(Circulation. 1995;91:2775-2784.)
© 1995 American Heart Association, Inc.
Articles |
Exercise Training Improves Left Ventricular Diastolic Filling in Patients With Dilated Cardiomyopathy
Clinical and Prognostic Implications
Presented at the 43rd Scientific Sessions of the American College of Cardiology, Atlanta, Ga, 1994.
From Divisione di Cardiologia I, Ospedale Cardiologico "G.M. Lancisi," Ancona, Italy (R.B., G.C., A.P.); the Division of Cardiology, Saint John's Cardiovascular Research Center, Harbor-UCLA Medical Center, Torrance, Calif (D.G., L.G.); and the Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, Calif (N.B.).
Correspondence to Demetrios Georgiou, MD, South Valley Cardiovascular Group, 700 W 6th St, Suite K, Gilroy, CA 95020.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Patients with dilated cardiomyopathy (DCM) often have left ventricular (LV) diastolic dysfunction that can precede the development of systolic dysfunction. Recent reports showed that exercise training (ET) improves the exercise capacity of these patients. Although this improvement is primarily due to peripheral adaptations, the contribution of LV diastolic filling has not been well defined. The purpose of this study was to determine whether ET can induce changes in LV diastolic filling that can account for an increase in exercise capacity and whether these changes can influence prognosis.
Methods and Results We prospectively studied 55 consecutive patients (mean age, 55±7 years) with DCM. Patients were randomized into a training group (36 patients) or a control untrained group (19 patients) and matched for clinical and functional characteristics. All patients underwent a pulsed Doppler echocardiographic study, a radionuclide angiographic study, and a cardiopulmonary exercise test before and after a 2-month ET program. On the basis of the Doppler LV diastolic filling pattern at the beginning of the study, patients were prospectively divided into three subgroups: A (restrictive pattern), B ("normal" pattern), and C (abnormal relaxation pattern). In the trained group, peak VO2 (+12%; P<.0001), peak workload (+8.5%; P<.005), and lactic acidosis threshold (+12%; P<.0001) were significantly increased after training without changes in LV ejection fraction. However, only subgroup C demonstrated significant improvement in peak VO2 (+15%; P<.005). No changes were observed in the untrained group. In the trained subgroups a significant increase in rapid filling fraction (RFF), peak filling rate (PFR), peak early filling velocity (E), and E/A ratio was noted. A significant decrease in atrial filling fraction (AFF), peak atrial filling velocity (A), deceleration time of early filling velocity (EDT), and isovolumic relaxation time (IVRT) was observed only in subgroup C. No changes were found in untrained subgroups. A good correlation was found between Doppler and radionuclide LV diastolic filling parameters before and after training (P<.0001). Multiple stepwise regression analysis demonstrated that pretraining E/A ratio (P<.0001) and peak heart rate (P<.0002) were positive predictors of pretraining peak VO2. Posttraining increase in exercise tolerance (P<.0001) and increase in E/A ratio (P<.0001) were the strongest predictors of an increase in peak VO2. The independent predictors of cardiac events were a greater RFF and a shorter IVRT and EDT. Stepwise logistic regression showed that Doppler LV diastolic filling patterns are independent predictors of overall cardiac events (P=.02), and restrictive pattern has a worse prognosis compared with B (P=.04) and C (P=.007). However, ET did not reach statistical significance (P=.54) as a predictor of cardiac events.
Conclusions These data demonstrate that ET induces significant improvement in exercise capacity only in patients with DCM and a pattern of abnormal LV relaxation. The improvement in peak VO2 is significantly correlated with an increase in peak early filling rate and peak filling rate as well as a decrease in atrial filling rate. Doppler echocardiography may be a valuable tool in the prognostic assessment of patients with DCM who will benefit from exercise training.
Key Words: exercise • echocardiography • prognosis • cardiomyopathy
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Over the last decade, several studies have reported that exercise training improves the functional capacity of patients with dilated cardiomyopathy (DCM).1 2 3 4 In these patients, several observations suggest that abnormalities of left ventricular (LV) diastolic function occur and often precede the development of systolic dysfunction.5 6 Although improved LV systolic performance has been observed after training in patients with DCM that can partially account for the increase in peak oxygen consumption,7 8 the contribution of LV diastolic function to the exercise-induced improvement in exercise capacity is not clear. Moreover, the magnitude and the prognostic significance of training-induced changes in LV diastolic abnormalities have not been defined.
Recently, measurement of transmitral blood flow velocity by pulsed Doppler echocardiography has been used to distinguish different patterns of LV diastolic dysfunction9 10 11 and to provide information about prognosis in patients with DCM.12 13 Although diastole is a complex sequence of interrelated events influenced by changes in loading conditions, myocardial contractility, and heart rate,14 15 16 17 18 19 20 three main Doppler patterns of diastolic dysfunction have been described: restrictive, abnormal relaxation, and "normal." These patterns reflect different clinical and hemodynamic profiles. Although a restrictive pattern has been found to be associated with a more severe disease and a worse prognosis, the clinical and prognostic significance of the other patterns is not clear. Moreover, the effects of exercise training on Doppler diastolic filling patterns has not been assessed.
The purpose of the study was first, to determine whether exercise training can induce changes in Doppler LV diastolic filling patterns; second, to examine the relationship between training-induced changes in diastolic filling profiles and aerobic capacity; and third, to determine whether these changes are associated with a different prognosis.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patients
We studied 55 consecutive patients (55±7 years) with a history of chronic heart failure (CHF) for at least 6 months who were clinically stable for at least 3 months before enrollment in the study. DCM was diagnosed by M-mode echocardiographic demonstration of an increased LV end-diastolic diameter (LVEDD) of >5.8 cm, a fractional shortening of less than 25%, and an increased E point–septal separation of
0.8 cm (see Reference 2626 ).
