ACE2 in the Heart
Dr. Gavin Oudit’s research on heart enzymes could help prevent heart failure and improve the quality of life for patients with heart disease.
Story by Tara Narwani/Illustration by Guy Parsons
Heart failure—a condition where the heart is unable to pump sufficient blood to the rest of the body—is on the rise in Canada. Without sufficient blood, the body’s organs are starved of oxygen and nutrients, which causes damage. According to the Heart and Stroke Foundation, between 40% and 50% of people with heart failure die within five years of diagnosis.
For Dr. Gavin Oudit, a cardiologist and assistant professor at the University of Alberta, these figures are “unacceptably high.” New results coming out of his lab, however, give Dr. Oudit hope that a new approach to treating heart failure is on the horizon.
Dr. Oudit’s research group focuses on how the renin–angiotensin system (RAS) contributes to heart failure. The RAS is responsible for regulating the body’s long-term blood pressure. When blood pressure drops, the kidneys release a protein called renin into the bloodstream that, in turn, generates the molecule angiotensin I (Ang I). Then an enzyme called ACE (angiotensin converting enzyme) breaks down Ang I into angiotensin II (Ang II).
Dr. Oudit calls Ang II a “bad peptide.” Studies have shown that exposure to high levels of Ang II causes high blood pressure, thickening of the heart muscle and heart valves, and stiffening of heart chambers—all of which are risk factors for heart failure.
Since ACE activity is key to the production of the bad peptide, one of the primary treatment approaches for heart failure is to use a drug—an ACE inhibitor—that blocks ACE activity.
The problem is that ACE inhibitors aren’t always fully effective. “We know that, even if you’re on these medications, these bad peptide levels can still be high. We know that there are escape paths through which Ang II can be made,” explains Dr. Oudit.
A potential solution to this problem has emerged from studies on another enzyme involved in RAS: ACE2 converts Ang II into the “good peptide” Ang-(1-7) and, therefore, counteracts the action of ACE.
“ACE2 is central here. Using ACE2, you can block the bad peptide while enhancing the good peptide. This is the double whammy,” says Dr. Oudit.
The importance of ACE2 in protecting heart function has been clearly demonstrated in the lab. Use of an engineered form of ACE2, called rhACE2, counteracted the negative effects of exposure to high levels of Ang II, namely the thickening of heart walls and heart valves that contribute to heart failure.
A research group in Switzerland recently completed a Phase 1 clinical trial of rhACE2 in healthy volunteers and showed that the protein is safe for patients.
According to Dr. Oudit, the researchers "don’t fully understand the effects they saw. But, peptide levels changed as expected, without causing low blood pressure or kidney failure, which is a problem with ACE inhibitors and other related medications.”
In preparation for a Phase 2 clinical trial of rhACE2 in patients with heart failure, Dr. Oudit is currently launching a study in Edmonton to profile the peptide levels of patients with a range of heart conditions. He anticipates that ACE2 might become part of future therapies tailored for particular groups of patients.
“We don’t think that ACE2 will be something we can use for all patients. In the case of the subgroup of patients that have elevated Ang II levels despite being on medication,” says Dr. Oudit, “they might benefit from ACE2.”
Although it’s early, Dr. Oudit is excited about the prospects for ACE2. “By giving ACE2 to patients, we expect to see improvements in their heart function—for example, in the way their blood vessels work. And, hopefully, we can make them feel better and live longer.”