Download Change in Diastolic Left Ventricular Filling After One Year of

Change in Diastolic Left Ventricular Filling After One Year
of Antihypertensive Treatment
The Losartan Intervention For Endpoint Reduction in Hypertension
(LIFE) Study
Kristian Wachtell, MD, PhD; Jonathan N. Bella, MD; Jens Rokkedal, MD; Vittorio Palmieri, MD;
Vasilios Papademetriou, MD; Björn Dahlöf, MD, PhD; Tapio Aalto, MD;
Eva Gerdts, MD, PhD; Richard B. Devereux, MD
Background—It is well established that hypertensive patients with left ventricular (LV) hypertrophy have impaired
diastolic filling. However, the impact of antihypertensive treatment and LV mass reduction on LV diastolic filling
remains unclear.
Methods and Results—Echocardiograms were recorded in 728 hypertensive patients with ECG-verified LV hypertrophy
(Cornell voltage-duration or Sokolow-Lyon) at baseline and after 1 year of blinded treatment with either losartan or
atenolol-based regimen. Systolic and diastolic blood pressures (BP) were reduced on average 23/11 mm Hg; isovolumic
relaxation time and E/A ratio became more normal, and LV inflow deceleration time prolonged (all P⬍0.001).
Directionally opposite changes in isovolumic relaxation time (IVRT) and deceleration time indicate improvement in
active LV relaxation and passive chamber stiffness during early diastole. Prevalences of normal LV filling increased,
abnormal relaxation and pseudonormalization decreased, and restrictive filling pattern remained unchanged (P⬍0.05).
Patients with reduction in LV mass had smaller left atrial diameter, shortened IVRT, increased E/A ratio, and prolonged
LV inflow deceleration time (all P⬍0.001). Patients without LV mass reduction had no change in diastolic filling
parameters (P⫽NS). IVRT shortening was independently associated with reduction in LV mass. Increase in E/A ratio
was independently associated with reduction in diastolic BP, and increase in the deceleration time was independently
associated with reduced end-systolic relative wall thickness.
Conclusions—Antihypertensive therapy resulting in LV mass or relative wall thickness regression is associated with
significant improvement of diastolic filling parameters related to active relaxation and passive chamber stiffness
compared with patients without regression, independent of BP reduction; however, abnormalities of diastolic LV filling
remain common. (Circulation. 2002;105:●●●-●●●.)
Key Words: diastole 䡲 ventricles 䡲 hypertension 䡲 blood pressure
H
ypertensive patients have a 2- to 3-fold higher risk of
development of congestive heart failure than normotensive adults.1 Furthermore, patients with congestive heart
failure and normal left ventricular (LV) ejection fraction have
a 4-fold increase in mortality rate.2 There is evidence that
hypertensive LV hypertrophy plays an important role in the
development of heart failure.3 We have shown that diastolic
filling parameters are strongly related to LV hypertrophy and
relative wall thickness (RWT) in hypertensive patients.4 This
might be a result of remodeling, muscle hypertrophy, and
alterations of collagen structure.5 Several animal and small
human studies examining regression of LV hypertrophy and
diastolic dysfunction in hypertensive patients showed that
treatment-induced regression of LV hypertrophy did not
decrease myocardial collagen levels or reduce the abnormal
LV diastolic stiffness and hence improve LV diastolic filling.6 –11 However, other small studies show improvement of
diastolic filling parameters along with systolic and diastolic
blood pressure (BP) and/or LV mass reduction.12–14 Furthermore, studies in patients with diastolic dysfunction without
concomitant LV hypertrophy have either shown no improvement15 or improvement after multiyear antihypertensive treatment.16 This might be a result of simultaneous changes in
active LV relaxation and passive LV chamber stiffness.17
To our knowledge, there are no large studies examining the
effect of antihypertensive treatment on LV diastolic function
Received October 23, 2001; revision received December 13, 2001; accepted December 21, 2001.
From Copenhagen County University Hospital, Glostrup, Denmark (K.W., J.R.); Weill Medical College of Cornell University, New York, NY (K.W.,
J.N.B., V.P., R.B.D.); Veterans Affairs Medical Center, Washington, DC (V.P.); Sahlgrenska University Hospital-Östra, Göteborg, Sweden (B.D.);
Helsinki University Central Hospital, Helsinki, Finland (T.A.); and Haukeland Hospital, Bergen, Norway (E.G.).