Two-dimensional echocardiography showed a dilated nonhypertrophic LV
(posterior wall and interventricular septum end-diastolic
thickness of 
1.2 cm) with diffuse wall motion abnormalities in all
patients. Patients' clinical characteristics are summarized in Table
1
. The etiology of CHF was idiopathic DCM in 18 patients
and ischemic cardiomyopathy (ICM) in 37. Patients with alcoholic DCM,
hypertensive CM, or other known etiologies were excluded. Unstable
angina patients were excluded. Only two patients in the ICM group had
stable angina. All patients with ICM had documented previous myocardial
infarction. Thirty of the ICM patients underwent coronary angiography.
LV ejection fraction (LVEF) was 27±7%. Mitral insufficiency was
present in 35 patients and was mild in all 35. All patients had a
reduced peak oxygen uptake (15.6±1.3
mL · kg-1 · min-1).
Thirty-eight
patients had New York Heart Association (NYHA) functional class II
symptoms and 17 had functional class III symptoms. All patients were in
sinus rhythm. Patients were excluded if they had myocardial infarction
or unstable angina within the last 6 months. Other exclusion criteria
were CHF with NYHA class IV symptoms, significant chronic obstructive
pulmonary disease, hemodynamically significant valvular heart disease,
uncontrolled hypertension, hypotension, severe anemia, arthritis, or
any other orthopedic, peripheral vascular, or neurological disease that
would limit their ability to exercise. Patients did not have pulmonary
rales, and their exercise test was limited only by dyspnea or fatigue.
Medications were not altered throughout the duration of the study.
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The protocol was approved by the Research Committee of Lancisi Heart Hospital. All patients gave written informed consent.
Pulsed Doppler echocardiography, radionuclide angiography (RNA), and a cardiopulmonary exercise test were performed before and after the completion of the exercise training program.
Echocardiography
M-mode, two-dimensional, and pulsed Doppler
echocardiographic
examinations were performed with an ultrasound system combining a
two-dimensional mechanical sector scanner (2.5 MHz) with a pulsed
Doppler flow analyzer. Each patient was examined in the supine, left
lateral position, acccording to the standards of the American Society
of Echocardiography.27 M-mode measurements included LVEDD,
LV end-systolic diameter (LVESD), and fractional shortening.
Measurements of left ventricular end-diastolic volume and
left ventricular end-systolic volume were obtained from the apical view
using a modified single-plane Simpson's rule from which LVEF was
calculated. Images were recorded on videotape and interpreted by two
experienced cardiologists blinded to each other's interpretation. All
studies were read twice (once by each observer), and the values were
averaged for analysis. The average values of the two measurements
were used to categorize the patients into subgroups. Disagreement
between the two readers occurred in 8% of the cases. The two
cardiologists then reviewed the discordant studies and made a consensus
decision.
Pulsed Doppler Mitral Flow Velocity Analysis
Care was taken
to position the cursor line through a plane
traversing the left ventricle from the apex to the mitral valve annulus
in order to achieve the smallest possible angle between the LV inflow
and the orientation of the ultrasound beam. The sample volume was set
in the mitral orifice on the atrial side between the mitral leaflet
tips during diastole. In each patient, LV diastolic flow velocity
waveforms from 5 cardiac cycles were obtained and averaged. The
following measurements were obtained: peak velocity of early diastolic
filling wave (E); peak velocity of late filling (A); deceleration time
of E velocity (EDT); E to A ratio (E/A); and isovolumic relaxation time
(IVRT), the interval between the end of aortic velocity profile (aortic
closure) and the onset of mitral flow. Rapid filling fraction (RFF) was
obtained by dividing rapid filling velocity area by the total diastolic
filling velocity area, whereas the atrial filling fraction was obtained
by dividing atrial filling velocity area by the total diastolic filling
velocity area. The IVRT was measured from the apical five-chamber view,
with the sample volume placed between the mitral valve and the LV
outflow. The diastolic filling period was defined as the interval from
the onset to the end of transmitral flow.
The patients were
prospectively assigned to three subgroups before
beginning the exercise training program, subgroups A, B, and C (Fig
1), based on the Doppler measurements of LV diastolic
filling. Subgroup A consisted of patients with a restrictive Doppler
pattern characterized by a short or normal IVRT (50 ms), an increased
early filling velocity (>105 cm/s) with a shorter deceleration time
(<150 ms), and a decreased atrial filling velocity (<50 cm/s).
Subgroup B was characterized by a normal Doppler pattern, with normal
intervals and velocity profiles. Subgroup C comprised patients with
abnormal relaxation characterized by a prolonged IVRT (>80 ms) and EDT
(>190 ms), a reduced early filling velocity (<65 cm/s), and an
abnormally increased atrial filling velocity (>90 cm/s). Color-flow
imaging was performed to assess the severity of mitral regurgitation by
grading for area, extent, and duration of regurgitant
jet.28
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Radionuclide Angiography
After the baseline Doppler
echocardiographic study, patients
underwent in vivo blood pool labeling using stannous pyrophosphate
followed by 740 MBq 99mTc (15 to 20 mCi) 30 minutes later.
