Combined antiretroviral therapy causes cardiomyopathy and elevates plasma lactate in transgenic AIDS mice

Highly active antiretroviral therapy (HAART) is implicated in cardiomyopath y (CM) and in elevated plasma lactate (LA) in AIDS through mechanisms of mi tochondrial dysfunction. To determine mitochondrial events from HAART in vi vo, 8-week-old hemizygous transgenic AIDS mice (NL4-3 Delta gag/pol; TG) an d wild-type FVB/n littermates were treated with the HAART combination of zi dovudine, lamivudine, and indinavir or vehicle control for 10 days or 35 da ys. At termination of the experiments, mice underwent echocardiography, qua ntitation of abundance of molecular markers of CM (ventricular mRNA encodin g atrial natriuretic factor [ANF] and sarcoplasmic calcium ATPase [SERCA2]) , and determination of plasma LA. Myocardial histologic features were analy zed semiquantitatively and results were confirmed by transmission electron microscopy. After 35 days in the TG + HAART cohort, left ventricular mass i ncreased 160% by echo cardiography. Molecularly, ANF mRNA increased 250% an d SERCA2 mRNA decreased 57%. Biochemically, LA was elevated (8.5 +/- 2.0 mm ). Pathologically, granular cytoplasmic changes were found in cardiac myocy tes, indicating enlarged, damaged mitochondria. Findings were confirmed ult rastructurally. No changes were found in other cohorts. After 10 days, only ANF was elevated, and only in the TG + HAART cohort. Results show that cum ulative HAART caused mitochondrial CM with elevated LA in AIDS transgenic m ice.