Correspondence to Dr Kristian Wachtell, Laboratory of Cardiology, Department of Medicine, Copenhagen County University Hospital, Glostrup,
DK-2600 Glostrup, Denmark. E-mail [email protected]
© 2002 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/hc0902.104599
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Circulation
March 5, 2002
in hypertensive patients. The aim of this study was to
investigate changes in LV diastolic filling and their relation to
regression of LV hypertrophy due to systematic antihypertensive treatment.
As part of the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) trial,18 ⬎10% of study participants enrolled in a substudy in which echocardiograms are
performed at study baseline and yearly thereafter.4,19,20 This
report uses the baseline and follow-up year-1 echocardiograms from this substudy to determine the effect of antihypertensive treatment on LV diastolic filling in hypertensive
patients.
Methods
Patients gave informed consent, and the Committees of Ethical
Science accepted this study. All patients had a screening ECG with
LV hypertrophy by either sex-adjusted Cornell voltage duration
ⱖ2440 mV · ms or Sokolow-Lyon voltage criteria ⬎38 mV;
exclusion criteria have been previously described.18
Subjects
Eligible individuals were 960 hypertensive patients; 876 had echocardiograms at baseline and at year-1, as 84 follow-up studies were
not performed because of death (n⫽10) or disability or failure to
cooperate (n⫽74). A total of 148 participants in the echocardiography substudy were ineligible for the present study because of
inability to obtain baseline and/or year-1 measurements of LV mass
(n⫽19) or transmitral Doppler flow profiles (n⫽129). Compared
with ineligible patients, the present study patients were younger at
enrollment (mean 66.2⫾6.7 versus 68.4⫾7.7 years, P⬍0.01) but did
not differ in sex distribution, body mass index, systolic or diastolic
BP, LV mass, RWT, isovolumic relaxation time (IVRT), E/A ratio,
or mitral valve deceleration time.
Echocardiographic Methods
Echocardiographic procedures for this study are previously described.4,19,20 End-diastolic LV dimensions were used to calculate
LV mass by an anatomically validated formula (r⫽0.90 versus
necropsy LV mass).21 RWT at end-diastole was calculated as
end-diastolic posterior wall thickness/LV internal radius22; RWT at
end-systole was also calculated by a similar formula because this
contributes to the LV geometric component of passive ventricular
stiffness that is superimposed on the active process of myocardial
relaxation in early diastole. LV hypertrophy was considered present
when LV mass indexed for body surface area was ⬎116 g/m2 for
men and ⬎104 g/m2 for women.23 Increased diastolic RWT was
present when this ratio was ⬎0.430.24 LV geometry definitions19 and
methods of pulsed Doppler recordings4 have previously been
described.
Statistics
Statistical software (SPSS Version 9.0, SPSS, Inc) was used for
statistical analysis. Results are mean⫾SD when appropriate, and
frequencies are expressed as percentages. Differences in continuous
variables between two groups were assessed by Student’s t test for
parametric data and by ␹2 analysis for categorical data; comparison
among multiple groups was performed by ANOVA with the Scheffé
post hoc test.
A study from the Reading Center showed that LV mass on serial
echocardiograms has high reliability and little regression to the
mean.25 Between-study LV mass change of ⫾35 g or ⫾17 g had
ⱖ95% or ⱖ80% likelihood of being true change. Explanatory
analyses dichotomized patients at LV mass reduction partitions of
⫺35 and ⫺17 g, respectively, from baseline values. However, this
did not alter any conclusions (data not shown). Therefore, patients
were dichotomized to whether LV mass decreased or, alternatively,
either remained unchanged or increased. Independent correlates of
continuous measures of LV transmitral flow patterns were identified
by multiple linear regression analysis with an enter procedure with
assessment of colinearity diagnostics. A value of P⬍0.05 (2-tailed)
was considered statistically significant.
Results
Patient Characteristics
Descriptive data of the whole LIFE population18 and LV
diastolic function at baseline in the LIFE echocardiography
substudy have been reported elsewhere.4 Of the total 960
patients, 728 patients had paired imaging and Doppler measurements at baseline, and year-1 follow-up was needed for
inclusion in the present study. Mean age was 67⫾7 years, and
41% were women.
