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755
Progressive Left Ventricular Dysfunction and
Remodeling After Myocardial Infarction
Potential Mechanisms and Early Predictors
Peter Gaudron, MD; Christoph Eilles, MD; Ingrid Kugler; and Georg Ertl, MD
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Background. Left ventricular enlargement and the development of chronic heart failure are potent
predictors of survival in patients after myocardial infarction. Prospective studies relating progressive
ventricular enlargement in individual patients to global and regional cardiac dysfunction and the onset
of late chronic heart failure are not available. It was the aim of this study to define the relation between
left ventricular dilatation and global and regional cardiac dysfunction and to identify early predictors of
enlargement and chronic heart failure in patients after myocardial infarction.
Methods and Results. Left ventricular volumes, regional area shrinkage fraction in 18 predefined sectors
(gated single photon emission computed tomography), global ejection fraction, and hemodynamics at rest
and during exercise (supine bicycle, 50 W, 4 minutes, Swan-Ganz catheter) were assessed prospectively 4
days, 4 weeks, 6 months, and 1.5 and 3 years after first myocardial infarction. Seventy patients were
assigned to groups with progressive, limited, or no dilatation. Patients without dilatation (n=38)
maintained normal volumes and hemodynamics until 3 years. With limited dilatation (n= 18), left
ventricular volume increased up to 4 weeks after infarction and stabilized thereafter, depressed stroke
volume was restored 4 weeks after infarction and then remained stable at rest. Wedge pressure during
exercise, however, progressively increased. With progressive dilatation (n = 14), depressed cardiac and
stroke indexes were also restored by 4 weeks but progressively deteriorated thereafter. Area shrinkage
fraction as an estimate of regional left ventricular function in normokinetic sectors at 4 days gradually
deteriorated during 3 years, but hypokinetic and dyskinetic sectors remained unchanged. Global ejection
fraction fell after 1.5 years, whereas right atrial pressure, wedge pressure, and systemic vascular
resistance increased. By multivariate analysis, ejection fraction and stroke index at 4 days, ventriculographic infarct size, infarct location, and Thrombolysis in Myocardial Infarction trial grade of infarct
artery perfusion were significant predictors of progressive ventricular enlargement and chronic
dysfunction.
Conclusions. Almost 26% of patients may develop limited left ventricular dilatation within 4 weeks after
first infarction, which helps to restore cardiac index and stroke index at rest and to preserve exercise
performance and therefore remains compensatory. A somewhat smaller group (20%) develops progressive
structural left ventricular dilatation, which is compensatory at first, then progresses to noncompensatory
dilatation, and finally results in severe global left ventricular dysfunction. In these patients, depression of
global ejection fraction probably results from impairment of function of initially normally contracting
myocardium. Early predictors from multivariate analysis allow identification of patients at high risk for
progressive left ventricular dilatation and chronic ventricular dysfunction within 4 weeks after acute
infarction. (Circulation 1993;87:755-763)
KEY WORDs * dilatation, ventricular * heart failure * hemodynamics * prognosis
T he cumulative incidence of heart failure rises in the
years after infarction, and its clinical manifestation is associated with an adverse prognosis.'
Dilatation of the left ventricle may play an important
active role in the development of chronic heart failure,2-8
and left ventricular volume is the most powerful predictor
of survival in patients with coronary heart disease.9-11
From the Departments of Medicine (P.G., I.K., G.E.) and
Nuclear Medicine (C.E.), Julius-Maximilians-University, Wurzburg, FRG.
Supported by grants Er 100/3-3 and Ko 210/9-2 from the
Deutsche Forschungsgemeinschaft.
Address for correspondence: Dr. Peter Gaudron, Medizinische
Klinik, Universitat Wurzburg, Josef-Schneider-Strasse 2, 8700 Wurzburg, FRG.
Received April 2, 1992; revision accepted November 11, 1992.
Deterioration of cardiac performance correlates with the
degree of dilatation in experimental infarction,3 and left
ventricular dilatation precedes deterioration of exercise
performance in patients.8 However, the relation of left
ventricular dilatation to chronic heart failure is based
primarily on indirect evidence and has not been carefully
studied in individual patients. Dilatation of infarcted and
noninfarcted sections of the left ventricle has been observed.7 The time course and interaction of regional
function of noninfarcted and infarcted myocardium and
global left ventricular dysfunction have not been assessed
in detail. One reason for lack of this information may be
the chronicity of the process, which requires an observation time of several years.
Animal experiments have defined myocardial infarct
size as a major determinant of left ventricular dilata-
756
Circulation Vol 87, No 3 March 1993
tion,4 and recent clinical studies have confirmed this
observation.6 Infarct size, prognosis, and ejection fraction are closely related; the latter has been used to
select patients prone to ventricular dilatation.2 In patients, left ventricular dilatation appears to be the result
of a long-term interactive process of multiple variables.
