In vivo model of drug-induced valvular heart disease in rats: pergolide-induced valvular heart disease demonstrated with echocardiography and correlation with pathology

Abstract

Valvular heart disease (VHD), inducing valvular regurgitation, has been described in carcinoid heart disease and recently in Parkinson's patients treated with pergolide. The aim of this study was to develop an in vivo model of drug-induced valvulopathy with pergolide in rats. Thirty male Wistar rats were given daily injections of either pergolide (0.5 mg/kg intraperitoneally) (n = 8), serotonin (20 mg/kg subcutaneously) (n = 8), or the vehicle only (n = 14) for 5 months. At 20 weeks, echocardiography demonstrated the presence of aortic regurgitation (AR) and/or mitral regurgitation (MR) in serotonin (86% AR, P = 0.0001; 57% MR, P = 0.006) and in pergolide animals (67% AR, P = 0.003; 67% MR, P = 0.003) compared with none in placebo. Pulmonary regurgitation (PR) and tricuspid regurgitation (TR) were found in the serotonin (71% PR, P = 0.19; 100% TR, P = 0.06 vs. placebo), pergolide (100% PR, P = 0.014; 83% TR, P = 0.35 vs. placebo), and placebo groups (36% PR; 57% TR). Tricuspid regurgitant area ratio (jet/atrium), however, was more severe in the serotonin [median 26.5 (range 17-42)%; P = 0.02] and pergolide animals [32 (17-39) %; P = 0.03] compared with placebo [12.5 (5-33)%]. We found a good correlation between valvular regurgitation and histologically assessed valvular thickness. Histological examination revealed the presence of diffusely thickened and myxoid aortic, mitral, and tricuspid valves in serotonin and pergolide animals as seen in VHD. We demonstrated, for the first time, that long-term pergolide administration led to VHD in rats. This small animal model will permit further in vivo investigation of drug-induced valvulopathies.