in CHF
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Table 3. Independent Predictors of Event-Free Survival by Cox
Proportional Hazards Model
Variable
Risk
Ratio
p
Value
Requiring intravenous inotropes
Doppler-derived risk group
Blood urea nitrogen
6.204
3.068*
1.017†
0.0001
0.0002
0.0284
*For adjacent risk groups; †For each 1 mg/dl increase.
Figure 3. Kaplan-Meier survival curves of patients trichotomized by
Doppler-derived ⫺dP/dt.
Doppler-derived risk groups, it too was a significant independent predictor of outcome (p ⫽ 0.0373).
DISCUSSION
This study demonstrates the potential of Doppler-derived
dP/dt and ⫺dP/dt to predict survival in patients with
chronic CHF. Low-, intermediate- and high-risk groups
could be identified based on the combined parameters of
Doppler-derived dP/dt and ⫺dP/dt. The strong predictive
value obtained by combining Doppler-derived dP/dt and
⫺dP/dt illustrates the interplay of systolic and diastolic
function in determining prognosis in patients with CHF.
This has been suggested in previous studies in which
impaired diastolic function as determined by mitral filling
was a significant predictor of outcome in patients with low
ejection fractions (8 –10,12). The present study further
supports the role of diastolic function in determining
prognosis in patients with impaired systolic function and
proposes a new sensitive index for combining parameters of
systolic and diastolic function for the purpose of risk
stratification.
Doppler-derived dP/dt was determined in this study by
measuring the mean rate of pressure rise of the MR jet
Figure 4. Kaplan-Meier survival curves of patients divided into three risk
groups based on the combination of Doppler-derived dP/dt and ⫺dP/dt.
between 1 and 3 m/s, and as such it represents the mean
dP/dt between 1 and 3 m/s. This method has been shown
to correlate well with invasively derived peak dP/dt (17).
Likewise, Doppler-derived ⫺dP/dt was determined by
measuring the mean rate of pressure fall of the MR jet
between 3 and 1 m/s. The time required to go from 3 to 1
m/s has been shown previously to correlate reasonably well
to the time constant of relaxation, tau (21). Although more
sophisticated methods of determining dP/dt and tau using
digitization of the MR velocity spectrum were previously
found to correlate with invasive parameters more closely
(18,21), we chose this simplified method for its ease of
applicability and greater potential for widespread use.
Although these Doppler indices of cardiac function have
been described previously, to our knowledge, they have
never been applied to a CHF population to predict survival.
Only a few clinical uses have been reported, such as the use
of Doppler-derived dP/dt to predict postoperative ejection
fraction (22) and inotropic requirement (23) in patients
undergoing mitral valve surgery. Doppler-derived dP/dt and
⫺dP/dt are well-suited, however, for application to patients
with chronic CHF because most of these patients have some
degree of central MR secondary to annular dilatation and
chordal tethering. As seen in this study, obtaining dP/dt
and ⫺dP/dt is feasible in most patients. Furthermore, the
noninvasive nature of this technique makes it easy to apply
serially and in a variety of settings. In many cases, echocardiography and Doppler are routine aspects of management
in patients with CHF, and obtaining these measures requires only minimal additional effort. Another advantage is
their feasibility in patients with atrial fibrillation, in whom
obtaining a mitral E/A ratio is not feasible.
Doppler-derived dP/dt and ⫺dP/dt are sensitive measures of LV systolic and diastolic function, which may
explain their enhanced ability to predict survival. Previous
studies of other markers of LV systolic and diastolic
function have shown that markers of worsening function are
related to worse prognosis. Previously used markers include
ejection fraction for systolic function and mitral inflow E/A
ratio for diastolic function. In this study, Doppler-derived
dP/dt and ⫺dP/dt as well as the Doppler-derived risk
groups outperformed both of these measures with respect to
predicting survival. In addition, other previously described
echocardiographic variables such as LV internal dimension
at end-systole and LV internal dimension at end-diastole
(24) were also less powerful than Doppler indices in
predicting survival.
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Kolias et al.
Doppler-Derived dP/dt and ⴚdP/dt in CHF
The validity of Doppler-derived dP/dt and ⫺dt/dt as
determined by taking the mean rate of pressure rise or fall
between 1 to 3 or 3 to 1 m/s has been questioned in the past.
The concern is that since these are measured during MR,
they are not true isovolumic measures of function. Although
a valid point, the change in atrial pressure during the time
course of these measurements is small compared with the
change in overall pressure, suggesting that its role is minor.
In addition, our patient population included patients with
all degrees of MR, suggesting that the applicability of these
measures is widespread and not limited only to those
patients with severe MR. Another concern with this technique is that it provides mean dP/dt rather than peak dP/dt
as has been used in other studies. Since mean dP/dt is
always calculated between 1 and 3 m/s, it is always determined at a constant developed pressure that is almost
invariably prior to the opening of the aortic valve. In this
regard, this technique may hold an advantage compared
with peak dP/dt, since peak dP/dt often occurs near the
time of opening of the aortic valve and may be more affected
by afterload (25). Ultimately, the technique should be
judged on its ability to contribute to the clinical management of the patient, and the present study suggests that the
present method has potential to do so.
Study limitations. A limitation of this study is that these
were very ill patients: the majority of them were in New
York Heart Association class III or IV, with several requiring intravenous inotropes. Whether these indices are able to
predict outcome in a less ill, more ambulatory population of
patients needs to be evaluated. In addition, we evaluated
these indices in a relatively small group of patients. Further
investigation in a larger population of heart failure patients
is warranted. Finally, only one of the patients with a
dP/dt ⱖ 600 had a ⫺dP/dt ⬍ 450; further study is
warranted to determine if this subgroup has a different
prognosis compared with patients with a dP/dt ⱖ 600
combined with a ⫺dP/dt ⱖ 450.
CONCLUSIONS
This study demonstrates that the Doppler indices of dP/dt
and ⫺dP/dt predict survival in patients with CHF. These
simple, noninvasive measures have potential to play a role in
the management of heart failure patients in the future.
Acknowledgments
The authors gratefully acknowledge Mary Sue LeMire,
Linda Dziekan, Diane Eberhart and Deborah Strong for
their technical support.
Reprint requests and correspondence: Dr. Theodore J. Kolias,
Division of Cardiology, University of Michigan Medical Center,
L3119 Women’s, 1500 E Medical Center Dr, Ann Arbor,
Michigan 48109-0273. E-mail: [email protected].
JACC Vol. 36, No. 5, 2000
November 1, 2000:1594–9
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