Adjunctive effect of hyperbaric oxygen treatment

after thrombolysis on left ventricular function in

patients with acute myocardial infarction
Milica Dekleva, MD, PhD,a Aleksandar Neskovic, MD, PhD, FESC,d Alja Vlahovic, MD,d
Biljana Putnikovic, MD, PhD,b Branko Beleslin, MD, FESC,c and Miodrag Ostojic, MD, PhD, FESC, FACCc
Belgrade, Serbia and Montenegro

Background The role of hyperbaric oxygen in patients with acute myocardial infarction is controversial, ranging
from not beneficial to having a favorable effect. This randomized study was conducted to further assess the benefit of hy-
perbaric oxygen treatment after thrombolysis on left ventricular function and remodeling in patients with acute myocardial
infarction.
Methods Seventy-four consecutive patients with first acute myocardial infarction were randomly assigned to treat-
ment with hyperbaric oxygen treatment combined with streptokinase (HBO) or streptokinase alone (HBO).
Results There was a significant decrease of end-systolic volume index from the first day to the third week in HBO
patients compared with HBO patients (from 30.40 to 28.18 vs from 30.89 to 36.68 mL/m2, P .05) accompanied
with no changes of end-diastolic volume index in HBO compared with increased values in HBO (from 55.68 to 55.10
vs from 55.87 to 63.82 mL/m2, P .05). Ejection fraction significantly improved in the HBO group and decreased in
the HBO group of patients after 3 weeks of acute myocardial infarction (from 46.27% to 50.81% vs from 45.54% to
44.05 %, P .05).
Conclusions Adjunctive hyperbaric oxygen therapy after thrombolysis in acute myocardial infarction has a favor-
able effect on left ventricular systolic function and the remodeling process. (Am Heart J 2004;148:e14.)

Normobaric therapy has been in use for many years
in the treatment of ischemic heart disease.1 When oxy-
gen is breathed in concentrations higher than those
found in the atmospheric air, it is considered to be a
drug. A limited amount of oxygen is dissolved in blood
in normal atmospheric pressure, but under hyperbaric
conditions, it is possible to dissolve sufficient oxygen,
for example, 6%, in plasma to meet the usual require-
ments of the body. The oxygen physically dissolved in
solution will be utilized more readily than that bound
to hemoglobin, and this effect may normalize or in-
crease oxygen tension in ischemic tissue.1
Calvert et al2 reported that hyperbaric oxygen (HBO)
could be a treatment for neonatal hypoxia-ischemia in
a neonatal rat model and could prevent brain injury. In
From aClinical Medical Center Dr Dradisa Misovic-Dedinje, bClinical Medical Center
Zemun, cInstitute for Cardiovascular Diseases Clinical Center of Serbia, and dInstitute
for Cardiovascular Diseases, Dedinje, Belgrade, Serbia and Montenegro.
Reprint requests: Milica Dekleva, MD, PhD, Clinical Medical Center Dr Dragisa Miso-
vic-Dedinje. Department of Echocardiography. Milana Tepica 1 St, 11000 Belgrade,
Serbia and Montenegro.
E-mail: mildek@eunet.yu
0002-8703/$ - see front matter
2004, Elsevier Inc. All rights reserved.
doi:10.1016/j.ahj.2004.03.031
that study, HBO was administered in a chamber for 1
hour at 3 ATA (absolute pressure of 1 atmosphere), 1
hour after hypoxia exposure. Results suggested that
HBO, as a single therapy, is able to attenuate hypoxia-
ischemia brain insult and offer neuroprotectivity. HBO
reduced neuronal injury with much less atrophy and
apoptosis of immature neurons, resulting in further
improvement of sensorimotor function of neonatal
brain.
The role of HBO in patients with acute myocardial
infarction is controversial, ranging from no beneficial
effect3,4 to a favorable effect.5,6 The only controlled
trial done by Thurston et al,5 in the prethrombolytic
era, revealed a trend but not a statistically significant
decrease in mortality rates, especially in high-risk pa-
tients. An animal study conducted by Thomas et al6
proved the hypothesis that a combination of thrombo-
lytic therapy and HBO would be more effective in re-
ducing the size of the myocardial infarction than either
of these modalities alone. Therefore, a randomized pi-
lot trial conducted by Shandling et al7 demonstrated
that adjunctive treatment with HBO appears to be fea-
sible and safe for patients in the acute phase of myo-
cardial infarction. Finally, the Hyperbaric Oxygen and