Their relative importance for dilatation and heart failure has not been assessed, and no prospective criteria
are available to identify individual patients who may be
at high risk for progressive dilatation and chronic heart
failure.
The objectives of the present study were to determine
hemodynamic consequences at rest and during exercise
of progressive left ventricular dilatation, the time course
of regional function of noninfarcted and infarcted myocardium from 4 days until 3 years after infarction, and
whether variables that are likely to predict progressive
left ventricular dilatation and chronic dysfunction can
be identified early after infarction.
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Methods
Patient Population and Group Assignment
Acute myocardial infarction was confirmed by ECG
and creatine kinase enzymes in 193 patients admitted to
our intensive care unit from January 1987 to September
1988. Of these, 99 matched our inclusion criteria, which
were age <70 years, first infarction, and signed informed consent. Patients with clinical signs of heart
failure or cardiogenic shock in the first week after
myocardial infarction, unstable angina, life-limiting
noncardiac disease, conditions precluding cardiac catheterization or exercise testing, or delayed (>6 days)
See p 1037
hospital admission for acute infarction were excluded.
Thirteen patients refused to participate in the study.
Later, further exclusions were due to reinfarction (four
patients) and death before the 3-year assessment (three
patients); an additional nine patients did not adhere to
the follow-up protocol. Patients received conventional
drug therapy according to individual needs, which remained the responsibility of the attending physician.
The currently prescribed drug therapy was monitored,
and changes were analyzed over time within and between groups. Thrombolytic therapy was administered if
not contraindicated according to currently accepted
criteria. Patients were categorized according to the
individual course of left ventricular end-diastolic volume index (EDVI). Patients in whom EDVI rose (>8%
of preceding EDVI) with each subsequent examination
were assigned to a group with "progressive dilatation."
Patients with a rise (>8%) of EDVI until 6 months but
without further increase thereafter were assigned to a
group with "limited dilatation." A third group consisted
of patients without any increase of EDVI beyond 8%
from baseline ("no dilatation").
Radionuclide Studies
Gated blood pool radionuclide ventriculograms were
sequentially obtained in each patient as described in
detail elsewhere.8,12 In brief, erythrocytes were labeled
in vivo by 15-20 mCi [9'Tc]pertechnetate. The angiograms were acquired by a rotating camera (gated single
photon emission computerized tomography [gated
SPECT]) in 32 projections or 180°, respectively, from
the right anterior oblique to the left posterior (280300°/100°-1200) view. Radionuclide counts were collected for 40 seconds per projection and cardiac cycle
gated into eight frames triggered by ECG. Coronal
tomograms in 900 position to the long axis of the left
ventricle were reconstructed, which served to calculate
left ventricular volumes by Simpson's rule. Automatic
edge finding of the left ventricle was used after application of a region of interest (PDP 1184 computer,
Digital Equipment Co.). The region of interest was
divided into 90-150 segments originating from its center
of gravity and then transformed in a polar coordinate
system. End-diastolic and end-systolic volumes were
defined as maximum or minimum, respectively, of the
sum of all coronal tomograms of the left ventricle and
related to body surface area as EDVI and end-systolic
volume index. Left ventricular volume measurements by
gated SPECT were previously validated by contrast
angiography.6 Normal values for left ventricular end-diastolic and end-systolic volumes obtained from 18 persons without cardiac disease were 75±3 and 29±2
mL/m2, respectively. Immediately after the gated
SPECT, planar radionuclide ventriculography was performed in a 300 ("best septal") left anterior oblique view
for determination of global left ventricular ejection
fraction according to standard techniques (16 frames
per heart cycle, automatic region of interest detection
for each frame of the cardiac cycle).
Regional Wall Motion
Regional left ventricular wall motion was assessed by
gated SPECT using area shrinkage fraction in 18 predefined regions of interest of the left ventricle. The
difference between end-diastolic and end-systolic area
of each region was calculated and expressed as the
percentage of end-diastolic area. To define these regions, the 300 right anterior oblique plane of the left
ventricle was divided clockwise from 00 to 3600 into 18
equidistant radial sectors originating from the center of
gravity. The position of 00 was determined by Fourier
analysis as the change from atrial to ventricular phase of
contraction. Normal values for wall motion were derived from measurements in 18 patients without cardiac
disease. Normokinetic or abnormally contracting segments of patients of the present study were defined as
sectors with area shrinkage fraction values within or
outside 2 SD of the normal population, respectively. To
account for variation in magnitude of normal wall
motion in different regions and to allow comparisons
between different regions of the same heart and between different hearts, the extent of wall motion abnormality in abnormally contracting segments was standardized by means of a regional area shrinkage fraction
score.13 This score relates area shrinkage fraction of
sectors with abnormal wall motion (ASFa) to the mean
value for this sector (ASF.) and its variability (standard
deviation, SDQ) in the normal population: Score=
(ASFa-ASFn)/SDn. Area shrinkage fractions and score
values of sectors defined as "normokinetic" or "abnormally contracting segments" at 4 days were averaged
and followed sequentially until 3 years after infarction
in patients with progressive, limited, or no left ventricular dilatation.
