Eugene Braunwald, MD, and colleagues discuss the role of myocardial reperfusion injury and whether treatment could one day improve patient care.
The last 35 years in intervention have been nothing short of a
revolution. From the initiation of balloon angioplasty in 1977 to the
development of stents and then drug-eluting stents in the following decades,
there has been no rest to the innovative spirit that has transformed the
treatment of occluded arteries.
And as a result of these and other medical advances, mortality rates for
patients with acute MI have been on a sharp decline.
The advances in treating MI have been just spectacular,
Eugene Braunwald, MD, Distinguished Hersey Professor of Medicine,
Harvard Medical School, Boston, told Cardiology Today
Intervention. Weve gone from a mortality rate [associated
with an acute MI] of 30% down to 15% with the development of the coronary care
unit and now with successful reperfusion its down to 7.5%. So its a
quarter of what it used to be.
Despite this significant drop, Braunwald believes the mortality rate in
patients with MI can and should be lower and represents an important direction
for future research.
If appendectomy was associated with a 7.5% mortality, you would
say something is really wrong. Well, there was a time when it was associated
with a 7.5% mortality and that was before antibiotics, he said. Now
an appendectomy in most hospitals and patients is associated with less than a
0.1% risk of mortality. In other words, 7.5% mortality [for MI] is too high and
we have to drive it down.
And one way this rate could be further improved, Braunwald said, is by
preventing injury caused by reperfusion.
However, after many decades of research into this topic, there is still
no consensus in the cardiology community as to whether the treatment of
reperfusion injury is a viable option or whether it is even needed.
A Journey Decades in the Making
The question of whether restoring blood flow to ischemic myocardium
induces injury has been on the radar in cardiology for more than 50 years. This
phenomenon, known as myocardial reperfusion injury, was first proposed by
Jennings and colleagues in 1960 after observing the histologic features of
reperfused ischemic canine myocardium.
A decade later, one of the landmark studies in the treatment of acute MI
that illuminated another facet of reperfusion therapy was published by
Braunwald, Maroko and colleagues in Circulation. What they found
in a population of dogs was that the severity and extent of myocardial ischemic
injury due to coronary occlusion could be substantially altered not only by
pretreatment but also by appropriate intervention as late as 3 hours after
We predicted that measures designed for the reduction of
myocardial oxygen demands and improvement of coronary perfusion when effected
promptly after a patient has been brought to a hospital might reduce the size
of the infarct. Nobody was researching that or even thinking about it at the
time, Braunwald said. I think that started a lot of people
hypothesizing and doing experiments.
One of the studies that followed in its path and continued to build upon
these findings was conducted by Reimer and Jennings, according to Robert A.
Kloner, MD, PhD, professor of medicine at the Keck School of Medicine at
the University of Southern California, Los Angeles, and director of research of
the Heart Institute of Good Samaritan Hospital, Los Angeles.
What they found in experimental models suggested that a wavefront
of necrosis occurred after a coronary occlusion, such that all the cells did
not die at the same time but the cell death progressed from the subendocardium
to the subepicardium and progressed over a period of 6 hours, he said.
In other words, if you interrupted the occlusion as you reperfused blood,
especially if you reperfused the myocardium within 3 hours of the coronary
occlusion, you could save tissue.
This study, along with the Braunwald et al study, were crucial in
showing that at the time of a coronary occlusion all the cells dont die
at the same time and paved the way for the concept of early reperfusion as the
best therapy for a heart attack, Kloner said.
This concept has persisted over the years, with therapy being fine-tuned
to meet the medical innovations of the time. Initially, thrombolysis was the
therapy of choice but that changed with the emergence of PCI.
PCI with angioplasty has been shown to be better than thrombolysis
because it opens up the artery earlier, quicker and keeps it open, Kloner
said. This was then followed by stenting, which seems to be the best: The
stent expands the artery, stays in place and keeps the artery open. So,
currently PCI with angioplasty/stenting and opening up the artery as early as
possible is the standard of therapy and then keeping it open with various
drugs, like clopidogrel (Plavix, Sanofi-Aventis) and aspirin, is crucial.
With PCI firmly established as the reperfusion therapy of choice, the
question was once again raised as to whether therapy did in fact also cause
There is very little doubt that when you reperfuse ischemic
myocardium, you do some good and some harm, Braunwald said.
Although the return of blood flow is ultimately good for the myocardium
that is undergoing ischemic necrosis, there is some tissue that is killed by
the return of blood; the reperfusion itself damages the endothelium and causes
calcium overload in the myocardial fibers, which in turn stimulates enzymes
that reduce the amount of energy in the heart muscles. And the oxygen itself
can be toxic.