Thirteen patients refused to undergo RNA studies, so radionuclide data
are presented for 42 patients (Table 4). The system, previously
validated in other centers,29 30 has been also
validated
in our laboratory using a conventional gamma camera (Elscint)
(unpublished data). When the optimal position of the nonimaging nuclear
probe was identified, the skin was marked. Background radioactivity was
then automatically estimated as 74% of end-diastolic
counts. After each study, data were smoothed and then processed into a
commercially available statistical software package. The time-activity
curve was obtained by transforming data into frequency domains. From
this curve and its first derivative, we determined the time of end
diastole (maximal counts), the time of end systole (minimal counts),
the normalized peak filling rate (maximal slope of the first derivative
of the early filling portion), the peak early filling rate, and the
peak atrial filling rate. Time to peak early filling rate and time to
peak atrial filling rate were also calculated. At heart rates of more
than 100 beats per minute, single peak filling rate was considered, and
the time to single peak filling rate was also measured. Time from end
systole to peak early filling rate and time from end systole to peak
atrial filling rate were calculated and expressed in milliseconds.
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Cardiopulmonary Exercise Test
All patients underwent a
familiarization maximal exercise test
on a cycle ergometer 4 to 15 days before the beginning of training.
After 2 minutes of rest and 3 minutes of unloaded pedaling, the work
rate was increased 5 W every 20 seconds (ramp) until volitional
fatigue. Heart rate and blood pressure were monitored continuously. All
patients repeated an exercise test with the same protocol on an
electronically braked, computerized cycle ergometer with gas exchange
analysis. The expired volume calibration was carried out by a 3-L
syringe. Expired gases were analyzed breath-by-breath using a
SensorMedics 2900 Z unit. The O2 and CO2
analyzers were calibrated automatically. During the tests, patients
pedaled at a constant rate of 60 rpm. Peak oxygen uptake (peak
VO2) was determined in the last 20 to 30
seconds of exercise. The lactic acidosis threshold was calculated by
the V-slope method.31 Body mass index was calculated in
all patients before and after the end of the study as weight
(kg)/height2 (cm). In all patients, a cardiopulmonary
exercise test was repeated with the same modalities 3 to 7 days after
the last training session for trained patients and after a similar time
for the untrained patients.
Exercise Training
Patients were randomly assigned to a
training group or to an
untrained control group. Randomization was performed with the table of
casual numbers.32 After a learning phase of 1 week,
patients underwent a supervised program of exercise training (60% of
peak VO2) three times per week for 8 weeks
(in 24 sessions). Each session lasted about 1 hour, beginning with a
warm-up phase of stretching exercise (15 to 20 minutes) followed by 40
minutes of work on a cycle ergometer. All patients were monitored by
means of telemetry. A cardiologist was present during the whole
session. The intensity of work was calculated on the basis of the value
of heart rate corresponding to 60% of peak
VO2 achieved. Periodic adjustments of
training intensity were made according to the individual patient's
progression of exercise capacity. Care was taken to avoid intensities
above the initial target.
Follow-up
The follow-up period began the day after the second
Doppler
echocardiographic study and ended at the time of study closure or with
a cardiac event (death, heart failure, angina). The presence of rales
and/or S3 gallop constituted evidence of heart failure.
Patients regularly visited our institution every 3 months. During the
follow-up period, patients or their families filled in a standard
questionnaire at home. Heart failure was graded as definite, possible,
or unlikely, using clinical information.33 Angina pectoris
was scored using the Canadian Cardiovascular Society
criteria.34 Patients were followed for 12±6 months.
Statistical Analysis
Data were entered into a commercially
available statistical
program (SAS Institute Inc) for analysis. A two-tailed paired
t test was used for intragroup comparisons; an unpaired
t test or ANOVA was used for intergroup comparisons. For
comparisons among patterns before and after training, two-way ANOVA was
used. The 
2 test was performed to compare groups
on categorical variables. Correlation of peak exercise oxygen uptake
with metabolic and pulsed Doppler variables before training and after
training using change was performed. Variables with significant
correlations were then entered into a stepwise linear regression model
to determine the best predictors of peak exercise oxygen uptake.
Stepwise logistic regression of occurrence of events on pretraining and
change in Doppler variables was performed. A stepwise survival model
with all pretraining variables as covariates was also done using a
single curve for all subjects. Cardiac mortality was compared among
subgroups using log rank tests. Cardiac event–free (cardiac death,
worsening heart failure, or worsening angina) curves for the trained
and untrained groups and for different subgroups were computed using
the Kaplan-Meier method. Data were expressed as mean±SD. Statistical
significance was assumed for P values <.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Clinical and Doppler Echocardiographic Characteristics
Clinical features are summarized in Table 1
. Patients
were well
matched regarding age, diagnosis, NYHA functional class, presence and
severity of mitral insufficiency, resting LVEF, peak oxygen uptake, and
medications. Mitral insufficiency, when present, was mild in all
patients. Idiopathic DCM was diagnosed in 31% of the trained group and
in 37% of the untrained group. Ischemic cardiomyopathy was more
frequent than DCM in both groups (trained, 69%; untrained, 63%). Through pulsed Doppler echocardiography, a restrictive pattern of LV diastolic filling was found in 17 patients of the trained group and 8 patients of the untrained group (subgroup A). A "normal" pattern of Doppler LV diastolic filling (subgroup B) was observed in 7 patients of the trained group and 4 patients of the untrained group. A pattern of abnormal LV relaxation (subgroup C) was identified in 12 patients of the trained group and 7 patients of the untrained group. Subgroup A had DCM more frequently (11 of 25, 44%) than subgroup B (2 of 11, 18%) and subgroup C (5 of 19, 26%) (P<.005).