Gaudron et al Remodeling 3 Years After Infarction
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Cardiac Catheterization
In all patients, left and right heart catheterization was
performed 3-5 weeks after myocardial infarction. The
right brachial artery and a concomitant vein were
exposed after local anesthesia, and coronary angiography in multiple views and biplane left ventricular angiography were performed by use of a Sones catheter.
Infarct size was quantified as the percentage of akinetic
and dyskinetic segment length of the total end-diastolic
circumferences84 of the biplane contrast left ventriculogram obtained 4 weeks after infarction. The presence of
a left ventricular aneurysm was assessed during cineangiography and defined as a paradoxical systolic expansion of a portion of the ventricular wall with or without
protrusion during diastole.'s Perfusion of the infarct
region by the infarct-related coronary artery was assessed according to the criteria of the Thrombolysis in
Myocardial Infarction (TIMI) trial.16 A grade of 0
indicated no flow of contrast beyond the point of
occlusion; 1, penetration with minimal perfusion; 2,
partial perfusion; and 3, complete perfusion. These
measurements were performed by an operator blinded
for the other measurements.
Right heart catheterizations at 4 days, 6 months, and
1.5 and 3 years were performed from a transcutaneous
right or left cubital access by standard Seldinger techniques and a Swan-Ganz thermodilution catheter (7F
Edwards). A Siemens Sirecust 404-1 A cardiac output
computer calibrated for 10.0 ml iced injectate was
applied. At each time point, three measurements (coefficient of variation, 7.0+2.9%) were obtained, and the
average was calculated. Left ventricular stroke volume
was calculated by division of cardiac output by heart
rate and related to body surface area and expressed as
stroke volume index.
Protocol
Four days (2-6 days), 4 weeks (3-5 weeks), 6 months
(5-8 months), 1.5 years (16-20 months), and 3 years
(34-38 months) after admission for acute infarction,
gated SPECT, planar radionuclide ventriculography,
and right heart catheterization were performed simultaneously at rest. At 4 weeks, 6 months, and 1.5 and 3
years, right heart catheterization was repeated during
supine bicycle exercise. Left ventricular ejection fraction, pulmonary capillary wedge pressure, and cardiac
output were measured after baseline resting parameters
had been obtained and during steady-state conditions
after 4 minutes at an exercise level of 50 W. In addition,
4 weeks after admission, coronary angiography and
biplane cineangiography were performed in all patients.
No attempt was made to control medical or any other
therapy. Patients were fasting the night before and off
medication for the previous 24 hours. This protocol was
approved by our interdisciplinary University Ethics
Committee.
Statistical Analysis
To test for differences between two groups, an unpaired t test was used. To test for significant changes of
variables over time (4 days, 4 weeks, 6 months, 1.5 years,
3 years) within each study group (progressive dilatation,
limited dilatation, no dilatation), one-way ANOVA and,
if significant, multiple comparison procedures were per-
757
formed.17 One-way ANOVA and appropriate multiple
comparison procedures were performed at 4 days, 4
weeks, 6 months, 1.5 years, and 3 years to test for
differences between the three study groups. To test for
differences in discrete variables, a x2 statistic was applied. Variables were subjected to multivariate discriminant analysis'8 based on the stepwise addition of the
variable that contributed the largest increase in the "Rao
V"9 value. These computations were performed by the
programs of the Statistical Package for the Social Sciences (SPSS Inc., Chicago). Analyzed variables included
sex, age, body weight, ventriculographic infarct size,
infarct location, TIMI grade of infarct-related artery
perfusion, hypertension, diabetes mellitus, drug therapy,
coronary bypass surgery, percutaneous coronary angioplasty, ejection fraction, stroke volume index, left ventricular end-diastolic and end-systolic volume index on
day 4 and at 4 weeks, and the change of ejection fraction,
stroke volume index, left ventricular EDVI and endsystolic volume index from 4 days to 4 weeks after
infarction. The factors that had significant but statistically independent relations to the three study groups
were then weighted to construct the discriminant function that best maximized the multivariate F ratio and
minimized the Wilks' lambda value. Using these weights,
it was possible to place each patient along the unidimensional discriminant function by multiplying any factor the
patient possessed by the appropriate weight. By use of
the unstandardized canonical discriminant function coefficients, the discriminant score for each patient was
calculated. This score was obtained by multiplying the
coefficients (B) by the values for the selected variables
(X), summing these products, and adding the constant
(Bo): Score=B0+BlX,+B2X2+. . .+BpXp. For each
study group (progressive dilatation, limited dilatation, no
dilatation), the mean score and its 95% confidence
interval were calculated. Statistical significance was assumed at p<0.05. Only two-sided p values were used.
