Drug that could prevent cardiac symptoms of Chagas disease

Chagas disease, a result of infection with the parasite Trypanosoma cruzi, represents the main cause of dilated cardiomyopathy throughout the American continent (World Health Organization, 2015). According to the latest consensus on Chagas disease prepared by the Argentine Society of Cardiology, in Argentina more than 1,500,000 people suffer from this disease, and more than 375,000 present cardiological symptoms (Sociedad Argentina de Cardiología, 2019).

Antiparasitic treatment depends fundamentally on benznidazole which, although it effectively eliminates parasites, does not improve the cardiac dysfunction caused by the infection and characterized by persistent inflammatory processes.

Specialists from the National Council for Scientific and Technical Research (CONICET) in Argentina have identified a drug that could prevent the cardiac symptoms of Chagas disease.

This medication, which is called fenofibrate and is currently used to reduce triglyceride and cholesterol levels, improved cardiac dysfunction in an experimental model of this cardiac pathology caused by Chagas disease.

The study has been published in the academic journal ACS Infectious Diseases.

The next step would be to carry out clinical trials to demonstrate the therapeutic efficacy of this drug in its new function.

“These findings support and reinforce the potential repositioning of fenofibrate as a complementary therapeutic drug to antiparasitics to alleviate, delay or prevent cardiac symptoms of this neglected disease,” says Federico Penas, leader of the work and CONICET researcher at the Research Institute. Biomedical Studies in Retroviruses and AIDS (INBIRS, from CONICET and the University of Buenos Aires (UBA)).

Taking into account the limitations of benznidazole, “during the last few years, our laboratory, led by CONICET researcher Nora Goren, has investigated and delved into in vitro and in vivo studies on a joint therapy that involves not only the antiparasitic benznidazole, but also to an inflammation-modulating drug such as fenofibrate,” indicates Ágata Cevey, co-author of the new study and CONICET researcher at INBIRS.

In a work, published in 2022 in the academic journal Frontiers in Cellular and Infection Microbiology, the same research team and colleagues carried out in vitro experiments on peripheral blood mononuclear cells from patients with different degrees of severity of Chagas disease, and verified that treatment with fenofibrate increases the proportion of populations of one type of white blood cells towards an anti-inflammatory profile and therefore beneficial for cardiovascular health. This study was carried out in collaboration with the Cardiology services of the Dr. Cosme Argerich General Acute Hospital and the María Ferrer Respiratory Rehabilitation Hospital.

In a study published in 2023, also in the academic journal ACS Infectious Diseases, the CONICET research team demonstrated for the first time in an experimental model (mice with Chagas disease) that cells of the immune system, cardiac macrophages, play a fundamental role in the protective effects of fenofibrate on the inflammatory and fibrotic response in the chronic stage of infection. “We show that cardiac macrophages are necessary for fenofibrate to improve ventricular function in infected mice,” Penas points out.

In the new work, the researchers verified that in the animal model of the disease, fenofibrate reduces the activity of enzymes that mark tissue damage and decreases the proportion of circulating pro-inflammatory monocytes. “These cells of the immune system have the ability to internalize themselves into tissues, differentiate into macrophages and initiate a powerful proinflammatory response,” explains Penas. And he adds: “We observed that fenofibrate induces a change in the profile of cardiac macrophages, towards an anti-inflammatory or reparative one, which results in a reduction in fibrosis (changes in the collagen matrix that leads to alterations in cardiac function), inflammation and an improvement in ventricular function in early stages of Chagas disease.”

Fenofibrate changes the profile of cardiac macrophages, decreases inflammation and fibrosis, and improves ventricular function in an experimental model of Chagas disease. (Image: CONICET)

“In the future, we will continue to delve deeper into the mechanisms of action of the joint treatment with benznidazole and fenofibrate in different cell populations,” Penas points out. And he adds. “In parallel, and considering all the background described, we will begin planning a pilot clinical trial that will consist of treatment with fenofibrate and benznidazole to patients with different degrees of severity of Chagas disease. This trial will have the approval of the Ethics Committees of the participating hospitals.”

For Cevey, “the interesting thing about exploring the use of fenofibrate in patients with Chagas is that this medication does not have adverse cardiac effects, so it is suitable for prolonged use and is also approved by the ANMAT, as well as by the main global regulatory entities. (FDA, EMA) and is produced by several pharmaceutical laboratories in Argentina.”

For his part, Penas concludes that “it is crucial to develop new strategies accessible to both the public health system and patients, with the purpose of preventing cardiac complications associated with this infection.” (Source: Bruno Geller / CONICET. CC BY 2.5 AR)