Effects of Exercise Training on Different Subgroups
Cardiovascular Parameters
Peak VO2
was significantly increased
after exercise training only in the trained patients with abnormal
relaxation (pattern C) (+15%; P<.005) (Table
2). No changes were observed in the trained patients
with pattern A, and only a modest increase occurred in the trained
patients with pattern B (+6%; P=NS). This is not
unexpected, since group B is too small to obtain statistically
significant data for the peak VO2. In all
untrained groups, peak VO2 was slightly
reduced in the 2 months between the exercise tests. However,
statistical significance was reached only in those with pattern B
(-7%; P<.005). The lactic acidosis threshold was only
slightly greater in trained patients after training, whereas it did not
change in untrained subgroups. Peak exercise workload increased
significantly only in the trained patients with "normal" filling
(pattern B) and those with abnormal relaxation (pattern C) (+13% and
+15%, respectively; P<.005 for both). Conversely, all
untrained subgroups had a trend toward a reduced peak workload that did
not achieve significance. Resting heart rate was slightly reduced in
all trained subgroups, whereas no changes were observed in untrained
subgroups. However, peak heart rate increased significantly only in the
trained group with "normal" filling pattern (subgroup B). Both
resting and peak exercise systolic blood pressures, diastolic blood
pressure, and resting LVEF were unchanged in all trained and untrained
subgroups.
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Diastolic Filling Parameters
Doppler LV
diastolic filling variables before and after
exercise training and for the untrained patients over the same time
period are summarized in Table 3. No significant changes
in overall Doppler parameters were observed in the three untrained
subgroups. Among the trained subgroups, the most significant changes
before and after training were observed in subgroup C, those with
initial abnormal relaxation (Fig 2). In this subgroup,
peak early filling velocity was significantly increased (+26%;
P<.005), whereas peak atrial filling velocity was
significantly reduced (-23%; P<.005) by training, so that
the E/A ratio was increased (+70%; P<.005). The
deceleration time of peak early filling velocity was significantly
reduced only in this subgroup (-21%; P<.005). The
isovolumic relaxation time was significantly shorter after training in
the patients with the restrictive pattern (subgroup A) and those with
abnormal relaxation (subgroup C) and was unchanged in those with a
"normal" pattern (subgroup B). Diastolic filling time increased
significantly in all trained subgroups, and the increase was greatest
in the patients with abnormal relaxation compared with the other two
subgroups. After training, the rapid filling fraction increased (+35%;
P<.005) and atrial filling fraction decreased (-30%;
P<.005) only in the patients with abnormal relaxation. No
changes were observed in untrained subgroups.
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Measurements from Doppler
echocardiography and radionuclide
technique were similar (Table 4). Correlation
coefficients computed in all subjects (before and after exercise
training) were as follows: rapid filling fraction, r=.71,
.75; atrial filling fraction, r=.85, .83; time from aortic
valve closure to peak early filling velocity, r=.69, .70;
time from aortic valve closure to atrial filling velocity,
r=.82, .74. P values were <.0001 for all
correlations.
Exercise Training
No significant cardiovascular events were
observed during the
training sessions, and no patients were withdrawn from the study. One
patient had a self-limited episode of atrial fibrillation during
cycling, spontaneously converting to sinus rhythm after 10 minutes of
rest. Sporadic ventricular extrasystoles were observed in 11 patients
during cycling and in 5 patients during early recovery. Two patients
had hypotension at the end of cycling, which promptly resolved by
resting supine for a few minutes.
Outcome
Table 5 shows a summary of cardiac
events during
the follow-up. Of the 55 patients, 23 overall (41.8%) had cardiac
events (cardiac death, worsening heart failure, and/or worsening angina
pectoris) during the follow-up. Eight patients (14.5%) had worsening
of angina pectoris. In 6 patients, angina was classified as Canadian
class III and in 2 patients as Canadian class IV. Nine patients (16%)
had heart failure, but hospitalization was required in only 4 of them.
Six patients died, 2 of them suddenly. There were no significant
differences between the trained and untrained groups in the frequency
of cardiac events during the following period. However, 16 of 23
patients in both groups who had complications had the restrictive
filling pattern (subgroup A). Thus, 70% (16 of 23) of the patients
with this finding had a poor outcome. Only 2 of 11 patients with a
"normal" pattern (subgroup B) and 5 of 19 patients with impaired
relaxation (subgroup C) had a poor outcome. In 6 patients, a Doppler
restrictive pattern was initially present that was not modified by
training. Six patients of the trained group (16.6%) and 3 patients of
the untrained group (15.7%) had heart failure. Canadian class IV
angina was present in the 2 patients of the trained subgroup A. In
the others, angina was classified as Canadian class III. Table
6
shows the clinical and Doppler echocardiographic
variables in patients with and without cardiac events during the
follow-up.
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Univariate Cox Model Analysis
Table 7 shows
the results of univariate
analysis performed using all clinical, echocardiographic, and
Doppler variables in decreasing order of strength for predicting
baseline peak oxygen uptake and change in peak oxygen uptake at the
follow-up examination. Pretraining peak oxygen uptake was significantly
correlated with all Doppler variables except for peak atrial
filling velocity, diastolic filling period, and resting LVEF. The best
predictor was the change in the lactic anaerobic threshold
(r=.95; P.0001). The change in peak
VO2 was correlated with changes in peak
atrial filling velocity, isovolumic relaxation time, peak heart rate,
and E/A ratio.