Results are presented as mean±SEM.
Results
Study Groups and Baseline Patient Data
Baseline data are shown for the individual groups in
Table 1. Of 70 patients, 38 had stable left ventricular
volumes, 18 had limited dilatation, and 14 had progressive left ventricular dilatation up to 3 years after myocardial infarction. Anterior infarct location was more
common in patients with progressive or limited dilatation. Ventriculographic infarct size was larger in patients with progressive than in those with limited dilatation and in patients with limited than in patients
without dilatation. In addition, the TIMI grade, which
assesses the arteriographic contrast flow in the infarct
artery, was reduced in patients with progressive dilatation, who also had a higher fraction of left ventricular
aneurysms.
Left Ventricular Volumes and Hemodynamic
Measurements at Rest
Time course of left ventricular volume index, ejection
fraction, systemic vascular resistance, right atrial pressure, and mean arterial pressure is shown in Figure 1.
By definition, left ventricular volume indexes were
stable throughout the study in patients with no dilata-
Circulation Vol 87, No 3 March 1993
758
TABLE 1. Assignment to Study Groups and Baseline
Patient Data
Study group
No
Limited
Progressive
dilatation
dilatation
dilatation
38
18
14
Number of patients
34/4
17/1
13/1
Sex (male/female)
56±1
53±2
58±3
Age (years)
10 (26)
10 (56)
6 (43)
Hypertension, n (%)
Infarct location
12 (32)
11* (61)
8* (57)
Anterior, n (%)
26 (68)
7 (39)
6 (43)
Inferior, n (%)
7±1
15±3t
20±3*t
Infarct size (%)
22 (58)
12 (67)
9 (64)
Thrombolysis, n (%)
2.2±0.2
2.1±0.2
1.3±0.3t
TIMI grade
10 (26)
13 (72)t
10 (71)t
Aneurysm
TIMI, Thrombolysis in Myocardial Infarction trial. Values are
given as mean±SEM.
*p<0.05 vs. no dilatation; tp<0.05 vs. limited dilatation.
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tion, increased during 4 weeks and stabilized thereafter
in patients with limited dilatation, and increased progressively in patients with progressive dilatation. Volumes tended to be larger at the beginning in patients
with dilatation, but these differences were statistically
not significant. From 4 weeks on, left ventricular volume
indexes were larger in patients with progressive dilatation. In patients with limited dilatation, EDVI decreased after 6 months. End-systolic volume stabilized
(mlni')
50 T
Left Ventricular End-Diastolic
Volume Index
(ml/m'
100-
125100
Regional Area Shrinkage Fraction
Normokinetic or abnormally contracting segments
did not change from 4 days until 3 years in patients
without or with limited left ventricular dilatation and
are, therefore, not shown. Figure 2 shows the time
course of radionuclide area shrinkage fraction in segments that were normokinetic and of area shrinkage
fraction scores of abnormally contracting segments 4
days after acute infarction in patients with progressive
left ventricular dilatation. Area shrinkage fraction
scores of segments defined as abnormal at day 4 were
similar at each reexamination, and the number of
abnormally contracting segments did not change (5.4±2
at 4 days and 5.3 ±2 at 3 years). In contrast, segments
that were normokinetic 4 days after infarction remained
unchanged until 4 weeks but then gradually deteriorated until 3 years. Since these segments remained
within the confidence interval of the normal population,
they were not abnormally contracting segments by definition. Area shrinkage fractions instead of score values
are therefore given.
Left Ventricular End-Systolic
Volume Index
*+11
*+4
75.
in this group. Patients with no or limited dilatation had
stable ejection fractions, systemic vascular resistance
indexes, and mean atrial and systemic arterial pressures.
Left ventricular ejection fraction was already reduced
early after infarction in the group with progressive
dilatation, and a further decrease of ejection fraction
was observed at 1.5-3 years after infarction. Concomitantly, systemic vascular resistance index and right atrial
pressure rose.
;
+$+
50
75.
25
50
0
4 days 4 weeks 6 months 1.5 years 3 years
Systemic Vascular Resistance Index
(dye - swc* cm4
*
mI
3000 T
A e
2800
2600{
2400k
22002000
0
j'
§
~
0
50.
