Circulation Research. 2008;103:1-3
doi: 10.1161/CIRCRESAHA.108.180216
(Circulation Research. 2008;103:1.)
© 2008 American Heart Association, Inc.
New Insights Into the Open Artery Hypothesis
Robert A. Kloner,
Hyosook Hwang
From the Heart Institute (R.A.K., H.H.), Good Samaritan Hospital, and the Division of Cardiovascular Medicine (R.A.K.), Keck School of Medicine, University of Southern California, Los Angeles.
Correspondence to Robert A. Kloner, MD, PhD, Heart Institute, Good Samaritan Hospital, 1225 Wilshire Boulevard, Los Angeles, CA 90017. E-mail rkloner{at}goodsam.org
See related article, pages 98–106
Key Words: myocardial infarction • infarct expansion • ventricular remodeling • ventricular dilation • reperfusion
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Factors Affecting Left Ventricular Remodeling
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Early coronary artery reperfusion is clearly the most important
therapy for acute ST segment elevation myocardial infarcts.
Early reperfusion reduces myocardial infarct size and in so
doing helps to prevent or minimize deleterious consequences
of a large myocardial infarction, including infarct expansion
(thinning and dilation of the infarct), subsequent eccentric
hypertrophy and dilation of the noninfarcted ventricular muscle,
and global dilation of the left ventricle.
1–4 These processes
encompass the phenomenon of ventricular remodeling. One of the
major determinants of death at 1 year after a myocardial infarction
is the degree of dilation of the left ventricle (LV).
5 However,
suppose early reperfusion is not available. A number of manipulations
and pharmacological therapies can be administered beyond the
time frame of reducing myocardial infarct size and still reduce
the extent of infarct expansion and LV remodeling (
Table 1).
Angiotensin converting enzyme inhibitors
6 and angiotensin receptor
blockers
7 have been shown to reduce LV dilation and remodeling
and in some studies reduce major cardiovascular events. Cell
therapy and even some noncellular therapies (collagen, alginate)
may thicken the infarct scar and prevent ventricular wall dyskinesis.
8–10 Aneurysmectomy and certain suturing techniques have been attempted
to prevent infarct expansion and remodeling.
11 Late reperfusion—too
late to reduce myocardial infarct size, but early enough to
favorably affect infarct healing
1—also appears to limit
infarct expansion and limit LV remodeling, and is the subject
of the accompanying article.
12
Certain features are associated with worse LV remodeling (Table 2), including a large myocardial infarct, lack of any reperfusion,1 a large zone of no reflow,13 and certain antiinflammatory agents14 (such as steroids and a host of nonsteroidal antiinflammatory agents) introduced early enough to inhibit the healing phase of myocardial infarction.
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Benefit of Late Reperfusion in Preclinical Studies
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The concept that late reperfusion resulting in a patent infarct
artery causes benefit beyond myocardial salvage (also referred
to as the open artery hypothesis)
1 remains somewhat controversial.
Experimental studies and various thrombolytic and observational
studies
1 have supported the concept that late reperfusion may
have certain therapeutic benefits. Hochman and Choo
15 published
a landmark study in 1987 demonstrating the benefit of late reperfusion.
Rats were subjected to left coronary artery ligation for 30
minutes followed by reperfusion, or coronary occlusion of 2
hours followed by reperfusion, or permanent coronary artery
ligation without reperfusion; the hearts were examined by histology
2 weeks later. The investigators used an "expansion index" calculation
that took into account both the degree of LV cavity dilation
as well as the degree of thinning of the infarct wall in relationship
to the noninfarcted LV wall thickness. Rats reperfused at 30
minutes after coronary occlusion demonstrated smaller myocardial
infarcts, less transmurality of the infarct, and less infarct
expansion compared to rats with permanent coronary occlusion.
However, although rats reperfused late (after 2 hours of coronary
occlusion) did not differ in infarct size nor transmurality
of the infarct compared to rats subjected to a permanent coronary
occlusion, those reperfused late did demonstrate less infarct
expansion. In a study by Hale and Kloner,
16 the effects of early
versus later reperfusion on long term left ventricular topography
were assessed. Rats were subjected to proximal coronary artery
occlusion for 30 minutes followed by reperfusion (early reperfusion)
or 90 minutes of occlusion followed by reperfusion (late reperfusion),
or permanent coronary occlusion, and then the rats were allowed
to survive for 6 weeks. Early reperfusion reduced scar circumference
and thinning of the infarcted wall and prevented LV cavity dilation.
Late reperfusion still thickened the scar without significantly
affecting scar circumference; late reperfusion resulted in a
nonsignificant trend toward smaller LV cavity diameter and area
compared to permanent coronary occlusion and did reduce expansion
index compared to permanent coronary occlusion.
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New Information on Late Reperfusion
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The present article by Nakagawa et al
12 extends these early
observations of late reperfusion on several fronts. Using the
rat coronary artery occlusion model, the investigators observed
a benefit of reperfusion as late as 24 hours postcoronary occlusion
on infarct wall thickness, infarct length, LV diameter, and
LV function—suggesting that even reperfusion at 24 hours
can prevent infarct expansion and remodeling. Furthermore, they
extended our knowledge of the benefit of late reperfusion by
examining the biological characteristics of the thickened wall
over a period of 4 weeks. They showed that the increased infarcted
ventricular wall thickness with late reperfusion was attributable
to greater cellularity, including more myofibroblasts and endothelial
cells—major components of granulation tissue. During the
subacute phase of infarction, the proliferation rate of cells
was greater and the incidence of apoptosis lower within the
granulation tissue of hearts that received late reperfusion
versus permanent coronary occlusion. Collagen fibers appeared
earlier and were thicker and myocardial debris disappeared earlier
with late reperfusion. Alterations in matrix metalloproteinase
(MMP) 2 and 9 were implicated; there was less expression of
these MMPs in the late reperfusion compared to the permanently
occluded group. All of these observations point to the concept
that late reperfusion enhanced the healing process. This makes
sense in that late reperfusion would allow access to the infarct
by those cells crucial to the scavenging of debris, laying down
collagen, and forming new blood vessels.