According to Kloner, reperfusion injury can be broken into four main
components: reperfusion arrhythmias; stunned myocardium, which results from the
salvaged tissue not recovering function right away when blood flow is restored;
microvascular obstruction or the no-reflow phenomenon, which is the
consequence of blood not returning uniformly to all portions of the previously
ischemic tissue after the release of the vascular occlusion; and lethal
myocardial cell injury in which cells alive at the end of ischemia die due to
reperfusion, as noted above.
Without this injury caused by reperfusion, it has been estimated that it
may be possible to salvage another 35% to 40% of the myocardium, Braunwald
Therapies Lead to More Questions
A number of pharmaceutical therapies for reducing myocardial reperfusion
injury have been proposed over the decades, but to date, none have been
incorporated into routine clinical practice. So far, according to Kloner, white
cell inhibitors, complement inhibitors, oxygen radical scavengers, protein
kinase C delta inhibitors and intra-aortic balloon counterpulsation have all
had negative studies published concerning their use in reducing myocardial
The field has not moved forward as rapidly as had been hoped
because its turned out to be more complicated than anyone imagined,
Braunwald said. There have been a lot of attempts to prevent or even
reduce reperfusion injury, and people have been disappointed because progress
has been so slow.
One of the reasons for this, he said, is that a lot of the trials have
been performed on patients with small infarctions and a small infarction
doesnt need any help. Its the patients with large infarcts
who require this additional therapy, Braunwald said. If you had a
large infarct, the prevention of myocardial reperfusion injury could clearly
mean the difference between a fatal and nonfatal outcome.
For Karin Przyklenk, PhD, director of the Cardiovascular Research
Institute at Wayne State University School of Medicine, Detroit, part of the
problem has also stemmed from the search for a magic bullet drug
This is a problem for two main reasons: the first is that
reperfusion injury is multi-factorial, so its not very realistic to
expect that a drug addressing any one aspect of the problem is going to make a
meaningful impact in a clinical population, Przyklenk said. The
other, more technical question is a logistic issue; we realize now that
reperfusion injury happens very quickly, within the first seconds to minutes of
reflow, so, to be effective, a drug must reach its subcellular target in an
appropriate concentration and rapidly enough to make a difference. Im not
sure how feasible that is, particularly in a setting of total occlusion, where
no drug is going to be delivered to the at-risk myocardium until blood flow is
Still, Kloner said therapeutic bright spots exist in the field, one of
which being adenosine. The AMISTAD I and II trials showed that adenosine
when given in the later phase of ischemia but at least 15 minutes prior
to reperfusion reduced infarct size in humans when they were large
anterior infarcts, he said. These were two large, multicenter
studies which both showed the same results.
In a substudy looking at patients who were reperfused within 3 hours,
Kloner said that the patients who received adenosine and were reperfused early
had a decrease in major adverse clinical events, including death and HF.
Another therapeutic strategy gaining attention is post-conditioning,
which involves reperfusing in a stuttering fashion, so that reperfusion only
lasts seconds to minutes followed by reocclusion of the artery, and the process
is then repeated several times, Kloner said.
According to Braunwald, post-conditioning represents the most promising
technique to date for reducing myocardial reperfusion injury and, similar to
adenosine, has been clinically documented. In a recent paper published in the
Journal of Cardiovascular Pharmacology and Therapeutics (JCPT),
Braunwald wrote that in five studies testing post-conditioning in patients
experiencing STEMI, a reduction in the release of ischemic injury biomarkers
was observed in those who underwent post-conditioning compared with patients in
whom the strategy was not carried out.
However, Matthew T. Roe, MD, MHS, associate professor of medicine
at Duke Clinical Research Institute in Duke University Medical Center, Durham,
N.C., remained cautious about the potential role of both adenosine and
post-conditioning in clinical practice.
Regarding adenosine, the question is whether it should be given
intravenously or through direct coronary injection, and then what dose should
be given and how long it should be administered. Those are questions that
havent been fully understood, he said. Although it does look
promising, the challenge with adenosine is that it does lower BP, so you have
to be careful because it could potentially cause hypotension and some problems.
And with post-conditioning, it involves the patient staying in the
cath lab for a longer period of time, its not certain that it will
improve outcomes and risks are associated with the procedure, including vessel
trauma from repeated balloon inflations (dissection, perforation), repeat
ischemic insults and bleeding from additional catheter manipulation in the
groin, Roe said. Many physicians also may feel that it is not
ethical to study this treatment because we know that opening an artery quickly
and restoring normal blood flow to the tissue helps the patient and [with
post-conditioning] youre saying, Okay, weve done that, but
now we are going to occlude the vessel again. So, ultimately, I think
its going to be tough to do a trial with post-conditioning.
