Bleeding Heart

Redefining hemorrhage as a major contributor to reperfusion injury opens up new avenues for treatment

June 15, 2015

Medicine is not perfect. Medications often have unwanted side effects. Surgeries can have complications. Only by recognizing and understanding these obstacles can we limit their impact. Nowhere is this arguably truer than in the treatment of heart attacks.

Heart attacks occur when blood flow to the heart is restricted and oxygen-rich blood cannot reach the heart muscle. If the blockage is not removed fast enough, then the heart cells become starved of oxygen and die, leading to irreversible tissue damage.

Treatments for heart attacks aim to reestablish blood flow to the heart, either by dissolving blood clots or by mechanically opening up obstructed arteries. However, restoring blood flow back to the heart, also known as reperfusion or revascularization, brings its own set of challenges. Between 35% and 50% of patients who have severe heart attacks experience complications following reperfusion, including hemorrhage, inflammation and injury to small blood vessels. Patients with these symptoms, known as reperfusion injury, fall into a high-risk group whose members have poor long-term prognoses. For these patients, revascularization is a double-edged sword: life-saving on the one hand, harmful on the other.

“By opening up the artery, you’re helping the patient, but you’re also introducing these other factors that may cause additional damage. But you have to do it. The question is, how do you manage after that?” says Dr. Nilesh Ghugre, a junior scientist in the Schulich Heart Research Program at Sunnybrook Research Institute (SRI).

Under the mentorship of Dr. Graham Wright, director of the Schulich Heart Research Program, Ghugre is challenging the current paradigm that hemorrhage is a passive bystander in the adverse events following reperfusion.

Because patients who experience hemorrhage often have other complications, it is difficult to dissect the relationship between hemorrhage and reperfusion injury. To tease apart the effects of hemorrhage on these co-occurring conditions, Ghugre worked with Wright and Dr. Bradley Strauss, a senior scientist at SRI and head of the Schulich Heart Program at Sunnybrook, to develop a new preclinical model of myocardial hemorrhage that could be used for research. In a study published in the Journal of Cardiovascular Magnetic Resonance (JCMR), the scientists showed that they could induce hemorrhage in the heart with the enzyme collagenase, which weakens the blood vessel wall and makes it more likely to leak blood into surrounding tissue. Leaked blood pools in the heart muscle, thereby mimicking the myocardial hemorrhage caused by reperfusion without the other heart attack- and reperfusion-related injuries. In the course of these studies, Ghugre and Wright partnered with GE Healthcare to develop and optimize new imaging techniques that enabled them to identify areas of hemorrhage and inflammation on an MRI scan.

If hemorrhage is a major cause of adverse downstream events, [then] trying to only block the downstream events is like trying to stop the flood after the dam has broken.

Building on his new model, Ghugre devised a strategy wherein he induced an artery occlusion (to mimic a heart attack) with or without hemorrhage. To test if hemorrhage by itself would cause harm, he included a third group that only experienced hemorrhage. When he looked at inflammation and cardiac function, Ghugre found that a blocked artery with hemorrhage resulted in worse outcomes than a blocked artery without hemorrhage. More surprisingly, he found that inducing hemorrhage alone resulted in inflammation and reduced cardiac function similar to that caused by a blocked artery. The results, published last year in JCMR, indicate that hemorrhage is an active contributor to cell damage and inflammation.

“It’s actually a combination of restricted blood flow to the heart and hemorrhage that seems to make things worse,” says Wright. “This makes sense because restricting blood flow followed by reperfusion creates factors like free radicals, which are extremely damaging to cells and set the stage for inflammation. Hemorrhage may further enhance the effects of those factors to create a kind of chronic inflammation.”

Wright notes that the implications of these findings are significant. “If hemorrhage is a major cause of adverse downstream events, [then] trying to only block the downstream events is like trying to stop the flood after the dam has broken. Instead, this may be an opportunity to fix the root of the other problems,” he says.

During hemorrhage, hemoglobin, iron-containing molecules that trap oxygen, are released from red blood cells and broken down into iron byproducts, which creates an excess of iron at the site. This type of overload is harmful to the heart because it induces an inflammatory response and produces toxic free radicals, both of which, as Wright notes, can damage cells. Ghugre hypothesized that it was actually this flood of excess iron from the hemorrhage that was interfering with recovery. If this were true, he reasoned, then getting rid of the iron should lessen the impact of hemorrhage on inflammation and other reperfusion-related symptoms.

Drawing on his PhD research, which focused on excess iron burden in the liver and heart of patients with thalassemia and sickle cell disease, genetic blood disorders that cause anemia, Ghugre turned to examining the effectiveness of iron chelators in treating reperfusion injury. Iron chelators are chemical compounds that track down and neutralize excess free iron circulating in the body and deposited in organs. For the pilot study, Ghugre chose the iron chelator deferiprone because it is small and can penetrate tissues easily.

Preliminary results in a preclinical model showed that deferiprone was a fast and effective remedy for hemorrhage and swelling. It also helped maintain cardiac function after a heart attack. This was the first study to show that deferiprone is successful at treating myocardial hemorrhage and reperfusion injury. The study was published in JCMR and done in collaboration with Children’s Hospital Los Angeles and ApoPharma, a Toronto-based pharmaceutical company.

Ghugre cautions that while these early results are promising, questions remain. “We still need to confirm our results. If these ongoing studies show benefit, then we need to know why,” he says.

He is now trying to figure out how deferiprone acts on the heart and how best to administer the drug. As Ghugre notes, “It’s not just dosage. Timing and duration of therapy is everything.”

He is working with ApoPharma to conduct preclinical studies that he hopes will pave the way for clinical trials. Because deferiprone is already authorized by Health Canada and the U.S. Food and Drug Administration to treat other iron overload diseases, Ghugre expects that if the drug makes it through to clinical trials, then the regulatory approval process will be easier and faster.

Ghugre’s work has opened up new avenues of research into mitigating the harmful effects of hemorrhage on recovery after a heart attack. In the balance between the benefits and risks of revascularization, his work could help tip the scales in favour of the patient. Ultimately, Ghugre says, “You want optimal healing so that patients do better in the long term.”

This research was supported by ApoPharma, Federal Economic Development Agency for Southern Ontario, Heart and Stroke Foundation, and Ontario Ministry of Research and Innovation (MRI). Equipment support came from the Canada Foundation for Innovation, GE Healthcare and MRI.

Dr. Nilesh Ghugre