Microvascular Permeabilization and Cardiomyocyte Injury Provoked by Myocardial Contrast Echocardiography in a Canine Model

Microvascular Permeabilization and Cardiomyocyte Injury Provoked by Myocardial Contrast Echocardiography in a Canine Model Douglas L. Miller, Edward M. Driscoll, Chunyan Dou, William F. Armstrong, Benedict R. Lucchesi The relationship of myocardial contrast echocardiography to microscale bioeffects was evaluated in a canine model. The ultrasound contrast agent was infused at a clinically relevant dose, and diagnostic ultrasound scanning was performed for 10 min. Microvascular leakage was found for closed- and open-chest ultrasound exposure. Canine myocardial contrast echocardiography induces myocardial injury comparable to that seen in small animal models, suggesting that bioeffects similar to those seen in this study could occur clinically under similar conditions of dosage and ultrasound exposure. The aim of this research was to evaluate the potential for myocardial contrast echocardiography (MCE) to provoke microscale bioeffects in a canine model. Myocardial contrast echocardiography induces bioeffects in rat hearts, but translation of such results to larger animal models is uncertain. Dogs were anesthetized and prepared for open- (n = 22) or closed- (n = 6) chest MCE. Evans blue dye was injected intravenously as an indicator of microvascular leakage, and propidium iodide was used to stain for irreversibly injured myocytes in frozen sections. The contrast agent (Definity, Bristol-Myers Squibb Medical Imaging Inc., North Billerica, Massachusetts) was diluted in saline and infused intravenously at 2 μl/kg/min. Myocardial contrast echocardiography in a short-axis (open-chest) or modified four-chamber view (closed-chest) with 1:4 end systolic electrocardiogram triggering was performed at 1.5 MHz for 10 min in a single imaging plane. Petechiae and leakage of Evans blue were observed in the ultrasound scan plane within the anterior left ventricle. For 1.2 MPa and 2.2 MPa, open- or closed-chest MCE, Evans blue content in tissue within the scan plane was significantly greater than in tissue outside this plane. Counts of propidium-iodide-stained nuclei for 2.2 MPa open-chest MCE were also significantly greater inside than outside the scan plane. In a canine model, MCE induces myocardial injury comparable to that seen in the rodent model.