Perhaps another mechanical intervention that may someday find a home in
clinical practice is remote ischemic conditioning, or the concept that ischemia
in one tissue can release protective factors that will then protect a remote
bed, Przyklenk said.
The way it has been put into practice is by applying a BP cuff to
the arms or legs and then inflating and deflating the cuffs for one or more
5-minute periods to induce limb ischemia-reperfusion, she said. The
largest clinical study to date was published by Bøtker et al in
The Lancet in 2010. They applied remote conditioning in the
ambulance and found that the outcome following angioplasty was improved in
patients who received remote conditioning when compared with placebo. The
mechanism is not well understood, but the phenomenon is becoming increasingly
The Debate Goes On
Whether prevention of reperfusion injury in the treatment of patients
with STEMI is in fact needed is still far from agreed upon by the cardiology
community. At last years European Society of Cardiology Congress in
Paris, this debate was center stage in a session called Controversies in
Acute Coronary Syndrome.
David Erlinge, MD, PhD, associate professor at Lund University,
Lund, Sweden, and one of the presenters during the session, took the con
position in terms of whether treatment is needed, saying that the hundreds of
millions of dollars in research money spent on cardioprotection may be better
utilized in other areas of research, such as therapies that have been
clinically shown to reduce the incidence of STEMI. We could also turn to
new therapies like stem cell therapies
or put the money on primary
prevention and get more for the dollar, Erlinge said in his presentation.
Roe agreed that further research into therapies to reduce reperfusion
injury may be obviated by priorities in other areas of research, and further
added that health care dollars are limited and will be even more so in the
However, I feel it is important to look at it more from a
scientific viewpoint because there is still clearly a scientific need and
interest to sort this out. If there is a therapy that looks very promising with
reconsideration of a development pathway for a given therapy, we should at
least consider it, Roe said. Novel therapies for reperfusion injury
will need to be stacked up against many other things, but I would hope that we
wont shut the door on therapies like these in the future.
Kloner also emphasized that MI is one of the leading killers in the
world, affecting nearly a million people in the United States alone every year,
and anything that can be done to aid in lowering the incidence should not be
Every time there is an MI, it chips away at viable heart tissue.
So the more that can be done to salvage heart tissue the better, Kloner
said. And the idea that we should just walk away from the concept of
treating myocardial reperfusion injury would be a mistake.
Search for a Breakthrough Continues
Despite the lack of practice-changing therapy for reducing reperfusion
injury, research continues to examine the role of therapies in saving tissue,
both in preclinical and clinical models.
There is a big European study being done with cyclosporine, the
pharmacologic way to post-condition, Kloner said. He added that a paper
by Piot and colleagues published in The New England Journal of
Medicine showed that using cyclosporine in patients with acute STEMI
immediately before undergoing PCI led to smaller infarct size when compared
Also upcoming, the Consortium for Preclinical Assessment of
Cardioprotective Therapies (CAESAR), a multicenter animal testing program
established by the NHLBI, will be assessing a number of what Braunwald said are
promising interventions for ischemic myocardial reperfusion injury following
timely and optimal reperfusion.
CAESAR is going to help push research in this field forward,
Braunwald said. Its a big step.
In the paper published in JCPT, Braunwald laid the
groundwork for what he said will be necessary criteria for future trials,
stating that they should be carried out in close consultation with CAESAR
investigators; supported by core laboratories with expertise in cardiac imaging
and biomarker measurement; conducted in multiple centers that enroll a sizeable
number of patients with STEMI who receive PCI within 6 hours of symptom onset;
and ideally funded by the NHLBI.
Although many debate as to whether future research into therapies for
limiting reperfusion injury will be able to accomplish what the previous
decades of investigation were unable to, Braunwald remains confident that it
Practice-changing research is not an overnight thing, he
said. It took a long time to progress from a coronary angiogram to
putting in a stent about 20 years. Although I have to admit the search
for therapies has been a long and frustrating process, now is the right time to
move it forward. by Brian Ellis
Bøtker HE. Lancet.
Braunwald E. J Cardiovasc Pharmacol
Ther. 2011; 16:349-353.
Braunwald E. J Clin Invest.
Jennings RB. Pathology.
Maroko PR. Circulation.
Piot C. N Engl J Med. 2008;
Yellon DM. N Engl J Med. 2007;
Disclosure: Drs. Braunwald and Przyklenk report
no relevant financial disclosures; Dr. Erlinge has received speakers fees
from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Philips and The Medicines
Company, and research grants from Eli Lilly; Dr. Kloner has received grants
from Stealth and Gilead to study products related to this topic in experimental
models and was an investigator in the AMISTAD trials; Dr. Roe has consulted for
and has helped conduct a study to test a product related to this topic for KAI