Ventricular
remodeling
C.A. Visser
Department of Cardiology, VU University Medical Center, Amsterdam,
The Netherlands. e-mail cardiol@vumc.nl
During the past 20 years it has been acknowledged
that large transmural myocardial infarcts in particular may result
in complex alterations in left ventricular architecture, involving
both the infarcted and noninfarcted zone. These alterations, usually
referred to as ‘left ventricular remodeling’, can profoundly affect
the patient’s prognosis.
From a clinical point of view, left ventricular remodeling is
a dynamic process, starting in the acute phase with infarct expansion
and progressing to left ventricular dilatation and hypertrophy.[1]
The remodeling process has regional and global effects on wall
thickness and chamber size, shape, and function.
Full patency of the infarct-related artery is crucial for reducing
both infarct expansion in the early phase of infarction and subsequent
left ventricular enlargement.[2] There is increasing
evidence to support the use of late reperfusion therapy, ie, after
the 6-h window, and thus beyond the timeframe for myocardial salvage.
Furthermore, studies investigating residual stenosis or reocclusion
after reperfusion therapy support efforts to establish full patency
of the infarct-related artery and to maintain patency in the long
term. A subset analysis of the APRICOT trial (which evaluated
the efficacy of antithrombotics in preventing reocclusion) demonstrated
the deleterious effect of reocclusion without reinfarction, in
terms of increased left ventricular dilatation combined with a
lack of improvement in both global and regional left ventricular
function.[3]
Apparently, an open infarct-related artery may provide a scaffold
that limits the distensibility of the infarct zone and therefore
the extent of dyskinesia, and may also obviate left ventricular
dilatation.
Various pharmacological interventions have been studied, and some
show great promise in their ability to alter the remodeling process.
Based on experimental data, three large studies, SAVE,[4]
Consensus II,[5] and GISSI,[6]
examined the effects of ACE inhibitors in this respect, and all
of them showed a reduction in left ventricular dilatation. This
beneficial effect has been translated into improved survival with
long-term treatment.[7,8] It is generally agreed
and recommended that infarct patients with left ventricular dilatation
or heart failure be treated with ACE inhibitors without undue
delay.
Nitrate therapy has also been suggested to have a beneficial effect
on cardiac remodeling and survival, despite the fact that there
is no clear evidence of long-term benefit.[7,9]
Furthermore, there is growing evidence that inflammation may also
play a role in this respect, yielding potential new therapeutic
avenues.
Summary
Development of left ventricular remodeling after acute myocardial
infarction is a complex process influenced by multiple factors,
some of which have yet to be elucidated. Nevertheless, a variety
of potential targets for limiting postinfarct remodeling have
been identified. It is clear, however, that a successful strategy
is likely to involve a combination of interventions that provide
additive, or even synergistic, benefits by altering one or more
factors that influence this process.
Finally, based on current evidence, a rational strategy for preventing
left ventricular remodeling should involve intervention starting
very early after infarction, spanning the entire healing process,
and continuing well beyond.
References
1. Visser CA, Delemarre BJ, Peels K. Left ventricular
remodeling following anterior wall myocardial infarction. Am J
Cardiac Imaging. 1992;6:127–133.
Reperfusion of the infarct-related coronary
artery limits left ventricular expansion beyond myocardial
salvage.
Marino P, Destro G, Barbieri E, Bicego D.
Division of Cardiology, University of Verona, Italy.
Previous echocardiographic data from the Gruppo Italiano per lo
Studio della Streptochinasi nell' Infarto Miocardico (GISSI 1)
trial suggest that the relation between left ventricular
end-systolic volume and infarct size could be altered by
thrombolysis, which would exert a restraining effect on
end-systolic volume beyond its reducing effect on infarct size.