25
t
25;>
*;+
Mean Right Atrial Pressure
0
I
0
+
-
+;
+
+
*;''*S
4 days 4 weeks 6 months 1.5 years 3 years
Mean Systemic Arterial Pressure
(mmHg)
12 T
(mmHg)
140 T
10o
8
6
120 t
100
80
.4*
604
2
w
754
gw#
4 days 4 weeks 6 months 1.5 years 3 years
4.
4 days 4 weeks 6 months 1.51 years 3 years
Left Ventricular Ejection Fraction
t(i)
01
4 days 4 weeks 6 months 1.5 years 3 years
4 days 4 weeks 6 months 1.5 years 3 years
FIGURE 1. Line graphs indicate course of left ventricular end-diastolic and end-systolic volume indexes, ejection fraction,
systemic vascular resistance index, and mean right atrial and systemic arterial pressures in patients with progressive (o), limited
(A), and no (-) left ventricular dilatation from 4 days until 3 years after myocardial infarction. Values are given as mean +SEM;
p<O.OS, * vs. limited dilatation; + vs. no dilatation; $ vs. 4 days; § vs. 4 weeks; ¶ vs. 4 days, 4 weeks, and 6 months; 11 vs. 1.5
years.
Gaudron et al Remodeling 3 Years After Infarction
40
Normokinetic segments (area shrinkagetractison)
~35
30-
-5
-10
Abnormally contracting segments
(area shrinkage fraction score)
e|
4 days 4 weeks 6 months 1.5 years 3 years
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FIGURE 2. Line graphs show the time course ofradionuclide
regional left ventricular contraction in the patient group with
progressive left ventricular dilatation (n=14) from 4 days
until 3 years after myocardial infarction. Wall motion in
segments with reduced regional area shrinkage fraction at 4
days after infarction (abnormally contracting segments) did
not change. Extent of wall motion abnormality in abnormally
contracting segments was quantified by an area shrinkage
fraction score that relates actual segmental area shrinkage
fraction to the respective value and its variability of the
normal population and is, therefore, without dimension. Wall
motion in segments with normal regional area shrinkage
fraction at 4 days (normokinetic segments) deteriorated
gradually beyond 4 weeks until 3 years after infarction. Values
are mean ±SD. $ p<O.05 vs. 4 days; #p<0.05 vs. 6 months.
Serial Hemodynamic Evaluation at Rest
and During Exercise
In patients with no dilatation (lower panels of Figure
3), cardiac index, stroke index, and pulmonary capillary
wedge pressure at rest were stable from 4 days until 3
years after infarction. During steady-state exercise,
these parameters rose significantly. In the group with
limited dilatation (middle panels of Figure 3), cardiac
index and stroke index at rest rose significantly from 4
days to 4 weeks after infarction. This occurred at stable
wedge pressures at rest. After 4 weeks, stroke index and
cardiac index remained stable at rest and rose to an
extent with exercise, which was similar to in the group
without dilatation except for wedge pressure, which rose
progressively over time during exercise. In patients with
progressive dilatation (upper panels of Figure 3), resting cardiac index at 4 days was depressed compared
with patients with no dilatation and stroke index at 4
days was depressed compared with patients with no and
with limited dilatation. Cardiac index and stroke index
improved from 4 days to 4 weeks after infarction at
unchanged wedge pressure at rest. With progressive
dilatation, cardiac index and stroke index both fell to
values similar to those at 4 days and were significantly
depressed compared with patients with limited and
without dilatation. Wedge pressures were elevated at
rest 1.5 and 3 years after infarction, and exercise
hemodynamics deteriorated. The ability to augment
stroke index during exercise was preserved for 6 months
but was lost thereafter; wedge pressures rose to higher
levels with each catheterization reassessment. Cardiac
index increased significantly during exercise until 3
years. The extent to which cardiac index rose, however,
decreased gradually and was generally less than in the
groups with limited and without dilatation.
759
Clinical Events
Except for the development of the New York Heart
Association (NYHA) functional class, no differences
were observed with regard to clinical events. At 3 years,
NYHA class I was registered less and class III more
often in patients with progressive dilatation than in the
other study groups (Table 2).
Drug Therapy
Table 3 shows that nitrates were taken less often in all
groups after 3 years compared with 4 days after infarction. The percentage of patients with angiotensin converting enzyme inhibitors increased and with al-blockers
decreased in the group with progressive dilatation.
Digitalis was taken more often by patients with limited
and progressive dilatation at 3 years compared with 4
days after infarction.
