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PRECLINICAL STUDY

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

Douglas L. Miller, PhD^_*,_*, Edward M. Driscoll, Chunyan Dou, MD^_*, William F. Armstrong, MD and Benedict R. Lucchesi, MD, PhD

^_* Department of Radiology, University of Michigan Medical Center, Ann Arbor, Michigan
Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan
Department of Internal Medicine (Cardiology), University of Michigan Medical Center, Ann Arbor, Michigan

Manuscript received May 31, 2005; revised manuscript received August 26, 2005, accepted September 8, 2005.

^_* Reprint requests and correspondence: Dr. Douglas L. Miller, 3315 Kresge III, University of Michigan Medical Center, 200 Zina Pitcher Place, Ann Arbor, Michigan 48109 (Email: douglm{at}umich.edu).

OBJECTIVES: The aim of this research was to evaluate the potential for myocardial contrast echocardiography (MCE) to provoke microscale bioeffects in a canine model.

BACKGROUND: Myocardial contrast echocardiography induces bioeffects in rat hearts, but translation of such results to larger animal models is uncertain.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: In a canine model, MCE induces myocardial injury comparable to that seen in the rodent model.

Abbreviations and Acronyms   IV = intravenous   LV = left ventricle/ventricular   MCE = myocardial contrast echocardiography   MI = mechanical index   MWRS = Mann-Whitney rank sum   PI = propidium iodide   RPA = rarefactional pressure amplitude

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