HIV protease inhibitors that block GLUT4 precipitate acute, decompensated heart failure in a mouse model of dilated cardiomyopathy.
The clinical use of HIV protease inhibitors is associated with insulin resistance and other metabolic changes that increase long-term cardiovascular risk. Since the failing heart has increased reliance on glucose, the influence of drug exposure on glucose homeostasis, myocardial glucose uptake, cardiac function, and survival was determined in TG9 mice, an established transgenic model of dilated cardiomyopathy generated by cardiac-specific overexpression of Cre-recombinase, as these animals progressed to overt heart failure. Beginning on day of life 75, TG9 mice and nontransgenic littermate controls were given a daily 10 mg/kg intraperitoneal injection of HIV protease inhibitors (ritonavir, lopinavir/ritonavir 4:1, atazanavir, atazanavir/ritonavir 4:1) or vehicle. Glucose tolerance testing, measurement of in vivo myocardial 2-deoxyglucose uptake, and echocardiography were performed before and 30 min following drug administration. The progression of dilated cardiomyopathy in TG9 animals was accompanied by impaired glucose tolerance, which was acutely exacerbated by exposure to ritonavir. Ritonavir and lopinavir precipitated acute, decompensated heart failure and death from pulmonary edema in TG9 mice. However, atazanavir, which does not inhibit glucose transport, had no effect. These studies demonstrate that, in the presence of dilated cardiomyopathy, HIV protease inhibitors that impair glucose transport induce acute, decompensated heart failure. The potential for HIV protease inhibitors to contribute to or exacerbate cardiomyopathy in human patients warrants further investigation.
Hruz
Paul W
PW
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA. hruz_p@kids.wustl.edu
Yan
Qingyun
Q
Struthers
Heidi
H
Jay
Patrick Y
PY
D000818:Animals; D000069446:Atazanavir Sulfate; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000150:complications*; D003847:Deoxyglucose / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000633:toxicity*; D006333:Heart Failure / Q000139:chemically induced / Q000209:etiology*; D006801:Humans; D007333:Insulin Resistance; D061466:Lopinavir; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D009842:Oligopeptides / Q000633:toxicity; D011654:Pulmonary Edema / Q000139:chemically induced; D011725:Pyridines / Q000633:toxicity; D011744:Pyrimidinones / Q000633:toxicity
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D003847:Deoxyglucose