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Resveratrol Reverses Functional Chagas Heart Disease in Mice
Glaucia Vilar-Pereira1, Vitor C Carneiro2, Hilton Mata-Santos3,4
1Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia das Interações, Rio de Janeiro, RJ, Brazil.
Insights
Antioxidants like resveratrol can reverse heart dysfunction in Chagas heart disease by activating AMPK and reducing oxidative stress. These treatments improved cardiac function even when initiated late, unlike traditional therapies.
Area of Science:
- Cardiology
- Parasitology
- Pharmacology
Background:
- Chronic chagasic cardiomyopathy (CCC) develops years after Trypanosoma cruzi infection.
- Cardiac dysfunction in CCC is linked to oxidative stress, arrhythmias, and contractile issues.
- Current trypanocidal therapies are ineffective in improving established cardiac function.
Purpose of the Study:
- To investigate the cardioprotective effects of antioxidants and AMPK activators in established Chagas heart disease.
- To determine if resveratrol, metformin, or tempol can improve cardiac function and reduce oxidative stress in a mouse model of CCC.
- To compare the efficacy of these agents with the trypanocidal drug benznidazole.
Main Methods:
- A mouse model mimicking the B1-B2 stage of human CCC was used.
- Mice were treated with resveratrol, metformin, or tempol.
- Cardiac function was assessed using electrocardiography and echocardiography.
- Oxidative stress markers, parasite burden, and myocarditis were evaluated.
Main Results:
- Resveratrol improved cardiac function, including heart rate, ejection fraction, and stroke volume, and reduced arrhythmias.
- Resveratrol activated the AMPK pathway, decreased reactive oxygen species (ROS) production, and reduced parasite burden.
- Metformin and tempol mimicked resveratrol's beneficial effects on cardiac function and reduced lipid peroxidation but did not affect parasite burden.
- Resveratrol improved cardiac function even when treatment was initiated late, outperforming benznidazole.
Conclusions:
- AMPK activation and ROS neutralization are crucial for inducing tolerance to Chagas heart disease.
- Physiological cardiac dysfunction in established CCC can be reversed by treatments like resveratrol, metformin, and tempol.
- These findings suggest novel therapeutic strategies for Chagas heart disease, focusing on cardioprotection and metabolic pathways.
Abstract:
Chronic chagasic cardiomyopathy (CCC) develops years after acute infection by Trypanosoma cruzi and does not improve after trypanocidal therapy, despite reduction of parasite burden. During disease, the heart undergoes oxidative stress, a potential causative factor for arrhythmias and contractile dysfunction. Here we tested whether antioxidants/ cardioprotective drugs could improve cardiac function in established Chagas heart disease. We chose a model that resembles B1-B2 stage of human CCC, treated mice with resveratrol and performed electrocardiography and echocardiography studies. Resveratrol reduced the prolonged PR and QTc intervals, increased heart rates and reversed sinus arrhythmia, atrial and atrioventricular conduction disorders; restored a normal left ventricular ejection fraction, improved stroke volume and cardiac output. Resveratrol activated the AMPK-pathway and reduced both ROS production and heart parasite burden, without interfering with vascularization or myocarditis intensity. Resveratrol was even capable of improving heart function of infected mice when treatment was started late after infection, while trypanocidal drug benznidazole failed. We attempted to mimic resveratrol's actions using metformin (AMPK-activator) or tempol (SOD-mimetic). Metformin and tempol mimicked the beneficial effects of resveratrol on heart function and decreased lipid peroxidation, but did not alter parasite burden. These results indicate that AMPK activation and ROS neutralization are key strategies to induce tolerance to Chagas heart disease. Despite all tissue damage observed in established Chagas heart disease, we found that a physiological dysfunction can still be reversed by treatment with resveratrol, metformin and tempol, resulting in improved heart function and representing a starting point to develop innovative therapies in CCC.