2 Dekleva et al
Thrombolysis in Myocardial Infarction (HOT MI) study
demonstrated that treatment with HBO in combination
with thrombolysis might result in an attenuated creat-
ine phosphokinase rise, more rapid resolution of pain,
and improved ejection fraction (EF).8
The following randomized study was designed to
further assess the benefit of thrombolysis in combina-
tion with HBO on the remodeling process and left ven-
tricular function preservation in patients with acute
myocardial infarction.
Methods
Study population
The study population consisted of consecutive patients
with first myocardial infarction who met the following crite-
ria: (1) age 70 years, (2) chest pain lasting 30 to 360 min-
utes, (3) ST-segment elevation 2 mm in 2 contagious elec-
trocardiographic leads, (4) transient creatine phosphokinase
and/or MB isoenzyme increase, and (5) first echocardiogram
performed within 24 hours of the onset of pain.
Exclusion criteria were standard for thrombolysis, includ-
ing suspected aortic dissection, recent surgery, recent peptic
ulcer, and stroke. Exclusion criteria also included patients
with malignant arrhythmias and severe hemodynamic instabil-
ity, with Killip classes III and IV, nonrapidly controlled with
intravenous medication, and patients with previous myocar-
dial infarction or bypass surgery. Further exclusions to HBO
were the inability to equilibrate pressure in the middle ear
space secondary to upper respiratory tract infections, otitis
or rhinitis, severe claustrophobia, and chronic obstructive
pulmonary disease.
From 92 patients with acute myocardial infarction origi-
nally considered for the study, 18 were subsequently ex-
cluded. Five patients were excluded because of rhythm and
hemodynamic instability in the emergency room. Six patients
refused coronary angiography, which also represents exclu-
sion criteria in this study. Three patients refused entry into
the HBO chamber: two because they felt claustrophobia in
the chamber and one because of chronic otitis media. Four
patients had chronic obstructive pulmonary disease with
marked CO2 retention. In patients who started HBO, there
were no complications inside the chamber or after the treat-
ment and no need for urgent decompression. Thus, the final
study population consisted of 74 patients (63 men, 11 wom-
en; mean age, 55 7 years).
Study procedure
Streptokinase was administered at the dose of 1.5 mU/L
over 30 to 60 minutes, followed by intravenous heparin infu-
sion. With a random number table, patients were randomly
assigned to streptokinase therapy alone (HBO group, 37
patients) or streptokinase with HBO (HBO group, 37 pa-
tients). The patients randomly assigned to streptokinase plus
HBO were transferred to the hyperbaric unit in the first 24
hours from the onset of symptoms and after thrombolytic
therapy. The time from cessation of thrombolytic therapy to
HBO ranged from 45 minutes to 18 hours, with average time
of 10 hours (Figure 1). The patients randomly assigned to
American Heart Journal
October 2004
Figure 1
Time distribution from thrombolysis to HBO.
HBO were pressurized during a 20-minute period up to 2
ATA. They remained at this pressure during 60 minutes in
the monoplace hyperbaric chamber. Decompression time
was 20 minutes with decreasing pressure change 0.2 ATA/
min. A critical care nurse and cardiologist were in attendance
at all times. By using electrocardiographic cables with 3 ter-
minals, all patients in the chamber were monitored, includ-
ing electrocardiograms and respiratory traces. Measuring of
noninvasive blood pressure inside the hyperbaric chamber
was done in an automatic reading system, which measures
the pressure displayed from the oscillometric method at pre-
set intervals. All monitoring devices, drug protocols, and
other procedures in the intensive care unit continued when
patients were discharged inside the chamber. Monoplace
chambers exclude possible nurse assistance, so these cham-
bers have an option of emergency decompression within at
least 1 minute, depending on the nature of critical situation.
All patients were assessed clinically at study entry for the
presence or absence of heart failure on the basis of Killip
criteria. Creatine phosphokinase samples were obtained on
admission, every 4 hours for the first 24 hours, and afterward
on daily basis.
Coronary angiography was performed after hospital dis-
charge. Perfusion of the infarct-related artery was assessed by
using criteria from the Thrombolysis In Myocardial Infarction
(TIMI) trial.11 Successful reperfusion was coded as TIMI
grade 3.
Echocardiography
Two-dimensional echocardiography was performed with an
Acuson 128 imaging system on day 1 after thrombolysis or
immediately after thrombolysis plus HBO treatment, on day
2, and after 3 weeks in all patients. All measurements were
performed off-line, calculated from the mean value of 3 best
consecutive cardiac cycles. The physician, who assessed left
ventricular function, was blinded to the random assignment
status of the patient. Left ventricular volumes and EF were
determined from apical 2- and 4-chamber views, using the
Simpson biplane formula. The left ventricular volumes, end-
American Heart Journal
Dekleva et al 3
Volume 148, Number 4