Thus in 63 patients with one-vessel disease and a recent anterior
myocardial infarction, we tested at angiography (1) if perfusion
of the anterior descending coronary artery exerts any restraining
effect on end-systolic volume above and beyond infarct size
reduction and (2) if ejection fraction reflects such an
additional, beneficial difference in the ventricular remodeling
process. End-systolic volume was calculated using the Dodge method
and the right anterior oblique projection, while infarct size was
quantified according to the number of ventricular radii whose
percent shortening fell below the mean -2 SD of a group of normal
individuals. Patients were then divided into two groups according
to the perfusion status of the vessel using Thrombolysis in
Myocardial infarction (TIMI) criteria (TIMI grade 0 to 1:
nonperfused vessel, 27 patients; TIMI grade 2 to 3: perfused
vessel, 36 patients). For both groups there was a significant
linear relation (p less than 0.001) between end-systolic volume
and infarct size; as in our echocardiographic data, the regression
lines relating volume to infarct size showed a different slope in
the two populations so that, for large and matched infarcts,
end-systolic volume was smaller in patients with a perfused vessel
(p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 1575127 [PubMed - indexed for MEDLINE]
Long-term implications of reocclusion on left
ventricular size and function after successful thrombolysis for
first anterior myocardial infarction.
Nijland F, Kamp O, Verheugt FW, Veen G, Visser CA.
Department of Cardiology, Research School Free University
Hospital, Amsterdam, Netherlands. cardiol@azvu.nl
BACKGROUND: Successful thrombolysis can prevent left ventricular
dilatation after acute myocardial infarction. However, in almost
30% of patients, reocclusion occurs. The aim of this study was to
assess the long-term implications of reocclusion on left
ventricular size and function. METHODS AND RESULTS: Fifty-six
patients were studied with two-dimensional echocardiography at
baseline (2 +/- 1.6 days) and 5.0 +/- 1.4 years after first
anterior myocardial infarction. All patients (a subset of those
enrolled in the APRICOT trial) had a patent infarct-related artery
when studied < 48 hours after thrombolysis and underwent repeat
coronary angiography at 3 months. Baseline characteristics were
comparable in patients with (n = 17) and without reocclusion (n =
39). Left ventricular volume indexes were stable in patients
without reocclusion. Patients with reocclusion, however, showed a
significant increase in end-diastolic volume index (EDVI; P =
.008) and end-systolic volume index (ESVI; P = .039). Furthermore,
patients without reocclusion demonstrated improvement in wall
motion score index (WMSI; P = .0001) and ejection fraction (EF; P
= .016), whereas patients with reocclusion did not. After 5 years,
patients with reocclusion had significantly larger volume indexes
(EDVI, 99 +/- 41 versus 76 +/- 22 mL/m2, P = .007; ESVI, 59 +/- 40
versus 39 +/- 20 mL/m2, P = .017) and more compromised left
ventricular function (WMSI, 1.63 +/- 0.33 versus 1.39 +/- 0.32, P
= .013; EF, 45 +/- 13% versus 51 +/- 11%, P = .077) than patients
without reocclusion. Multivariate analysis identified baseline
WMSI and reocclusion as significant independent predictors of left
ventricular dilatation. CONCLUSIONS: Reocclusion of the
infarct-related artery within 3 months of successful thrombolysis
is associated with left ventricular dilatation and is detrimental
to functional recovery of left ventricular function 5 years after
first anterior myocardial infarction.
PMID: 8994425 [PubMed - indexed for MEDLINE]
Quantitative two-dimensional echocardiographic
measurements are major predictors of adverse cardiovascular events
after acute myocardial infarction. The protective effects of
captopril.
St John Sutton M, Pfeffer MA, Plappert T, Rouleau JL, Moye LA,
Dagenais GR, Lamas GA, Klein M, Sussex B, Goldman S, et al.
Brompton Hospital, London, England.
