Heart failure with reduced ejection fraction (HFrEF) is a cardiovascular disease with a high degree of both severity and prevalence, with an estimated 3-4 million patients suffering from this condition in the US alone. Cardiomyopathy, including metabolic and contractile dysfunction of cardiomyocytes, is a major determinant of patient morbidity and mortality in HFrEF. Interventions that reduce the deterioration of myocardial metabolic and contractile function would significantly improve outcomes for the millions of patients afflicted with HFrEF.
Previous studies on HFrEF have pointed to oxidative stress, associated with an increase in mitochondrial oxidants, as a major factor in myocardial metabolic and contractile dysfunction. N-Acetylcysteine (NAC), a drug used clinically to treat Tylenol® overdose, both acts as an antioxidant on its own and promotes the synthesis of glutathione, one of the body’s main endogenous antioxidants that functions in redox homeostasis.
I will test the hypothesis that in vitro incubation of myocardial tissue from patients with end-stage HFrEF in NAC will lower oxidants and improve mitochondrial metabolism. I will conduct my investigation as part of a broader study involving patients with end-stage HFrEF who receive surgery for the placement of a left ventricular assistive device. During the procedure, the surgeon removes a large piece of the left ventricle. I will join members of the Ferreira Lab at the operating room to receive the cardiac biopsy and process for in vitro incubation in control conditions and NAC. After the incubation, I will measure a hydrogen peroxide emission assay with these tissue samples allowing me to determine oxidant content while a colleague simultaneously measures the respiratory function of isolated mitochondria.