Table I. Demographic, clinical, and angiographic Table II. Medical treatment of patients during in-hospital
characteristics of patients period

HBO HBO P HBO HBO P

(n 37) (n 37) value (n 37) (n 37) value

Age (y) 55 7 54 8 NS Heparin 37 (100%) 37 (100%) NS

Sex (F/M) 8/29 3/34 NS Aspirin 36 (97%) 36 (97%) NS
Hypertension 14 (38%) 13 (35%) NS Oral anticoagulation 5 (14%) 8 (22%) NS
Diabetes mellitus 8 (22%) 2 (5%) 0.05 Nitroglycerin IV 7 (19%) 8 (22%) NS
Smoking 30 (81%) 27 (73%) NS Long-acting nitrates 30 (81%) 31 (84%) NS
Killip class 2 2 (5%) 5 (14%) NS Calcium channel blockers 1 (3%) 1 (3%) NS
Time to STK (h) 2.4 1.6 3.0 1.5 NS -Blockers 26 (70%) 23 (62%) NS
Anterior MI 14 (38%) 16 (43%) NS Digitalis 1 (3%) 1 (3%) NS
Peak CK value (U/L) 989 643 1529 1187 0.05 Diuretics 3 (8%) 5 (14%) NS
Multivessel CAD 19 (51%) 20 (54%) NS ACE inhibitors 8 (22%) 12 (32%) NS
TIMI 3 flow 22 (59%) 22 (59%) NS
Collaterals 9 (24%) 9 (24%) NS
Cardiac mortality 0 (0%) 1 (3%) NS
Figure 2
CAD, Coronary artery disease; CK, creatine phosphokinase; STK, streptokinase.

diastolic and end-systolic, were normalized for body surface

area and expressed as indexes (EDVI and ESVI).12

Statistical analysis
The unpaired t test and 2 test were used to test the differ-
ences between 2 groups of patients. The paired t test was
used to compare initial left ventricular volume indexes and
EF, with results performed after 3 weeks. Analysis of variance
was used for analyzing repeated measures of left ventricular
volumes indexes, and EF. Probability values of .05 were
considered statistically significant.