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Multivariate Analysis
Stepwise multiple regression was
performed to assess the
independent predictors of peak oxygen uptake at baseline and after
exercise training using the univariate variables, with
P.10. As shown in Table 8, multivariate
analysis demonstrated that peak heart rate and E/A ratio were the
most significant pretraining independent predictors of peak
VO2. Changes in exercise tolerance and E/A
ratio were the best predictors of change in peak
VO2. Stepwise logistic regression
analysis showed an overall effect of Doppler pattern on predicting
overall cardiac events (P=.02). Contrasts showed significant
differences between subgroup A, with the restrictive Doppler pattern,
and subgroup B, with the "normal" pattern (P=.04),
and
between subgroups A and C, with the abnormal relaxation Doppler pattern
(P=.007), indicating a worse prognosis in patients with
baseline Doppler pattern of restrictive filling. Exercise training did
not reach statistical significance (P=.54) as a predictor of
cardiac events. Stepwise logistic regression with event as the outcome
produced the following results: Subjects who had cardiac events had
significantly higher values on E, RFF, and resting heart rate and
significantly lower values on IVRT, EDT, and peak
VO2 than patients who had no events. The
results were similar when patients who died were compared with those
who survived, with the exception that the former also had lower peak
atrial filling velocity and higher heart rates.
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The survival model (log
rank test) showed lower event-free
survival for patients with pattern A (2=11.53;
P=.003) than for either B or C (Fig 3). The
trend of survival curves was similar when patients were separated by
etiology (idiopathic or ischemic cardiomyopathy). However, there was no
significant difference between survival functions when separated by
exercise training (Fig 4).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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These data show that LV diastolic filling patterns assessed by Doppler echocardiography can identify patients with DCM who will increase their peak VO2 with exercise training. In this population, the most significant improvement in aerobic capacity was observed in patients with a baseline Doppler pattern of abnormal LV relaxation. However, in this study, there was no significant association between improved exercise capacity and prognosis.
The best independent predictors of morbidity and mortality were pretraining Doppler variables of LV restrictive filling. Patients with cardiac events during the follow-up had significantly higher values on E and RFF and significantly lower values on IVRT and EDT than patients who had no events. All the patients who died had the restrictive filling pattern and no improvement in aerobic capacity after training. Patients with a baseline Doppler pattern of abnormal LV relaxation had the best outcome compared with the other two patterns.
Exercise Training and Left Ventricular Diastolic Filling in Dilated
Cardiomyopathy
Abnormalities of LV diastolic function that often
precede
systolic dysfunction have been demonstrated in patients with DCM by
contrast LV angiography8 and radionuclide
angiography.35 Recently, pulsed Doppler echocardiography
has been shown to correlate with both
angiographic21 22 23
and radionuclide24 25 techniques in assessing
diastolic
filling in patients with DCM36 37 38 and
other cardiac
diseases.12 37 38 39
Moreover, Doppler recordings have proven
to be accurate in evaluating serial changes in LV diastolic
function40 41 as well as in defining prognosis in
patients
with DCM12 13 and cardiac amyloidosis.42
Although the Doppler pattern of diastolic mitral inflow directly reflects LV filling, it is influenced by multiple related factors such as LV relaxation,43 cardiac motion,44 intrinsic myocardial properties, heart rate, and loading conditions. Thus, it is not surprising that different inflow patterns have been identified in patients with DCM, reflecting different clinical and hemodynamic profiles.8 In the restrictive pattern, hemodynamic comparisons have shown an increase in mean left atrial pressure with a greater atrioventricular pressure gradient. This causes a more prominent early diastolic filling velocity and a more rapid deceleration rate due to a faster equalization between left atrial and LV pressures. By contrast, when impaired relaxation is present, the early diastolic pressure gradient between the left atrium and LV is small, resulting in a decreased rate of early filling velocity with a prolonged deceleration time as well as a greater residual atrial volume. A third pattern of mixed abnormalities resulting in a "normal" pattern involving both restrictive and impaired relaxation conditions may sometimes be evident in patients with DCM. In this case, it is possible that an initially abnormal relaxation pattern may be present, which later can progress to a restrictive pattern when left atrial pressure rises.
In this study, 45% of patients had a restrictive pattern, 25% had a pattern of abnormal relaxation, and 20% had a "normal" pattern. In our patients with the abnormal relaxation pattern, functional capacity was improved after training and the A wave was reduced. Because we observed no significant changes in LV chamber dimensions, loading conditions, and heart rate after training, the increase in transmural gradient may be related to a decrease in the LV minimal pressure, possibly produced by an increase in ventricular relaxation rate. These data are consistent with the findings of Levy et al,45 who found a significant correlation between a training-induced increase in early filling and peak VO2 in both young and old normal subjects. They suggested that the improvement in aerobic capacity could be explained through the increase in early diastolic filling, resulting in an increase in stroke volume and cardiac output. In this study, the increase in aerobic capacity was not associated with changes in echocardiographic indexes of systolic performance. This suggests that the improved aerobic capacity may be due to peripheral adaptations.
The observation that exercise training positively influences only patients with a Doppler pattern of abnormal LV relaxation has not been described before and needs further confirmation. Various mechanisms may play a role, such as a lower LV filling pressure, a lower transmitral left atrioventricular gradient, as well as a lower incidence of mitral insufficiency.
In our patients, the increase in early diastolic filling
was
accompanied by a significant reduction in the isovolumic relaxation
time (Table 3). Since isovolumic relaxation time is the most
energy-requiring phase of excitation-contraction
coupling46 and is primarily influenced by sympathetic
tone, its reduction after training probably reflects a greater calcium
reuptake from myofilaments. An increase in myocardial distensibility
can contribute to an increase in cardiac output and oxygen supply to
skeletal muscles. We hypothesize that this mechanism may play a role in
explaining the changes in LV diastolic filling in patients with DCM and
abnormal LV relaxation.
