An anti-depressant that is no longer prescribed could potentially be used to combat heart failure, according to a study conducted by researchers in the Cardiology Department at Hopkins in collaboration with researchers from other institutions across the country and in Italy.
In their paper, published in Circulation Research, the international group examined Monoamine Oxidases (MAOs), mitochondrial enzymes that generate hydrogen peroxide by breaking down specific neurotransmitters, such as norepinephrine and serotonin.
Hydrogen peroxide, like other reactive oxygen species, can at elevated concentrations contribute to heart failure; as such the presence and high activity of MAOs appears to play an important role in congestive heart failure.
According to the American Heart Association, 5.7 million Americans are currently living with heart failure, with an additional 670,000 new cases diagnosed each year.
Patients with this disease are not able to exert themselves physically as much as they normally could, as the heart is not able to function as efficiently and circulation slows.
Fluids may build up in parts of the body, resulting in edema that may affect the appearance of certain parts of the body or even cause breathing issues when buildup occurs in the lungs.
Finding and treating causes of heart failure can decrease the rate of new heart failure cases each year.
The researchers focused specifically on MAO-A. To test its role in the abnormal enlargement of myocardial cells, a symptom of heart failure, the group externally applied norepinephrine to stimulate MAO-A in cultured rat neonatal and adult cardiomyocytes.
Norepinephrine is a stress hormone involved in the fight-or-flight response. They found indications of enhanced MAO-A activity and oxidative stress that can lead to heart failure, including increased MAO-A gene expression, cell size and production of mitochondrial reactive oxygen species.
The group then tested the effect of clorgyline, an MAO-A inhibitor and previously used anti-depressant, on production of reactive oxygen species in cardiomyocytes. They found that norepinephrine-induced production of reactive oxygen species was significantly inhibited.
"We decided to pursue clorgyline as a MAO-A inhibitor because [it is] very specific for the isoform MAO-A and also because previously used in many experimental models (different from cardiovascular) and also in humans," Nazareno Paolocci, a professor of medicine at Hopkins and lead researcher, said in an email to the News-Letter.
"The drug was no longer used in humans for its many side effects due to the irreversibility of its action," he said. "Now we have reversible MAO-A inhibitors that we can test even in the cardiovascular setting, and we will validate our findings with clorgyline employing other MAO-A inhibitors."
Although the human body naturally produces an enzyme called catalase to decompose hydrogen peroxide, Paolocci suggests that this response is unable to effectively counter the increased oxidative stress.
"We didn't measure antioxidant defense directly but failure to buffer excess ROS signaling is strongly suggested by the fact that in vivo oxidative stress is sky-high after six weeks of TAC [Transverse Aortic Constriction]," he said.
Through a comparison of the function in the left ventricle of mice with a mutation that inhibits production of MAO-A with wild-type mice, the group also found further evidence that MAO-A activity contributes to an oxidative pressure overload.
Mice with the mutation exhibited almost no MAO-A activity, but some MAO-B activity persisted; their results still showed a significant difference in oxidative pressure as a result of the genetic inhibition.
Although they were not able to examine the role of MAO-B, the group notes that MAO-B has not been shown in previous studies to have a major role in the breakdown of norepinephrine.
While these results are only preliminary as regards the potential of clorgyline, they do confirm that MAO-A activity, combined with increased norepinephrine availability, directly contributes to heart failure.
This presents the possibility of reducing the incidence of heart failure by isolating a cause and exploring possible preventive treatments.