Changes of ESVI in acute myocardial infarction in HBO and

Results
Demographic, clinical, and angiographic data
Patient demographics and clinical and angiographic
data are listed in Table I. There was no significant dif-
ference between study groups with regard to the age,
sex, prevalence of hypertension, and smoking history.
According to anamnesis and adjusted analysis for dia-
betic status at baseline, there were more diabetic pa-
tients in the HBO group, but these distributions have
no obvious influence on the final results. The distribu-
tion of localization of myocardial infarction was similar
in both study groups. Patients in both groups were
evenly distributed in either Killip class I or II. With
regard to coronary angiography, there were no signifi-
cant differences between the two groups in infarction
artery patency, single or multivessel coronary artery
disease, or collateral vessel presence. However, pa-
tients receiving thrombolytic therapy alone showed a
higher peak creatine phosphokinase activity compared
with the HBO group (989 vs 1529 IU, P .05).
As shown in Table II, both groups of patients re-
ceived similar medication before HBO, during their
hospital stay, and at the time of discharge, including
HBO groups of patients. Large box/upper border, 75% percen-
tile; large box/lower border, 25% percentile; line in the middle of
the large box, median; small box inside large one, mean value.
*Confidence interval, 1% to 99%.
ACE inhibitors, anticoagulants, aspirin, -blockers, long-
acting nitrates, intravenous nitroglycerin, calcium channel
inhibitors, digitalis, and diuretics (P not significant).
Left ventricular function and remodeling
In the current study, using serial echocardiography
examinations, we were able to observe the pattern of
changes of left ventricular volumes and EF in respect
to HBO treatment and to compare the baseline values
with subsequent studies up to 3 weeks.
The changes in left ventricular volumes and EF are
presented in Figure 2, Figure 3, and Figure 4. Initial
left ventricular volume indexes and EF were similar in
two study groups (P not significant). In patients
treated with thrombolysis only, there were significant