Multivariate Discriminant Analysis: Estimation of
Risk for Progressive Left Ventricular Dilatation
Variables that were selected by multivariate discriminant analysis are listed in Table 4 according to decreasing
statistical significance. Ejection fraction on day 4, ventriculographic infarct size (percent akinesis and dyskinesis of
end-diastolic left ventricular circumference), infarct location, stroke index at day 4, and the rate of arteriographic
contrast flow in the infarct artery (TIMI grade) were
significant predictors of development of progressive, limited, or no left ventricular dilatation. These variables
classified 89% of the patients correctly. Using the discriminant coefficients listed in Table 4, a "risk equation" can
be provided: Score= -2.593+0.595 x (infarct location:
1=anterior, 2=inferior)+0.0427x(ejection fraction day
4) -0.132x (ventriculographic infarct size)+0.142x (stroke
index 4 days)+0.156x(TIMI grade). For each patient, the
discriminant score value was calculated and averaged for
each study group. As shown in Table 5, there is no overlap
of the 95% confidence intervals of the score means, and
the differences among the groups are highly significant.
Discussion
Progressive Dilatation and Development of Global
Chronic Cardiac Dysfunction
This study demonstrates that progressive left ventricular dilatation is associated with progressive global
cardiac dysfunction. Previous studies provide indirect
evidence that cardiac dysfunction may be linked to
ventricular dilatation. For example, wedge pressure and
pulmonary artery pressure tend to rise within 1 year of
ventricular dilatation,19 and exercise duration is reduced in patients with excessive distortion of left ventricular shape.20 Ejection fraction decreases with dilatation at 4 weeks after infarction but then remains
constant in the subsequent 5 months of dilatation,
whereas stroke index does not decrease.21 In contrast, in
the present study, direct hemodynamic evidence is
provided in individual patients that chronic cardiac
dysfunction develops insidiously in close relation to
progressive dilatation within 3 years after infarction.
Dilatation of the left ventricle precedes any detectable
deterioration of global cardiac performance at rest by 6
months. In fact, between 4 days and 4 weeks after
myocardial infarction, cardiac index and stroke index
Circulation Vol 87, No 3 March 1993
760
Cardiac Index (I/minom2)
Progressive Dilatation
50.
6
5.
4
3
~~~~50
i
40
30
4j. _
01
§
~
+ 1 ,,
s.
40-
30-
0
Limited Dilatation
Limited Dilatation
60T
7T.
Limited Dilatation
50
6.
5.f
4f
40j.
40
1T=
4:
9
9
+9#11
301.
20..
3
10~
2,
ol
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No Dilatation
60
7-
0
5.
4
No Dilatation
No Dilatation
50
so-
40
40.
30
6-
0
-
] n.s. 20.
Tpi
10
~~~
~~~*+§
,*+
0
*+§
WeEdge Pressure (mmHg)
pIrogressive Dilatation
Stroke Volume Index (mi/M2)
Progressive Dilatation
60.
30
4 days 4 weeks 6 months 1.5 years 3 years
0
4 days 4 weeks 6 months 1.5 years 3 years
401
4
days 4 weeks 6 months 1.5 years 3 years
FIGURE 3. Bar graphs demonstrate the development of cardiac index (left panel), stroke index (middle panel), and mean
pulmonary capillary wedge pressure (right panel) until 3 years after myocardial infarction. Measurements of patients with
progressive, limited, and no dilatation are given in the upper, middle, and lower part of each panel, respectively. Mean values and
standard errors for measurements at rest are indicated by the base (open boxes) and during supine bicycle exercise at 50 W by the
top (filled boxes) of each column. Except for stroke index in patients with progressive dilatation at 1.5 and 3 years, all values were
significantly higher during exercise than measurements at rest. p<O.OS, * vs. limited dilatation; + vs. no dilatation; $ vs. 4 days;
§ vs. 4 weeks; vs. 4 days, 4 weeks, and 6 months; # vs. 6 months; 11 vs. 1.5 years; n.s. denotes no statistical significance between
rest and exercise.
improve and pronounced left ventricular dilatation is
observed.
During exercise, however, the detrimental nature of
postinfarction dilatation becomes evident at 4 weeks,
when stroke index is reduced and wedge pressure
increases compared with patients without dilatation.
TABLE 2. Clinical Events
Study group
No LV
Progressive LV Limited LV
dilatation
dilatation
dilatation
Total
(n = 18)
(n= 14)
No.
(n=38)
3
7
3
13
ACVB
3
2
1
6
PTCA
NYHA (4 weeks/3 years)
I
20/18
1/3
4/0
9/6
II
16/20
16/12
1/3
III
2/0
1/7
IV
0/0
0/0
0/1
LV, left ventricular; ACVB, aortocoronary bypass grafting;
PTCA, percutaneous transluminal coronary angioplasty; NYHA,
New York Heart Association functional class.