The absence of significant changes in exercise capacity and LV diastolic filling in patients with Doppler restrictive "normal" patterns has not been previously described. Both hemodynamic and anatomic factors may be involved. Patients with restrictive LV filling may have a greater LV end-diastolic pressure and a stiffer ventricle. Such factors could limit the capacity of the left ventricle to adapt to exercise training, which may be caused by interstitial fibrosis and collagen abormalities. However, recent data have shown that the amount of interstitial fibrosis does not correlate with the Doppler pattern of LV diastolic filling.43 In this study, the absence of significant changes in LV diastolic filling as well as peak VO2 after training was similar in patients with "normal" and with Doppler restrictive patterns.
Prognostic Significance of the Effects of Exercise
Training
Previous studies have attempted to define prognostic
indicators in
patients with DCM. One report suggested that a significant Doppler
predictor of outcome was the early to atrial filling velocity
(E/A).47 A ratio of 2.3 was associated with a greater
capillary pulmonary wedge pressure, a lower cardiac index, and a lower
functional capacity. Our data confirm that pretraining E/A ratio and
posttraining change in E/A ratio, primarily due to a reduction in the
amplitude of the A wave, were independent predictors of peak
VO2. Stepwise logistic regression
analysis showed an overall effect of pretraining patterns on
predicting overall cardiac events. Patients with a baseline restrictive
pattern of LV diastolic dysfunction had a higher morbidity and
mortality compared with the other subgroups. However, exercise training
did not significantly modify the outcome of patients with DCM (Fig
4).
Patients with abnormal relaxation did have a greater increase in
exercise capacity and a lower incidence of overall cardiac events
compared with the patients with a restrictive pattern during follow-up
(P=.007). This trend was independent of the etiology of the
heart failure, confirming that the identification of these specific
patterns by Doppler echocardiography is very important in identifying
patients with DCM with a poor outcome.
Limitations of the Study
The number of patients studied was
relatively small, especially
since they were further subdivided into three subgroups. Of interest,
other investigators recently reported similar results13 on
the prognostic significance of Doppler patterns in similar numbers of
patients. However, they did not exercise their patients. We are the
first to describe the prognostic significance of the posttraining
changes in LV diastolic filling in patients with dilated
cardiomyopathy. A single load of exercise training was chosen. The
effects of different intensities of exercise training in patients with
DCM are not known and will need further study. But the fact that the
trained group demonstrated an increase in lactic acid threshold, peak
VO2, and work capacity compared with
the control group indicates that the exercise program was vigorous
enough to produce a training effect. Invasive studies such as muscle
biopsies and arterial venous O2 differences during exercise
might help to clarify some of the mechanisms by which DCM patients can
improve their functional capacity, but those were not part of the
design of this study. Left ventricular diastolic filling patterns
assessed by Doppler are influenced by a variety of factors, such as
valvular insufficiency, loading conditions, viscoelastic properties of
the myocardium, ventricular compliance, pericardial restraint, and left
and right ventricular interaction. However, Doppler LV filling
variables were highly correlated with radionuclide LV filling variables
both before and after exercise training, indicating the applicability
of Doppler measurements of LV filling. The training-induced reduction
in resting heart rate, evident in all trained subgroups, may have
increased the magnitude of LV filling. However, resting heart rate was
only modestly reduced after training (Table 2). By contrast,
changes in
filling fractions, observed only in the trained subgroup with abnormal
relaxation pattern, were more pronounced, suggesting that factors other
than the mechanism of training-induced bradycardia can be involved.
Changes in loading conditions induced by training could also account
for the changes in LV diastolic filling. We found no changes in LV
end-diastolic diameter or diastolic blood pressure,
suggesting that both preload and afterload were scarcely involved in
training-induced changes of diastolic filling. Although mitral
insufficiency was present in two thirds of the trained patients, in
particular in patients with restrictive pattern, its degree was mild in
all patients and was not modified by exercise training. Finally, the
accuracy of Doppler echocardiography for prognostic evaluation may be
decreased by the variability of LV diastolic filling. This variability
could be increased by exercise training. In our study, however, loading
conditions were not significantly modified by training except for the
pattern of abnormal relaxation.
Conclusions
Some patients with DCM can improve their
functional capacity with
training, whereas patients who do not exercise have a tendency to
further reduce their exercise capacity. The improvement in peak
exercise VO2 is significantly correlated with
the increase in early filling rate as well as a decrease in atrial
filling rate. Since the increase in exercise tolerance is statistically
significant only in patients with the initial Doppler pattern of
abnormal relaxation, and since this pattern has a better prognosis
compared with the other two patterns studied, we believe that the
Doppler pattern of abnormal LV relaxation may represent a
useful criterion for the identification of patients with DCM who will
benefit the most from exercise training and for the assessment of
outcome. Furthermore, Doppler echocardiography can identify patients
with restrictive LV diastolic filling as well as "normal" pattern
who will not benefit from exercising and will not have an amelioration
in prognosis by exercise training.
The results indicate that Doppler echocardiograpy is a valuable tool in the prognostic assessment of patients with DCM involved in exercise training programs. However, the small number of observations prevents us from reaching definitive conclusions about the clinical and prognostic significance of exercise-induced changes in LV diastolic filling patterns. The prognostic significance of these data should be confirmed in larger studies with a longer follow-up.
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Acknowledgments |
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The secretarial assistance of Edward Murray is greatly appreciated.
Received October 5, 1994; revision received December 5, 1994; accepted December 18, 1994.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Jetté M, Heller R, Landry F, Blümchen G. Randomized 4-week exercise program in patients with impaired left ventricular function. Circulation. 1991;84:1561-1567.