Changes in Left Atrial and Ventricular Structure
and Diastolic Function
As shown in Table 1, mean end-echo BPs were reduced by
23/11 mm Hg (P⬍0.001). Mean LV mass was reduced by
⬇12%. The reduction of LV mass was due to reduction of
interventricular septal, posterior wall, and end-diastolic RWT
by ⬇10%. Furthermore, we found an ⬇9% reduction in
end-systolic RWT and an ⬇3% reduction in left atrial size.
However, LV internal diameter in diastole increased by
⬍1%, as did mean body mass index. IVRT shortened and the
E/A ratio increased; deceleration time increased by ⬇7% and
atrial filling fraction decreased by ⬇10%.
Change in Left Ventricular Filling Patterns
At baseline, abnormal relaxation was by far the most common
abnormal transmitral flow pattern, whereas 15% had normal
mitral valve flow profile, 11% had pseudonormal flow
profile, and only 5% had restrictive flow pattern (Figure 1).
After 1 year of treatment, the prevalence of normal flow
pattern increased to ⬇26% and abnormal relaxation decreased to 57%. The prevalence of pseudonormal pattern
decreased to ⬇5%, whereas the restrictive pattern prevalence
changed little (P⬍0.05).
LV Hypertrophy Regression and Diastolic Filling
Comparing patients with LV mass decrease and those with no
decrease or an increase in LV mass, patients with LV mass
decrease had the same reduction in systolic and diastolic BP
(Table 1) as well as in mean BP (Figure 2) and a slight
increase in body mass index (P⬍0.05), compared with
patients without LV mass reduction.
Patients with LV mass regression had significant reduction
in left atrial diameter, shortened IVRT, increased E/A ratio,
prolonged mitral valve deceleration time, and decreased atrial
filling fraction. Patients without change or with increase in
LV mass, after 1 year of antihypertensive treatment, had no
change in left atrial size, IVRT, E/A ratio, or mitral valve
deceleration time but had decreased mean atrial filling fraction from baseline values (Table 1). In an analysis of the
changes between baseline and year-1 values, patients with LV
mass reduction, compared with patients without LV mass
reduction, had significantly greater reduction in left atrial size
and in IVRT but similar changes in E/A ratio, mitral valve
deceleration time, and atrial filling fraction (Table 1).
Wachtell et al
TABLE 1.
Change in Diastolic LV Filling During Treatment
3
Changes in Blood Pressure, LV Structure, and Diastolic Filling Parameters After One Year of Antihypertensive Treatment
Total
(n⫽726)
Baseline
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
174⫾20
LV Mass Decrease
(n⫽560)
No LV Mass Decrease
(n⫽166)
Difference in ⌬ Between
LV Mass Decrease
or No Decrease
Year 1
Baseline
Year 1
Baseline
Year 1
P
151⫾19*
174⫾20
150⫾19*
174⫾22
153⫾21*
NS
95⫾11
84⫾11*
95⫾12
84⫾11*
95⫾11
85⫾10*
NS
Body mass index, kg/m2
27.4⫾4.5
27.5⫾4.6†
27.4⫾4.5
27.4⫾4.6
26.8⫾3.9
27.3⫾4.4*
⬍0.05
LV mass, g
234⫾56
207⫾51*
239⫾57
200⫾46⫺
214⫾51
233⫾57⫺
䡠䡠䡠
LV mass/body surface area, g/m2
124⫾25
109⫾23*
126⫾25
105⫾21*
114⫾25
124⫾25*
䡠䡠䡠
LV mass/height2.7, g/m2.7
56.2⫾12.7
49.9⫾11.6*
57.4⫾12.9
48.0⫾10.5*
51.7⫾10.9
56.8⫾11.7*
䡠䡠䡠
⬍0.001
LV internal diameter, cm
5.29⫾0.58
5.34⫾0.56*
5.31⫾0.57
5.29⫾0.56*
5.19⫾0.57
5.49⫾0.59*
Interventricular septum, cm
1.16⫾0.15
1.04⫾0.14*
1.17⫾0.15
1.03⫾0.13*
1.11⫾0.15
1.10⫾0.17*
⬍0.001
Posterior wall thickness, cm
1.07⫾0.13
0.96⫾0.11*
1.08⫾0.13
0.96⫾0.11*
1.03⫾0.12
1.02⫾0.12*
⬍0.001
⬍0.001
Relative wall thickness in end-diastole
0.41⫾0.067
0.37⫾0.054*
0.41⫾0.07
0.36⫾0.05*
0.40⫾0.06
0.38⫾0.06*
Relative wall thickness in end-systole
0.93⫾0.19
0.85⫾0.16*
0.93⫾0.19
0.85⫾0.16*
0.91⫾0.18
0.83⫾0.17*
NS
Left atrial diameter, cm
3.93⫾0.02
3.81⫾0.02*
3.96⫾0.55
3.80⫾0.55*
3.85⫾0.59
3.86⫾0.60
⬍0.001
Isovolumic relaxation time, ms
115⫾25
105⫾22*
116⫾24
104⫾21*
115⫾25
110⫾24
⬍0.05
Mitral valve E/A-ratio
0.85⫾0.34
0.93⫾0.33*
0.83⫾0.29
0.92⫾0.32*
0.91⫾0.47
0.95⫾0.34
NS
Mitral valve deceleration time, ms
217⫾66
231⫾68*
216⫾63
231⫾68*
228⫾74
233⫾67
NS
Atrial filling fraction
0.42⫾0.10
0.38⫾0.11*
0.43⫾0.10
0.39⫾0.10*
0.42⫾0.10
0.38⫾0.09*
NS
*P⬍0.001, †P⬍0.05 between year 1 and baseline value.