4 Dekleva et al
Figure 3
Changes of EDVI in acute myocardial infarction in HBO and
HBO groups of patients. Large box/upper border, 75% percen-
tile; large box/lower border, 25% percentile; line in the middle of
the large box, median; small box inside large one, mean value.
*Confidence interval, 1% to 99%.
Figure 4
Changes of EF in acute myocardial infarction in HBO and
HBO groups of patients. Large box/upper border, 75% percen-
tile; large box/lower border, 25% percentile; line in the middle of
the large box, median; small box inside large one, mean value.
*Confidence interval, 1% to 99%.
increases of ESVI (from 30.89 to 36,68 mL/m2) and
EDVI (from 55.87 to 63.82 mL/m2) and decreases of
EF (45.8% to 44.2%) during the first 3 weeks. Con-
versely, in the HBO group, EDVI did not change sig-
nificantly (from 55.68 to 56.24 mL/m2), ESVI de-
creased significantly (from 30.40 to 28.18 mL/m2), and
EF improved during the follow-up period (from 46.27%
American Heart Journal
October 2004
to 50.81%). Thus, 3 weeks after acute myocardial in-
farction, the HBO group compared with the HBO
group of patients had lower ESVI (28.18 vs 36.68 mL/
m2, P .001) (Figure 2) and EDVI (56.2 vs 63.8 mL/
m2, P .001) (Figure 3) and higher EF (44.05% vs
50.,81%, P .001) (Figure 4).
As shown in the figures, the main effect of HBO was
achieved during the very first days of acute myocardial
infarction, with significant difference in ESVI and EF
on day 2 in favor of the HBO group. In the subse-
quent 3-week follow-up period, further changes of left
ventricular function indexes were slight and statisti-
cally nonsignificant.
Discussion
The major original findings of this study relate to the
changes of left ventricular volumes in the time course
estimated by echocardiography. We have shown that
HBO and streptokinase in acute myocardial infarction
reduced left ventricular volumes with associated in-
crease in EF during the first 3 weeks after acute myo-
cardial infarction. In contrast, there was progressive
left ventricular dilation, with no change in EF in pa-
tients treated with thrombolysis only.
Comparison with previous studies
Left ventricular dilation in the first 3 weeks of myo-
cardial infarction is determined mostly by the expan-
sion process, infarct-related artery patency, and infarct
localization.1113,15 Popovic et al16 have shown that
the degree of EDVI increase for the period of 3 weeks
after acute myocardial infarction was 6.0% in patients
treated with streptokinase only. In our study, a similar
increase of EDVI was found in the HBO group but a
lower degree was found in the HBO group (55.9 to
63.8 mL/m2, 14.1%, vs 55.7 to 56.2 mL/m2, 0.9%) (P
.001). Similarly, Chareonthaitawee et al14 have shown
that the degree of ESVI increase in thrombolytic-
treated patients was 12% in the acute phase, which
correlates well with our results in HBO patients
(30.1 to 36.7 mL/m2, 21.9%). In contrast, the decrease
of ESVI during 3 weeks (30.4 vs 28.2 mL/m2, 7%) dem-
onstrated a significant benefit of HBO. Concerning EF,
the Intravenous Streptokinase in Acute Myocardial In-
farction (ISAM) study demonstrated significant im-
provement of EF (5.3%) in patients treated with strep-
tokinase compared with the control group.17 This
difference was also seen in the study by White et al13
(10%), the GISSI-2 study18 (2% to 3%), the European
Cooperative study Grupo Trial19 (4%), and the Western
Washington Trial20 (5%). In our study, the difference
in EF was not observed in the HBO group, but in the
HBO group, EF significantly increased for 9.8%
(46.3% to 50.8%). A favorable effect of the combina-
tion of thrombolysis and HBO on left ventricular EF
has been demonstrated in the HOT MI study by Sta-
American Heart Journal
Volume 148, Number 4
vitsky et al.8 This multicenter study demonstrated
higher values of left ventricular EF at discharge time in
patients treated with adjunctive HBO compared with
control subjects treated with thrombolysis only (48.4%
vs 51.7%).8 Both of these studies reported a benefit of
HBO as a single adjuvant therapy, without repeated
exposure, but Wada et al9,10 showed a protective ef-
fect of repetitive HBO against ischemia in a brain ex-
perimental model. According to these results, the best
tolerance against neuronal damage of the hippocam-
pus of Mongolian gerbils was induced with pretreat-
ment in 5 sessions of HBO, every other day, compared
with single HBO pretreatment or with ischemic con-
trol group.
Regarding prognostic importance of left ventricular
volumes, White et al13 have shown that left ventricular
volumes were clearly associated with death; that is,
ESVI was the most powerful predictor of survival, and
the inclusion of EDVI or EF in a multivariate model
added no further prognostic power.
Myocardial enzymes
Standard reflow with thrombolysis is followed with
significant creatine phosphokinase enzyme leakage or
washout effect, evidenced as an increased total activity
in blood after thrombolysis. In our study, peak creat-
ine phosphokinase level was 35.3% lower in the
HBO group of patients than in the HBO group.
Very similar data were reported in a randomized pilot
trial by Shandling et al,7 demonstrating that mean
creatine phosphokinase level at 12 and 24 hours
was reduced in patients given HBO by approxi-
mately 35% (P .03). An attenuated rise in creatine
phosphokinase (7.5%) in patients treated with
thrombolysis and HBO is one of the main remarks of
the HOT MI study by Stavitsky et al.8 Also, in an ani-
mal study conducted by Thomas et al,6 HBO com-
bined with thrombolysis restored 95% of normal oxi-
dative enzyme activity and decreased the release of
creatine phosphokinase into blood, thus better pre-
serving myocardial fiber integrity.
Mechanism of improvement in left ventricular function
In the presence of a critical coronary artery stenosis,
the oxygen demand changes. In these circumstances,
increased dissolved oxygen fraction under hyperbaric
conditions could be enough to meet resting cellular
requirements without any contribution from oxygen
bound to hemoglobin from increased blood flow.1
The quantity of oxygen carried in the plasma and
tissue fluid under hyperbaric conditions in this study is
increased 10-fold compared with breathing room air.
The net effect, with an HBO treatment at 2 ATA abso-
lute pressure, is an approximately 25% enhanced oxy-
gen blood content and consumption and increased
Dekleva et al 5
tissue oxygen diffusion distance by a factor 3 or 4.
Therefore, high oxygen tension and an increased
amount of available tissue oxygen, pressure difference
between ischemic and nonischemic tissue, conse-
quently improved penetration of oxygen into hypoxic
tissues.6 Reduction in heart rate during compression
time that was based on decrease of sympathetic activ-
ity could be part of the mechanism of left ventricular
function improvement.5
Tissue oxygen tension remained elevated for some
hours after cessation of HBO treatment.21 Thus, the
tissue remains oxygenated after completion of the
HBO treatment. According to our results, the most
powerful effect was on left ventricular remodeling and
left ventricular function at the first days of acute myo-
cardial infarction. The late effect could result in sus-
tained beneficial effects even after decompression, al-
lowing improved myocardial salvage in that group of
patients who have late reperfusion.
Other mechanisms may be responsible for improved
regional wall motion. Through favorable changes in
myocardial oxygen supply and demand, HBO im-
proved contraction of hibernating myocardium after
myocardial infarction that is indicated in the study
conducted by Swift et al.21 In our study, the increase
of global left ventricular function is followed by im-
provement of global systolic function in HBO pa-
tients compared with the HBO group.
During left ventricular remodeling, there are struc-
tural changes in coronary microcirculation followed by
decreased capillary density, with enlarged diffusion
distances for oxygen and disturbed perfusion of the
capillary bed.22 Microvascular obstruction after reper-
fusion may be the consequence of low or no reflow
phenomena. These obstructive myocardial zones have
a great influence on the left ventricular remodeling
process and left ventricular function.23,24 Favorable
effects of HBO in decreasing leukocyte endothelial ad-
herence and improvement of angiogenesis is also a
contributory mechanism.23,25
There was initially concern that an increase in free
oxygen radicals, occurring by the high oxygen tension
state of HBO treatment, would emphasize tissue reper-
fusion injury.1,25 However, the results from our study
do not suggest that this mechanism occurs to any no-
ticeable clinical sign in patients treated with 2 ATA
HBO protocol. Recent and present investigators have
shown that HBO lessens or may inhibit reperfusion
injury by protection of oxidative metabolism in reper-
fusion-stunned myocardium.23,25,26 Results of the stud-
ies conducted by Wada et al showed an HBO effect on
immunoreactivity to apoptosis-regulating protein
(Bc1-2, Bax) and manganese superoxide dismutase (Mn
SOD), a radical scavenging system. This protective
mechanism of repeated HBO pretreatment induced
tolerance against ischemic neuronal damage in gerbil