BACKGROUND: Left ventricular enlargement after myocardial
infarction increases the likelihood of an adverse outcome. In an
echocardiographic substudy of the Survival and Ventricular
Enlargement (SAVE) Trial, we assessed whether captopril would
attenuate progressive left ventricular enlargement in patients
with left ventricular dysfunction after acute myocardial
infarction and, if so, whether this would be associated with
improved clinical outcome. METHODS AND RESULTS: Two-dimensional
transthoracic echocardiograms were obtained in 512 patients at a
mean of 11.1 +/- 3.2 days after infarction and were repeated at 1
year in 420 survivors. Left ventricular size was assessed as left
ventricular cavity areas at end diastole and end systole and left
ventricular function as percent change in cavity area from end
diastole to end systole. Patients were randomly assigned to
placebo or captopril, and the incidence of adverse cardiovascular
events consisting of cardiovascular death, heart failure requiring
either hospitalization or open-label angiotensin-converting enzyme
inhibitor therapy, and recurrent infarction were determined over a
follow-up period averaging 3.0 +/- 0.6 years. Irrespective of
treatment assignment, baseline left ventricular systolic area and
percent change in area were strong predictors of cardiovascular
mortality and adverse cardiovascular events. At 1 year, left
ventricular end-diastolic and end-systolic areas were larger in
the placebo than in the captopril group (P = .038, P = .015,
respectively), and percent change in cavity area was greater in
the captopril group (P = .005). One hundred eleven of the 420
1-year survivors with 1-year echo measurements (26.4%) experienced
a major adverse cardiovascular event, and these patients had more
than a threefold greater increase in left ventricular cavity areas
than those with an uncomplicated course. Sixty-nine patients with
adverse cardiovascular events were in the placebo group compared
with 42 patients in the captopril-treated group (a risk reduction
of 35%, P = .010). CONCLUSIONS: Two-dimensional echocardiography
provides important and independent prognostic information in
patients after infarction. Left ventricular enlargement and
function after infarction are associated with the development of
adverse cardiac events. Attenuation of ventricular enlargement
with captopril in these patients was associated with a reduction
in adverse events. This study demonstrates the linkage between
attenuation of left ventricular enlargement by captopril after
infarction and improved clinical outcome.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 8281697 [PubMed - indexed for MEDLINE]
Attenuation of left ventricular dilatation
after acute myocardial infarction by early initiation of enalapril
therapy. CONSENSUS II Multi-Echo Study Group.
Bonarjee VV, Carstensen S, Caidahl K, Nilsen DW, Edner M,
Berning J.
Department of Medicine, Central Hospital in Rogaland, Stavanger,
Norway.
This trial investigated the effect of enalapril, administered
early, on left ventricular (LV) volumes after myocardial
infarction. Four hundred twenty-eight patients included in the
Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS
II) were examined with echocardiography within 5 days, at 1 month
and at 6 months after myocardial infarction. Enalaprilat (1 mg) or
placebo infusion was initiated within 24 hours after infarction,
followed by oral treatment to a target dose of 20 mg/day. A
significant attenuation of LV dilatation was noted at 1 month in
patients treated with enalapril compared with those receiving
placebo. Changes in LV end-diastolic volume indexes during the
first month were (mean +/- SEM) 5.7 +/- 1.0 ml/m2 for the placebo
group and 1.9 +/- 0.8 ml/m2 for the enalapril group (p < 0.02).
Changes in LV end-systolic volume indexes were 3.1 +/- 0.8 and 0.5
+/- 0.6 ml/m2, respectively (p < 0.02). The between-group
difference was most marked in patients with anterior wall
infarction (p < 0.005). Volume changes beyond the first month were
similar in both groups but the differences observed at 1 month
were maintained. The larger volumes in the placebo versus
enalapril group were significant or borderline significant at 1
and 6 months. Thus, enalapril treatment initiated early after
myocardial infarction and continued for 6 months can attenuate LV
dilatation during the first month resulting in smaller LV volumes
after 1 and 6 months.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 8213578 [PubMed - indexed for MEDLINE]
Comment in:
GISSI-3: effects of lisinopril and transdermal
glyceryl trinitrate singly and together on 6-week mortality and
ventricular function after acute myocardial infarction. Gruppo
Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico.
GISSI-3 is a multicentre randomised clinical trial to assess the
efficacy of lisinopril, transdermal glyceryl trinitrate (GTN), and
their combination in improving survival and ventricular function
after acute myocardial infarction (AMI). Between June, 1991, and
July, 1993, 19,394 patients were randomised from 200 coronary care
units in Italy. Eligible patients presented within 24 h of symptom
onset and had no clear indications for or against the study
treatments. In a factorial design patients were randomly assigned
6 weeks of oral lisinopril (5 mg initial dose and then 10 mg
daily) or open control as well as nitrates (intravenous for the
first 24 h followed by transdermal GTN 10 mg daily) or open
control. Complete clinical data and 6-week follow-up were
available for 18,895 (97.4%) patients randomised. Two-dimensional
echocardiographic data were available for 14,209 patients. Overall
6-week mortality was 6.7%. Lisinopril, started within 24 h from
AMI symptoms, produced significant reductions in overall mortality
(odds ratio 0.88 [95% CI 0.79-0.99]) and in the combined outcome
measure of mortality and severe ventricular dysfunction (0.90
[0.84-0.98]). In the same trial the systematic administration of
transdermal GTN did not show any independent effect on the same
outcome measures (0.94 [0.84-1.05] and 0.94 [0.87-1.02]).