Patients with reduction of end-diastolic RWT (n⫽561) had
significantly reduced left atrial size (3.92⫾0.53 to 3.79⫾0.56
cm), shortened IVRT (117⫾24 to 104⫾22 ms), increased
E/A ratio (0.84⫾0.31 to 0.93⫾0.34), prolonged mitral valve
deceleration time (219⫾65 to 234⫾69 ms), and decreased
atrial filling fraction (0.42⫾0.10 to 0.38⫾0.12, all P⬍0.001)
from baseline values after 1 year of antihypertensive treatment. Patients without change or with increase in end-diastolic RWT after 1 year of antihypertensive treatment
(n⫽167) had no change in IVRT (112⫾27 to 108⫾20 ms),
E/A ratio (0.89⫾0.42 to 0.90⫾28), deceleration time
(215⫾67 to 220⫾51 ms), and atrial filling fraction
(0.42⫾0.10 to 0.40⫾0.11, all P⫽NS) but had reduced left
atrial size (4.00⫾0.63 to 3.89⫾0.56, P⬍0.05) from baseline
values. Patients with end-diastolic RWT reduction, compared
with patients without end-diastolic RWT reduction, had
Figure 1. Change in transmitral flow profiles after 1 year of antihypertensive treatment.
significantly greater IVRT shortening (⫺12.4⫾29 versus
⫺4.0⫾32 ms, respectively, P⬍0.01), E/A ratio increase
(0.09⫾0.32 versus 0.02⫾0.32, P⬍0.05), and atrial filling
fraction decrease (⫺0.05⫾0.11 versus ⫺0.02⫾0.12,
P⬍0.001) but similar changes of left atrial size (⫺0.10⫾0.59
versus ⫺0.13⫾0.49 cm) and mitral valve deceleration time
(14.4⫾83 versus 4.5⫾74 ms, both P⫽NS).
Correlates of Changes in Diastolic Filling Parameters
Univariate analyses (Table 2) showed that shortened IVRT
was related to younger age and reductions in LV mass and
end-diastolic and end-systolic RWT and left atrial dimension.
Multivariate analyses yielded a model (R⫽0.257, P⬍0.001)
in which younger age (␤⫽0.74, P⫽0.05) and reductions in
LV mass (␤⫽0.123), left atrial diameter (␤⫽0.120), and
end-diastolic RWT (␤⫽0.112, all P⬍0.01) were independently associated with IVRT reduction. In an alternative
Figure 2. Left ventricular hypertrophy regression and change in
mean blood pressure. LVM indicates LV mass.
4
Circulation
March 5, 2002
TABLE 2.