2.
Shabetai R. Beneficial effects of exercise
training in compensated heart failure.
Circulation. 1988;78:775-776.
3.
Sullivan MJ, Higginbotham MB, Cobb FR.
Exercise training in patients with chronic heart failure delays
ventilatory anaerobic threshold and improves submaximal exercise
performance. Circulation. 1989;79:324-329.
4.
Sullivan MJ, Higginbotham MB, Cobb FR. Exercise
training in patients with severe left ventricular dysfunction:
hemodynamic and metabolic effects.
Circulation. 1988;78:506-515.
5.
Bonow RO, Bacharach SL, Green MV, Kent KM, Rosing DR,
Lipson LC, Leon MB, Epstein SE. Impaired left ventricular
diastolic filling in patients with coronary artery disease: assessment
with radionuclide angiography.
Circulation. 1981;64:315-323.
6. Grossman W, McLaurin LP, Rolett EL. Alterations in left ventricular relaxation and diastolic compliance in congestive cardiomyopathy. Cardiovasc Res. 1979;13:514-522. [Medline] [Order article via Infotrieve]
7. Ehsani AA, Martin WH, Heath GW, Coyle EF. Cardiac effects of prolonged and intense exercise training in patients with coronary artery disease. Am J Cardiol. 1982;50:246-254. [Medline] [Order article via Infotrieve]
8. Arvan S. Exercise performance of the high risk acute myocardial infarction patient after cardiac rehabilitation. Am J Cardiol. 1988;62:197-201. [Medline] [Order article via Infotrieve]
9. DeMaria AN, Wisenbaugh TW, Smith MD, Harrison MR, Berk MR. Doppler echocardiographic evaluation of diastolic dysfunction. Circulation. 1991;84(suppl I):I-288-I-295.
10. Taylor R, Waggoner AD. Doppler assessment of left ventricular diastolic function: a review. J Am Soc Echocardiogr. 1992;5:603-612. [Medline] [Order article via Infotrieve]
11. Nishimura RA, Housmans PR, Hatle LK, Tajik AJ. Assessment of diastolic function of the heart: background and current applications of Doppler echocardiography, I: physiologic and pathophysiologic features. Mayo Clin Proc. 1989;64:71-81. [Medline] [Order article via Infotrieve]
12. Oh JK, Ding ZP, Gersh BJ, Bailey KR, Tajik AJ. Restrictive left ventricular diastolic filling identifies patients with heart failure after acute myocardial infarction. J Am Soc Echocardiogr. 1992;5:497-503. [Medline] [Order article via Infotrieve]
13. Weener GS, Schaefer C, Dirks R, Figulla HC, Kreuzer H. Prognostic value of Doppler echocardiographic assessment of left ventricular filling in idiopathic dilated cardiomyopathy. Am J Cardiol. 1994;73:792-798. [Medline] [Order article via Infotrieve]
14. Lavine SJ, Campbell CA, Held AC, Johnson V. Effect of nitroglycerin-induced reduction of left ventricular filling pressure on diastolic filling in acute dilated heart failure. J Am Coll Cardiol. 1989;13:233-241.
15.
Choong CY, Abascal VM, Thomas JD, Guerrero JL, McGlew
S, Weyman AE. Combined influence of ventricular loading and
relaxation on the transmitral flow velocity profile in dogs measured by
Doppler echocardiography. Circulation. 1988;78:672-683.
16.
Zile MR, Blaustein AS, Gaasch WH. The effect of
acute alterations in ventricular afterload and ß-adrenergic tone on
indexes of early diastolic filling rate. Circ
Res. 1989;65:406-416.
17. Gardin JM, Dabestani A, Takenaka K, Rohan MK, Knoll M, Russel D, Henry WL. Effect of imaging view and sample volume location on evaluation of mitral flow velocity by pulsed doppler echocardiography. Am J Cardiol. 1986;57:1335-1339. [Medline] [Order article via Infotrieve]
18. Iskandrian AS, HamidHakki A. Age-related changes in left ventricular diastolic performance. Am Heart J. 1986;112:75-78. [Medline] [Order article via Infotrieve]
19. Harrison MR, Clifton GD, Pennel AT, DeMaria AN. Effect of heart rate on left ventricular diastolic transmitral flow velocity patterns assessed by Doppler echocardiography in normal subjects. Am J Cardiol. 1991;67:622-627. [Medline] [Order article via Infotrieve]
20.
Gaasch WH, Cole JS, Quinones MA, Alexander JK.
Dynamic determinants of left ventricular diastolic
pressure-volume relation in man.
Circulation. 1975;51:317-323.
21.
Rokey R, Kuo LC, Zoghbi WA, Limacher MC, Quinones MA.
Determination of parameters of left ventricular diastolic
filling with pulsed Doppler echocardiography: comparison with
cineangiography. Circulation. 1985;71:543-550.
22. Appleton CP, Hatle LK, Popp RL. Relation of transmitral flow velocity patterns of left ventricular diastolic function: new insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol. 1988;12:426-440. [Abstract]
23. Stoddard MF, Pearson AC, Kern MJ, Ratcliff J, Mrosek DG, Labovitz AJ. Left ventricular diastolic function: comparison of pulsed Doppler echocardiographic and hemodynamic indexes in subjects with and without coronary artery disease. J Am Coll Cardiol. 1989;12:327-336.
24. Spirito P, Maron BJ, Bonow RO. Noninvasive assessment of left ventricular diastolic function: comparative analysis of Doppler echocardiographic and radionuclide angiographic techniques. J Am Coll Cardiol. 1989;12:327-336.