Systematic combined administration of lisinopril and GTN also
produced significant reductions in overall mortality (0.83
[0.70-0.97]) and in the combined endpoint (0.85 [0.76-0.94]). The
favourable effect of lisinopril alone or with GTN was clear also
in the predefined high-risk populations (elderly patients and
women) for the combined endpoint. These findings were obtained in
a population intensively exposed to recommended treatments (thrombolysis
72%, beta-blockade 31%, and aspirin 84%); non-protocol treatment
with angiotensin-converting-enzyme inhibitors and nitrates was
allowed for specific clinical indications. No excess of
unfavourable clinically relevant events in the treated groups was
reported.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 7910229 [PubMed - indexed for MEDLINE]
Comment in:
ISIS-4: a randomised factorial trial assessing
early oral captopril, oral mononitrate, and intravenous magnesium
sulphate in 58,050 patients with suspected acute myocardial
infarction. ISIS-4 (Fourth International Study of Infarct
Survival) Collaborative Group.
58,050 patients entering 1086 hospitals up to 24 h (median 8 h)
after the onset of suspected acute myocardial infarction (MI) with
no clear contraindications to the study treatments (in particular,
no cardiogenic shock or persistent severe hypotension) were
randomised in a "2 x 2 x 2 factorial" study. The treatment
comparisons were: (i) 1 month of oral captopril (6.25 mg initial
dose titrated up to 50 mg twice daily) versus matching placebo;
(ii) 1 month of oral controlled-release mononitrate (30 mg initial
dose titrated up to 60 mg once daily) versus matching placebo; and
(iii) 24 h of intravenous magnesium sulphate (8 mmol initial bolus
followed by 72 mmol) versus open control. There were no
significant "interactions" between the effects of these three
treatments, and the results for each are based on the randomised
comparison of about 29,000 active versus 29,000 control allocated
patients. Captopril There was a significant 7% (SD 3) proportional
reduction in 5-week mortality (2088 [7.19%] captopril-allocated
deaths vs 2231 [7.69%] placebo; 2p = 0.02), which corresponds to
an absolute difference of 4.9 SD 2.2 fewer deaths per 1000
patients treated for 1 month. The absolute benefits appeared to be
larger (perhaps about 10 fewer deaths per 1000) in certain
higher-risk groups, such as those presenting with a history of
previous MI or with heart failure. The survival advantage appeared
to be maintained in the longer term (5.4 [SD 2.8] fewer deaths per
1000 at 12 months). Captopril was associated with an increase of
52 (SD 2) patients per 1000 in hypotension considered severe
enough to require termination of study treatment, of 5 (SD 2) per
1000 in reported cardiogenic shock, and of 5 (SD 1) per 1000 in
some degree of renal dysfunction. It produced no excess of deaths
on days 0-1, even among patients with low blood pressure at entry.
Mononitrate There was no significant reduction in 5-week
mortality, either overall (2129 [7.34%] mononitrate-allocated
deaths vs 2190 [7.54%] placebo) or in any subgroup examined
(including those receiving short-term non-study intravenous or
oral nitrates at entry). Further follow-up did not indicate any
later survival advantage. The only significant side-effect of the
mononitrate regimen studied was an increase of 15 (SD 2) per 1000
in hypotension. Those allocated active treatment had somewhat
fewer deaths on days 0-1, which is reassuring a bout the safety of
using nitrates early in acute MI.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 7661937 [PubMed - indexed for MEDLINE]
Comment in:
Effect of captopril on mortality and morbidity
in patients with left ventricular dysfunction after myocardial
infarction. Results of the survival and ventricular enlargement
trial. The SAVE Investigators.
Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy
TE, Davis BR, Geltman EM, Goldman S, Flaker GC, et al.
Cardiovascular Division, Brigham and Women's Hospital, Harvard
Medical School, Boston, MA 02115.
BACKGROUND. Left ventricular dilatation and dysfunction after
myocardial infarction are major predictors of death. In
experimental and clinical studies, longterm therapy with the
angiotensin-converting--enzyme inhibitor captopril attenuated
ventricular dilatation and remodeling. We investigated whether
captopril could reduce morbidity and mortality in patients with
left ventricular dysfunction after a myocardial infarction.