Correlates of Differences in Diastolic Filling Parameters
Difference
in IVRT
Difference
in E/A
Difference in
Deceleration Time
Difference in Atrial
Filling Fraction
0.003
⫺0.021
0.030
Age
0.094‡
⫺0.003
⌬ Systolic blood pressure
0.017
⫺0.083‡
0.007
⌬ Diastolic blood pressure
0.042
⫺0.141*
⫺0.018
⌬ Body mass index
0.018
⫺0.011
0.058
⫺0.005
⌬ LV mass
0.156*
⫺0.001
⫺0.052
⫺0.026
0.109†
⌬ LV mass/body surface area
0.161†
⫺0.004
⫺0.049
⫺0.021
⌬ LV mass/height2.7
0.163†
⫺0.010
⫺0.029
⫺0.024
⌬ LV internal diameter
⫺0.034
0.075‡
0.045
⫺0.113†
⌬ LV interventricular septal thickness
0.166*
⫺0.072
⫺0.070
0.070
⌬ LV posterior wall thickness
0.187*
⫺0.059
⫺0.067
0.056
⌬ Relative wall thickness in end-diastole
0.153*
⫺0.081‡
⫺0.062
0.097‡
⌬ Relative wall thickness in end-systole
0.099†
0.011
⫺0.095‡
0.052
⌬ Left atrial dimension in systole
0.163*
0.065
⫺0.118†
⫺0.037
⌬ Isovolumic relaxation time
䡠䡠䡠
⫺0.120†
⫺0.026
0.022
⌬ E/A-ratio
䡠䡠䡠
䡠䡠䡠
⫺0.104†
⫺0.548*
⌬ Deceleration time
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
⫺0.194*
*P⬍0.001, †P⬍0.01, ‡P⬍0.05.
model (R⫽0.251), reduction in LV mass (␤⫽0.147), reduction in left atrial diameter (␤⫽0.121, all P⫽0.001), and
reduction in end-systolic RWT (␤⫽0.072, P⫽0.059) tended
to be independently associated with IVRT shortening. Because IVRT is closely negatively related to the rate of early
diastolic LV relaxation before the onset of LV inflow, IVRT
summates the effects of LV geometry and altered myocardial
properties on inflow.
Univariate analysis (Table 2) showed that increase in E/A
ratio correlated with reduction in BP, prolonged IVRT, and
increase in LV internal diameter in diastole and end-diastolic
RWT but not end-systolic RWT. Multivariate analysis
yielded a model (R⫽0.204) in which increased E/A ratio was
independently associated with reduced diastolic arterial BP
(␤⫽⫺0.137), prolonged IVRT (␤⫽⫺0.110, all P⬍0.01), and
reduction in end-diastolic RWT (␤⫽⫺0.082, P⬍0.05).
Univariate analysis (Table 2) showed that prolonged deceleration time correlated with smaller end-systolic RWT,
smaller left atrial dimension, and smaller E/A ratio. Multivariate analyses (R⫽0.171) showed that prolongation of
mitral valve deceleration time was independently associated
with reduced end-systolic RWT (␤⫽0.082), E/A ratio
( ␤ ⫽0.078, both P⬍0.05), and left atrial dimension
(␤⫽0.112, P⬍0.01).
Final univariate analysis (Table 2) showed that reduction in
atrial filling fraction correlated with reduced diastolic BP,
end-diastolic RWT, and E/A ratio, shortened deceleration
time and time-velocity integral, and increased LV internal
dimension. Reduced atrial filling fraction was independently
associated with both decreased diastolic BP (␤⫽ 0.116) and
increased LV internal dimension (␤⫽-0.102, both P⬍0.01) in
multivariate analysis (R⫽0.160, P⬍0.001).
Discussion
This study provides the first assessment of the relation of
changes in LV geometry to changes in diastolic LV function
during antihypertensive treatment in a large series of hypertensive patients with ECG-verified LV hypertrophy. This
study shows four new observations.
Antihypertensive treatment resulting in ⬇10% reduction in
LV mass results in a 3% reduction in left atrial diameter, 9%
shortened IVRT, and 10% decrease in atrial filling fraction,
and 9% and 7% increases in E/A ratio and mitral valve
deceleration time, respectively. The apparent paradoxical
prolongation of the mitral valve deceleration time with
shortening of IVRT may be due to improved active relaxation
and reduction of passive chamber stiffness associated with
reduction of end-systolic RWT26 as well as probable normalization of connective tissue.17,27
Our results support the finding by Yalcin and coworkers28
that 6 months antihypertensive treatment with perindopril led
to reduction in LV mass and left atrial volume and increased
E/A ratio. However, our study contrasts with a study by
Cuspidi et al7 in a smaller population (n⫽39) in which 6
months of antihypertensive treatment had no significant
effect on LV diastolic filling parameters.
Reduction of LV mass and RWT by ⬇10% are associated
with an increase in the proportion of the patients with normal
mitral valve flow pattern by 73%, reduction of abnormal
relaxation by 17%, and of the pseudonormal pattern by 60%,
with almost no change in restrictive pattern. The antihypertensive treatment normalized LV filling parameters in 20% of
patients, whereas 10% had LV filling abnormalities and 69%
remained unchanged.
