First, Do No Harm

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.

	Eugene Braunwald

“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. “We’ve 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 it’s down to 7.5%. So it’s 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 occlusion.

“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.”

	Robert A. Kloner

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 don’t 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 preventable injury.

“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 said.

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 injury.

“The field has not moved forward as rapidly as had been hoped because it’s 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 doesn’t need any help. “It’s 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.”

	Karin Przyklenk

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 candidate.

“This is a problem for two main reasons: the first is that reperfusion injury is multi-factorial, so it’s 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. I’m 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 restored.”

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.

	Matthew T. Roe

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 haven’t 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, it’s 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] you’re saying, ‘Okay, we’ve done that, but now we are going to occlude the vessel again.’ So, ultimately, I think it’s 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 well documented.”

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 year’s 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 future.

“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 won’t 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 overlooked.

“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 with placebo.

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. “It’s 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 will.

“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

References:

• Bøtker HE. Lancet. 2010;374:727-734.

• Braunwald E. J Cardiovasc Pharmacol Ther. 2011; 16:349-353.

• Braunwald E. J Clin Invest. 1985;76:1713-1719.

• Jennings RB. Pathology. 1960;70:68-78.

• Maroko PR. Circulation. 1971;43;67-82.

• Piot C. N Engl J Med. 2008; 359:473-481.

• Yellon DM. N Engl J Med. 2007; 357:1121-1135.

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 Pharmaceuticals.