25. Friedman BJ, Drinkovic N, Miles H, Shih WJ, Mazzoleni A, DeMaria AN. Assessment of left ventricular diastolic function: comparison of Doppler echocardiography and gated blood pool scintigraphy. J Am Coll Cardiol. 1986;8:1348-1354. [Abstract]
26. Feigenbaum H. Echocardiography. Philadelphia, Pa: Lea & Febiger; 1986:212-234.
27. Henry WL, DeMaria AN, Gramak R, King DL, Kisslo JA, Popp RL, Sahn DJ, Schiller NB, Tajik A, Teicholz LE, Weyman AE. Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Two-Dimensional Echocardiography. Circulation. 1980;
28. Spain MG, Smith MD, Grayburn PA, Harlamert EA, DeMaria AN. Quantitative assessment of mitral regurgitation by Doppler color flow imaging: angiographic and hemodynamic correlations. J Am Coll Cardiol. 1989;13:585-590. [Abstract]
29. Broadhurst XJ, Liu PMM, Cashman EB, Raftery EB, Lahiri A. Spontaneous variability of left ventricular ejection fraction assessed with the Cardioscint. Nucl Med Comm. 1992;13:312-320. [Medline] [Order article via Infotrieve]
30.
Broadhurst P, Cashman PMM, Crawley J, Raftery EB,
Lahiri A. Clinical validation of a miniature nuclear probe
system for continuous monitoring of left ventricular function and ST
segment. J Nucl Med. 1991;32:37-43.
31.
Beaver WL, Wasserman K, Whipp BJ. A new method
for detecting anaerobic threshold by gas exchange. J Appl
Physiol. 1986;60:2020-2027.
32. Armitage P. Statistical Methods in Medical Research. London, UK: Blackwell Scientific Publications; 1971:456-460.
33. Carlson KJ, Lee DCS, Goroll AH, Leahy M, Johnson RA. An analysis of physicians' reasons for prescribing long-term digitalis therapy in outpatients. J Chronic Dis. 1985;38:733-739. [Medline] [Order article via Infotrieve]
34. Campeau L. Grading of angina pectoris. Circulation. 1976;54:522-531. [Medline] [Order article via Infotrieve]
35. Packer M. Abnormalities of diastolic function as a potential cause of exercise intolerance in chronic heart failure. Circulation. 1990;8(suppl III):III-78-III-86.
36. Takenaka K, Dabestani A, Gardin JM, Russell D, Clark S, Allfie A, Henry W. Pulsed Doppler echocardiography study of left ventricular filling in dilated cardiomyopathy. Am J Cardiol. 1986;58:143-147. [Medline] [Order article via Infotrieve]
37. Lavine SJ, Arends. Importance of the left ventricular filling pressure on diastolic filling in idiopathic dilated cardiomyopathy. Am J Cardiol. 1989;64:61-65. [Medline] [Order article via Infotrieve]
38. Klein AL, Hatle LK, Burstow DJ, Seward JB, Kyle RA, Bailey KR, Luscher TF, Gertz MA, Tajik AJ. Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol. 1989;13:1017-1026. [Abstract]
39. Pearson AC, Labovitz AJ, Mrosek D, Williams GA, Kennedy HL. Assessment of diastolic function in normal and hypertrophied hearts: comparison of Doppler echocardiography and M-mode echocardiography. Am Heart J. 1987;113:1417-1425. [Medline] [Order article via Infotrieve]
40. Myreng Y, Myhre E. Effects of verapamil on left ventricular relaxation and filling dynamics in coronary artery disease: a study by pulsed Doppler echocardiography. Am Heart J. 1989;117:870-875. [Medline] [Order article via Infotrieve]
41. Wind E, Snider AR, Buda AJ, O'Neill WW, Topol EJ, Dilworth LR. Pulsed Doppler assessment of left ventricular diastolic filling in coronary artery disease before and immediately after coronary angioplasty. Am J Cardiol. 1987;59:1041-1046. [Medline] [Order article via Infotrieve]
42.
Klein AL, Hatle LK, Taliercio CP, Oh JK, Kyle RA, Gertz
MA, Bailey KR, Seward JB, Tajik AJ. Prognostic significance of
Doppler measures of diastolic function in cardiac amyloidosis: a
Doppler echocardiographic study.
Circulation. 1991;83:808-816.
43. Pinamonti B, DiLenarda A, Sinagra G, Camerini F. Restrictive left ventricular filling pattern in dilated cardiomyopathy assessed by Doppler echocardiography: clinical, echocardiographic and hemodynamic correlations and prognostic implications. J Am Coll Cardiol. 1993;22:808-815. [Abstract]
44. Cao T, Shapiro SM, Bersohn M, Lin SC, Ginzton LE. Influence of cardiac motion on Doppler measurements using in vitro and in vivo models. J Am Coll Cardiol. 1993;22:271-276. [Abstract]
45.
Levy WC, Cerqueira MD, Abrass IB, Schwartz RS, Stratton
JR. Endurance exercise training augments diastolic filling at
rest and during exercise in healthy young and older men.
Circulation. 1993;88:116-126.
46.
Stehno-Bittel L, Laughlin MH, Sturek M. Exercise
training depletes sarcoplasmic reticulum Ca in coronary smooth
muscle. J Appl Physiol. 1991;71:1764-1773.
47. Vanoverchelde JLJ, Raphael DA, Robert AR, Cosyns JR. Left ventricular filling in dilated cardiomyopathy: relation to functional class and hemodynamics. J Am Coll Cardiol. 1990;15:1288-1295.[Abstract]
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