Another major observation is that patients with reduction
in LV mass, as opposed to no change or an increase in LV
mass, had shortening of IVRT, reductions in left atrial
dimension and atrial filling fraction, and increase in E/A ratio
and mitral valve deceleration time, whereas no change in
diastolic filling parameters was seen in patients without LV
mass reduction. In parallel, patients with reduction of end-di-
Wachtell et al
astolic RWT, compared with patients without RWT reduction, had shortening of IVRT, reduction of in left atrial
dimension and atrial filling fraction, and increase in E/A ratio
and mitral valve deceleration time.
Finally, shortening of IVRT is independently associated
with LV mass reduction. Increase in E/A ratio is independently associated with reduction in diastolic BP, and finally,
increase in mitral valve deceleration time is independently
associated with decreased in mitral valve deceleration time.
This corresponds well with what is found in dogs,17 patients
with aortic stenosis and aortic valve replacement,29 and
hypertensive patients without LV hypertrophy who had RWT
regression.16 Decrease in hemodynamic overload and remodeling of the myocardium have been associated with a decrease in muscle mass but a “relative” increase in fibrous
tissue, which regresses less rapidly than myocardial tissue,
necessitating 7 years for normalization of myocardial stiffness in one study.29
Clinical Implications
Regression of hypertensive LV hypertrophy and of concentric
LV geometry is associated with partial normalization of
several LV diastolic filling parameters, including the IVRT,
E/A-ratio and atrial filling fraction. In multivariate analyses,
the associations were independent of the reduction in BP,
indicating direct effects of normalization of LV geometry on
diastolic filling parameters. The complexity of factors influencing LV diastolic filling is highlighted by the fact that the
deceleration time of early diastolic filling passive inflow
increased at the same time as the as the IVRT decreased. This
implies that the deceleration time at enrollment in the LIFE
echocardiography study was effected in opposite directions,
being lengthened by impaired relaxation and shortened by
increased LV stiffness due to increased relative wall thickness and probable alterations in myocardial connective tissue.
A strong relation between invasively-measured early diastolic
chamber stiffness and shortened deceleration time was reported in an experimental study by Little et al17 and in a
human study by Garcia et al.30 Treatment improved relaxation
predominated in shortening the IVRT while reducing chamber stiffness predominated by prolonging the deceleration
time of early diastolic transmitral flow. The improvement of
diastolic dysfunction parameters may contribute to the ability
of BP reduction to prevent congestive heart failure and
highlights the role of antihypertensive therapy in primary
prevention of congestive heart failure in hypertensive patients
with LV hypertrophy.31
Limitations of the Study
Data are analyzed in patients with ECG-verified LV hypertrophy, of whom 70% had echocardiographically verified LV
hypertrophy. Hence, our data may be representative of
patients with LV mass in the hypertrophied or high normal
range. No attempts were made to measure LV filling pressures, although it is likely that in outpatients volunteering for
a long-term treatment trial, they are in a relatively narrow
range of normal to mildly elevated levels. To simplify the
protocol, no measurements of pulmonary venous flow were
made, making it possible that the group with normal diastolic
Change in Diastolic LV Filling During Treatment
5
dysfunction may contain patients who should be classified as
“pseudonormal” and visa versa. The antihypertensive treatment regime is at the moment blinded and will remain so until
the LIFE study ends. Furthermore, because of the known
effect of ␤-blockers to reduce heart rate, the LIFE Steering
Committee has decided that change in heart rate during
treatment cannot be reported until the study is unblinded.
Therefore it was not possible to report findings in relation to
treatment with either atenolol or losartan. However,
␤-blockade has been shown to increase the deceleration time
of early diastolic transmitral flow in patients with dilated
cardiomyopathy.32 Therefore, where appropriate, data were
controlled for heart rate (data not shown), and this did not
alter any conclusions.
Acknowledgments
This study was supported by grants from Merck & Co, Inc, West
Point, Pa, and the Editor and Mrs Anders Kaarsens Foundation,
Copenhagen, Denmark. We thank Mary Paranicas for her valuable
work in reading echocardiograms and managing the database and
Anne-Grethe Thorn for her valuable help in preparing the manuscript. Furthermore, we would like to thank the LIFE echocardiography study investigators.4,15,19,20,33
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