METHODS. Within 3 to 16 days after myocardial infarction, 2231
patients with ejection fractions of 40 percent or less but without
overt heart failure or symptoms of myocardial ischemia were
randomly assigned to receive doubleblind treatment with either
placebo (1116 patients) or captopril (1115 patients) and were
followed for an average of 42 months. RESULTS. Mortality from all
causes was significantly reduced in the captopril group (228
deaths, or 20 percent) as compared with the placebo group (275
deaths, or 25 percent); the reduction in risk was 19 percent (95
percent confidence interval, 3 to 32 percent; P = 0.019). In
addition, the incidence of both fatal and nonfatal major
cardiovascular events was consistently reduced in the captopril
group. The reduction in risk was 21 percent (95 percent confidence
interval, 5 to 35 percent; P = 0.014) for death from
cardiovascular causes, 37 percent (95 percent confidence interval,
20 to 50 percent; P less than 0.001) for the development of severe
heart failure, 22 percent (95 percent confidence interval, 4 to 37
percent; P = 0.019) for congestive heart failure requiring
hospitalization, and 25 percent (95 percent confidence interval, 5
to 40 percent; P = 0.015) for recurrent myocardial infarction.
CONCLUSIONS. In patients with asymptomatic left ventricular
dysfunction after myocardial infarction, long-term administration
of captopril was associated with an improvement in survival and
reduced morbidity and mortality due to major cardiovascular
events. These benefits were observed in patients who received
thrombolytic therapy, aspirin, or beta-blockers, as well as those
who did not, suggesting that treatment with captopril leads to
additional improvement in outcome among selected survivors of
myocardial infarction.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 1386652 [PubMed - indexed for MEDLINE]
Erratum in:
- Circulation 1989 May;79(5):1151
Intravenous nitroglycerin therapy to limit
myocardial infarct size, expansion, and complications. Effect of
timing, dosage, and infarct location.
Jugdutt BI, Warnica JW.
Department of Medicine, University of Alberta, Edmonton, Canada.
To determine 1) whether the effect of intravenous nitroglycerin
(NG) therapy during acute myocardial infarction on creatine kinase
infarct size is influenced by infarct location (anterior vs.
inferior), timing (therapy less than 4 hours vs. greater than or
equal to 4 hours after onset of pain), and dose response (mean
blood pressure greater than or equal to 80 mm Hg vs. less than 80
mm Hg during the first 12 hours) and 2) whether NG therapy
modifies infarct expansion, 310 patients were randomly allocated
to NG (n = 154) and control (n = 156) groups. NG infusion was
titrated to lower mean blood pressure by 10% in normotensive and
30% in hypertensive patients, but not below 80 mm Hg, and was
maintained for 39 hours. Measurements included clinical variables,
creatine kinase infarct size (geq) as well as left ventricular (LV)
asynergy, LV ejection fraction, expansion index, and thinning
ratio on serial two-dimensional echocardiography. Compared with
controls, creatine kinase infarct size was less in the NG group
(41 vs. 55 geq, p less than 0.001), in anterior (44 vs. 58 geq, p
less than 0.05), and inferior (39 vs. 53 geq, p less than 0.025)
NG subgroups, and in early than late NG subgroups (43% vs. 22%
decrease). Other indexes of infarct size also improved (p less
than or equal to 0.05) with NG compared with controls. Thus, by 10
days, LV asynergy was 40% less, LV ejection fraction was 22% more,
and Killip class score was 41% less. A negative effect of mean
blood pressure less than 80 mm Hg with NG was reflected in these
indexes. In addition, expansion index increased (p less than
0.001) by 31% and thinning ratio decreased (p less than 0.001) by
17% in controls by 10 days but remained unchanged with NG.
Infarct-related major complications were less frequent in the NG
than the control groups: infarct expansion syndrome (2% vs. 15%, p
less than 0.0005), LV thrombus (5% vs. 22%, p less than 0.0005),
cardiogenic shock (5% vs. 15%, p less than 0.005), and infarct
extension (11% vs. 22%, p less than 0.025). Mortality was less in
NG than in control groups in-hospital (14% vs. 26%, p less than
0.01), at 3 months (16% vs. 28%, p less than 0.025) and 12 months
(21% vs. 31%, p less than 0.05), but this advantage was only found
in the anterior subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 3139326 [PubMed - indexed for MEDLINE]
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