Cardiac dysfunction occurs in the HIV-1 transgenic mouse treated with zidovudine

Cardiomyopathy in AIDS is an increasingly important clinical problem. Mecha nisms of AIDS cardiomyopathy were explored using AIDS transgenic mice that express replication-incompetent HIV-I (NL4-3 Delta gag/pol). Transgenic and FVB/n mice (n = 3 to 6 per cohort) received water ad libitum with and with out zidovudine (3'-azido-2',3'-deoxythymidine; AZT; 0.7 mg/ml) for 21 or 35 days. After 21 days, echocardiographic studies were performed and abundanc e of mRNA for cardiac sarcoplasmic reticulum calcium ATPase (SERCA2), sodiu m calcium exchanger (NCX1), and atrial natriuretic factor were determined i ndividually using Northern analysis of extracts of left ventricles. After 3 5 days, contractile function and relaxation were analyzed in isolated work- performing hearts. Histopathological and ultrastructural (transmission elec tron microscopy) changes were identified. After 21 days, molecular indicato rs of cardiac dysfunction were found. Depressed SERCA2 and increased atrial natriuretic factor mRNA abundance occurred in left ventricles from ATT-tre ated transgenic mice. NCX1 abundance was unchanged. Eccentric left ventricl e hypertrophy was determined echocardiographically. After 35 days, cardiac dysfunction was worst in AZT-treated and ATT-untreated transgenic mice. Dec reases in the first derivative of the maximal change in left ventricle syst olic pressure with respect to time (+dP/dt) occurred in transgenic mice wit h and without AZT. Increased half-time of relaxation and ventricular relaxa tion (-dP/dt) occurred in ATT-treated and -untreated transgenic mice. Incre ased time to peak pressure was found only in AZT-treated transgenic mice. I n AZT-treated FVB/n mice, -dP/dt was decreased. Ultrastructurally, mitochon drial destruction was most pronounced in AZT-treated transgenic mice, but a lso was found in AZT-treated FVB/n mice. Transgenic mice that express HIV-1 demonstrate cardiac dysfunction. AZT treatment of FVB/n mice causes mitoch ondrial ultrastructural alterations that are similar to those in other spec ies. In transgenic mice, AZT treatment worsens molecular and ultrastructura l features of cardiomyopathy. HIV-I constructs and AZT each contribute to c ardiac dysfunction in this murine model of AIDS cardiomyopathy.