Another intriguing feature of the present analysis was that late reperfusion did not affect the incidence of apoptosis of cardiomyocytes, which has been one theory regarding how late reperfusion might help prevent heart failure. Instead, these authors state that true apoptosis of cardiomyocytes is a very rare event. However, the authors did note a reduction of degenerative ultrastructural changes (myofibrillar loss, increased numbers of mitochondria) within surviving cardiomyocytes in the late reperfusion group compared to the permanently occluded group.
The present study as well as the earlier works by Hochman and Choo15 and Hale and Kloner16 support the open artery hypothesis. These studies suggest that reperfusion too late to reduce myocardial infarct size may still improve healing of the infarct, resulting in a thicker infarct wall, less infarct expansion, less LV dilation, and improved cardiac function. What remains unanswered by these preclinical studies is the determination of the exact duration of the window of opportunity during which late reperfusion can still enhance healing and at what time it is too late for reperfusion to benefit the healing and remodeling process.
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Recent Clinical Trials
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The enthusiasm for late reperfusion in the clinical setting
was diminished by the Occluded Artery Trial or OAT trial, published
in 2006.
17 This was a large, multicenter, randomized study of
2166 patients with acute myocardial infarction who had total
occlusion of the infarct related artery 3 to 28 days after myocardial
infarction and qualified as high risk, with a left ventricular
ejection fraction of less than 50% or a proximal coronary artery
occlusion with a large risk region. Patients were randomized
to routine percutaneous coronary intervention and stenting plus
optimal medical therapy (n=1082) or optimal medical therapy
without invasive opening of the infarct-related vessel (n=1084).
The primary end point of this study was a composite of "death
from any cause, reinfarction, or NYHA Class IV heart failure
with hospitalization or admission ... to a short-stay unit."
There was no significant difference in the primary end point
between groups over 4 years, with 17.2% reaching it in the PCI
group versus 15.6% in the medical group (hazard ratio=1.16;
95% confidence interval of 0.92 to 1.45;
P=0.20). Why were these
results negative? One possibility was that reinfarction rates
tended to be higher in the PCI groups, so it is possible that
reinfarction might have negated any benefit of reduced LV remodeling.
In the design of the study, patients were randomized from 3
to 28 days after onset of acute myocardial infarction, and the
median interval between myocardial infarction and randomization
was 8 days. However, in the early description of myocardial
infarct expansion in humans
18 the process was well underway
within the first week of acute myocardial infarction. Therefore
initiating reperfusion at 8 days may simply have been too late
to have a beneficial effect on remodeling. That reperfusion
at this time may have been too late to prevent infarct expansion
and left ventricular dilation was also suggested by an ancillary
study of OAT, the TOSCA-2 study (The Total Occlusion Study of
Canada-2), from the same investigators.
19 Three hundred eighty-one
patients who presented with an acute myocardial infarction and
had an occluded infarct related artery at 3 to 28 days were
randomized to either PCI with stenting or optimal medical therapy
alone. After 1 year patients underwent repeat coronary and left
ventricular angiography. Over the course of 1 year left ventricular
ejection fraction increased in both groups without a significant
difference between them. The PCI group showed an increase in
ejection fraction of 4.2±8.9% (n=150) and the medical
group showed an increase of 3.5±8.2% (n=136;
P=0.47).
There was no significant difference in median change in LV end-systolic
volume index or end-diastolic volume index between groups. Again,
in this study PCI could be initiated 3 to 28 days after MI;
the median was 10 days. The authors concluded that based on
the OAT and TOSCA-2 study "routine PCI is not recommended for
stable patients with a persistently occluded infarct related
artery after myocardial infarction." However, if reperfusion
is not begun until 10 days after onset of acute myocardial infarction,
the chances of interfering with LV remodeling may be very small
as infarct expansion and LV dilation are already well underway.
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Conclusions
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The preclinical studies consistently show a reduction of infarct
expansion and left ventricular dilation when reperfusion is
initiated late—meaning too late to reduce myocardial infarct
size. However, it is likely that there is only a finite time
window of opportunity in which late reperfusion can be initiated
and still have a benefit; if reperfusion is induced beyond this
window of opportunity, then LV remodeling is not affected. The
present article by Nakagawa suggests that reperfusion even at
24 hours after coronary occlusion has benefit in a rat model.
Their study suggests that the open artery hypothesis is alive
and well and suggests that there is a need to revisit the issue
with an OAT-like trial in which PCI is initiated at an earlier
time point, such as 24 hours, rather than 8 to 10 days, after
onset of acute myocardial infarction.
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Acknowledgments
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Disclosures
None.
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Footnotes
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The opinions expressed in this editorial are not necessarily
those of the editors or of the American Heart Association.
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[Abstract]
[Full Text]
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