Impact of myocardial contrast echocardiography on vascular permeability: comparison of three different contrast agents

Abstract

Microvascular permeabilization, petechial hemorrhage and premature ventricular contractions (PVCs) have been demonstrated in an in vivo rat model of myocardial contrast echocardiography (MCE). The purpose of this study was to compare these effects for three US Food and Drug Administration (FDA)-approved ultrasound (US) contrast agents (US CA): Optison®, Definity® and Imagent®. Evans blue dye, an indicator of microvascular permeability, and a contrast agent were injected IV in anesthetized rats suspended in a water bath to mimic scanning depths seen in clinical echocardiology. Diagnostic US B-mode scans with 1:4 end-systolic triggering were performed at 1.7 MHz using a cardiac phased-array scanhead to provide a short axis view of the left ventricle. To elicit readily measurable effects for comparisons, relatively high doses of the agent were used (50 to 500 μL kg −1 for Optison®, 25 to 200 μL kg −1 for Imagent®, 10 to 100 μL kg −1 for Definity®). Microvascular leakage was characterized by the area of Evans blue dye coloration on the hearts and by extraction of the dye from tissue samples. The number of petechia were counted on the epicardial surface of excised hearts. PVCs were counted from ECG traces recorded with the MCE images. Neither evidence of capillary leakage nor PVCs were seen in sham animals. Based on volume dose, Definity® MCE produced more microvascular leakage, but there was no apparent difference between the three agents' microvascular damage potential, which increased linearly with dose at low doses, when expressed in terms of the number of stabilized microbubbles. Definity® MCE resulted in fewer PVCs than the other agents. The effects increased strongly with peak rarefactional pressure amplitude, with apparent thresholds for petechiae at 0.4 MPa and for PVCs at about 1.0 MPa. These results should be of value for minimizing adverse potential in diagnosis and optimizing efficacy in therapeutic applications. (E-mail: douglm@umich.edu)