Progressive rise of wedge pressure in patients with
limited dilatation suggests that activation of FrankStarling compensation is required to maintain stroke
index during exercise. In patients with progressive dilatation, cardiac index and stroke index deteriorate gradually after 6 months, and wedge pressure increases, first
during exercise and later at rest. Elevation of systemic
vascular resistance index, reduced stroke index, and
reduced ejection fraction concurrent with 3 years of
progressive dilatation indicate severe cardiac dysfunction at rest. Elevated right and left ventricular filling
pressures may indicate transition to congestive dysfunction consistent with a shift of patients to higher NYHA
functional classes. These measurements support the
concept that dilatation is a cause rather than a consequence of further decline of pump function. It was not
until 1.5 years after myocardial infarction that clear
hemodynamic signs of left ventricular dysfunction became apparent at rest. Recent studies show that development of heart failure may be postponed by therapy
with angiotensin converting enzyme inhibitors.22'23 In
accordance with the present study, the survival advantage provided by an angiotensin converting enzyme
Gaudron et al Remodeling 3 Years After Infarction
761
TABLE 3. Medications Given Patients at Various Time Points
4 Weeks
3 Years
4 Days
N
L
N
P
L
P
N
P
L
28*
20*
33*
45
28
39
65
65
72
Nitrates
3
5
17*
5
3
0
0
5
0
ACE inhibitors
17
11
20
21
39
40
34
65
33
Ca antagonists
0
10*
22*
0
11
0
3
0
11
Digitalis
21
20
7
5*
22
15
20
30
17
(-Blocker
3
5
28
0
10
0
17
10
28
Diuretics
limited
dilatation;
L,
dilatation;
medication.
progressive
receiving
respective
of
P,
patients
Numbers give percentage
N, no dilatation; ACE, angiotensin converting enzyme; Ca, calcium.
*p<0.05 vs. 4 days.
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inhibitor in postinfarction patients does not become
apparent until 1 year after infarction.22
However, dilatation of the left ventricle after infarction is not necessarily progressive and does not necessarily portend a poor outcome. In patients of the
present study, left ventricular dilatation occurred in
46% and was progressive in only 20%. This is in
accordance with previous studies in which dilatation
occurred in about 42%6,8,21,24 but was progressive within
6 months after infarction in only 16%.25 An acutely
depressed stroke index at rest was restored to normal
within 2-4 weeks after infarction with early dilatation in
the present and in previous studies6'8.21,24 and therefore
has been named "compensatory dilatation."8 However,
sequential hemodynamic and volumetric observations
beyond 6 months have not been available previous to
this report.
Progressive Dilatation and Development of Regional
Cardiac Dysfunction
Progressive deterioration of global left ventricular
ejection fraction in patients with progressive dilatation
was most likely due to deterioration of function of
regions with wall motion classified as normal by radionuclide area shrinkage fraction at 4 days. Regions with
hypokinesia, akinesia, and dyskinesia showed no significant changes of area shrinkage fraction over time. The
mechanism of deteriorating function in regions with
initially normal wall motion remains unclear. It may be
speculated that systolic or diastolic dysfunction of noninfarcted myocardium as sequelae of regional hypertrophy may have occurred. Contractile function in cardiac
muscle with experimental hypertrophy eventually dete-
riorates.26 Increased preload (wedge pressure) should
improve the force of contraction by recruitment of
Frank-Starling mechanism. However, increased afterload (systemic vascular resistance and left ventricular
dilatation) in the presence of limited preload reserve
could cause afterload mismatch and thereby depression
of cardiac performance.27 In the recent Study of Left
Ventricular Dysfunction (SOLVD), neurohumoral activity was already elevated in patients with asymptomatic or minimally symptomatic left ventricular dysfunction.28 Thus, systemic vasoconstriction may be the result
of very early compensatory neurohumoral activation to
maintain blood pressure in view of reduced myocardial
function, stroke volume, and cardiac index. Further
studies are needed to analyze the interaction of contractility and diastolic function of residual myocardium,
global hemodynamics, and neurohumoral activity in the
years after myocardial infarction.
It is unlikely that hemodynamic deterioration was due
to additional loss of contractile myocardium or progression of coronary artery disease, since patients with
reinfarction were excluded, those with critical stenoses
received coronary bypass surgery or angioplasty, and
serial exercise ECGs were negative. Analysis of therapeutic interventions indicates that neither cardiac depressant drugs (e.g., 3-adrenergic blockers) nor revascularization procedures account for the remodeling. Of
interest, 3-blockers were frequently stopped and vasodilators instituted in the group with progressive dilatation.
Potential Determinants and Early Predictors of
Progression to Failure
Several variables have been identified that predict an
increase in left ventricular volume after myocardial
TABLE 4. Risk Factors for Left Ventricular Dilatation Identified by Multivariate
the Study Groups
Risk factor
Multivariate analysis
Significance Discriminant-function
coefficient*
level
0.132
Ventriculographic infarct size (%) p<0.00001
0.0427
4
p<0.00001
fraction
day (%)
Ejection
0.595
p<0.00001
Infarct location (% anterior)
0.142
p<0.001
Stroke index day 4 (mLlm2)
0.156
p=0.044
TIMI grade
*Unstandardized canonical discriminant function coefficients.
tConfidence interval in parentheses.