6 Dekleva et al
hippocampus. Protection against mitochondrial alter-
ations after ischemia through Mn SOD and/or Bc1-2
expression may be related to induction of ischemic
tolerance by HBO.10,27
Study limitations
The data apply to the patients treated only with
streptokinase, and the results may be different for the
patients treated with other lytic agents or combination
therapies.
Because HBO treatment requires additional logistic
support, we excluded from the study high-risk patients
with severe heart failure as well as patients with signif-
icant electrical complications, who may actually have
the greatest benefit from combined HBO and throm-
bolysis therapy.
In the current study, the time from streptokinase to
HBO treatment was prolonged because of the distance
between hyperbaric unit and the coronary care unit.
A larger group of patients treated with HBO after
thrombolysis may demonstrate event-free survival ben-
efits, as compared with those treated with thromboly-
sis alone.
Clinical implications
Our data indicate the adjunctive effect of HBO after
thrombolysis, resulting in attenuated creatine phos-
phokinase rise and improvement of left ventricular
function in the acute phase of myocardial infarction.
Repeated HBO sessions during the acute phase of myo-
cardial infarction could be of great importance by in-
ducing ischemic tolerance and attenuating left ventric-
ular remodeling. Further multicenter clinical trials are
needed to evaluate possible improvement of event-free
survival and mortality rates.
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