Characterization of the Cytoskeleton in a Model of HAART-Induced Cardiomyopathy

Abstract

Background: Dilated cardiomyopathy (DCM) in HIV-positive patients is an increasingly important clinical problem, resulting in symptomatic heart failure in up to 5% of patients. Patients with HIV-associated DCM have a worse prognosis than those with idiopathic DCM. Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality of AIDS, but has resulted in an increase in cardiac and skeletal mitochondrial myopathies. Idiopathic DCM is associated with cytoskeletal disruption, but the role of the cytoskeleton in mitochondrial myopathies is unknown. Objectives: The goals of this study were to develop a murine model of HAART-induced DCM and investigate the effects on cytoskeletal integrity. Methods: Cytoskeletal disruption and cardiac function were investigated in a transgenic mouse model with myocardial restricted Fas ligand expression (MHCsFasL). Transgenic (TG) and non-transgenic (NTG) mice (n=3 to 6) received water ad libitum with and without zidovudine (3′-azido-2′,3′-deoxythymidine; AZT; 1 mg/ml) for 14 days beginning at 8, 10, and 12 weeks of age. After 14 days, echocardiographic studies were performed and the mice were sacrificed and histopathological, immunohistochemical and ultrastructural (transmission electron microscopy; TEM) characterization of the heart performed. Results: NTG mice (treated and untreated), as well as untreated TG showed little or no changes in cardiac function and pathology. In contrast, AZT-treated TG mice developed cardiac hypertrophy, dilated left ventricles, reduced cardiac function and had inflammatory infiltration of both chambers. These changes were associated with disruption of the cytoskeleton, as determined by loss of dystrophin staining and actin filament disarray, along with increased in the number of cells undergoing apoptosis. TEM studies are on-going. Conclusions: The expression of Fas ligand in the myocardium, as identified in children with HIV-associated heart disease, may increase the susceptibility to HAART-induced cardiomyopathy, which is characterized by cytoskeletal disruption, as seen in other forms of acquired cardiomyopathy.