*p<O.OS vs. limited dilatation; §p<0.05 vs. no dilatation.
Analysis and Univariate Relations Among
Univariate analysis
Mean value and 95% confidence intervalt for risk factor
No
Limited
Progressive
dilatation
dilatation
dilatation
7 (5-11)
15 (7-24)§
20 (14-27)t§
52 (47-60)
63 (54-64)
39 (34-46)§
32%
61%§
57%§
40 (35-43)
38 (32-39)
31 (25-364§
2.1 (1.7-2.6)
2.2 (1.8-2.6)
1.3 (0.6-1.9)§
762
Circulation Vol 87, No 3 March 1993
TABLE 5. Average Discriminant for Study Groups
Discriminant score
n
Mean
95% Confidence interval
Study group
-2.596, - 1.130
Progressive dilatation 14 - 1.963 * t
-0.739, 0.300
18 -0.219t
Limited dilatation
+0.871,1.466
38 +1.169
No dilatation
*p<0.00001 vs. limited dilatation; tp<0.00001 vs. no dilatation.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
infarction. These include infarct size3,21,29 and the location (anterior) of the infarct.25 A patent infarct-related
artery is also associated with a smaller left ventricular
volume30 and better survival in patients after myocardial
infarction.31,32 But their relative importance and predictive value in identifying patients at high risk for progressive dilatation and heart failure are not known.
Multivariate analysis of the present data identifies variables that significantly and independently correlate with
progressive dilatation and chronic ventricular dysfunction. Values for these variables and their discriminant
coefficients listed in Table 4 may be entered into a risk
equation. By this, a score value can be calculated for a
single patient. This allows one to estimate the probability that a patient will develop one of our three postmyocardial infarction patterns. Since the variability of
the score mean for the groups in the present study is
small (no overlap of 95% confidence interval in Table
5), the likelihood of belonging to a certain group is very
high if the score value of a patient is close to the mean
value of the respective group. If applied to the population of the present study, 89% of the patients were
classified correctly by the selected variables. Although
left ventricular volumes at 4 weeks are highly significantly correlated (p<O.OO1) with the percentage of
akinesis and dyskinesis, neither end-systolic nor end-diastolic ventricular volume at 4 days nor the change of
these volumes from 4 days to 4 weeks is a significant
predictor of late progressive dilatation and heart failure
in the population of the present study. This may be
because even patients with considerable dilatation
within 6 months after infarction may eventually demonstrate only limited dilatation. If ventriculographic infarct size and TIMI grade, which may not be routinely
available in many institutions, were omitted from multivariate analysis, only 71% of the patients could be
classified correctly, and there was considerable overlap
of the confidence intervals of the score means among
the groups. Thus, the predictive value of the variables
listed in Table 4 is highest if they all are used together.
Multivariate discriminant analysis has been successfully
applied in various clinical problems.18'33 But it is important to note that variables and coefficients selected by
multivariate discriminant analysis must be validated by
prospective application, and conclusions from this study
should be applied only to populations similar to the
present study. Recent preventive studies show that
ventricular dilatation34'35 and progression to symptomatic congestive heart failure can be reduced in patients
with chronic hemodynamic dysfunction,22'23 and survival
may be improved in patients after infarction by an
angiotensin converting enzyme inhibitor.22 However,
many patients who are not destined to have progressive
disease have been treated to prevent adverse outcomes
in the subgroup at risk. The predictive variables identi-
fied in the present study may be used to select patients
at high risk for late cardiac failure for early intervention
after infarction. By this approach, unnecessary preventive therapy may be avoided in the 80% of patients with
low probability of development of chronic heart failure.
Multivariate analysis of the present study suggests that
progression from dilatation to dysfunction is multifactorial. Therefore, early multifactorial interventions
might be necessary to arrest the process of myocardial
remodeling before left ventricular dilatation has
occurred.36
Acknowledgments
We gratefully acknowledge the help of Dr. Gary S. Francis,
University of Minnesota Medical School, Minneapolis, who
kindly participated in the final writing of the manuscript. The
authors appreciate the great support from our technicians
Carmen Bundschuh, Charlotte Dienesch, and Ingrid Wendl
and the secretarial assistance of Christel Wolff.
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Progressive left ventricular dysfunction and remodeling after myocardial infarction. Potential
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P Gaudron, C Eilles, I Kugler and G Ertl
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Circulation. 1993;87:755-763
doi: 10.1161/01.CIR.87.3.755
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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