Contrast Agent-induced Cardiac Arrhythmias in Rats

Although no known meaningful health risks have been reported following the use of microbubble ultrasound echogenic contrast imaging agents (MUECIA) in the United States, premature ventricular contractions have been documented in a report from the Netherlands and anecdotally noted in clinical use. Based on this information, we designed a study to characterize electrocardiogram conduction abnormalities in rat hearts exposed to pulsed ultrasound following injection of contrast agent. A focused 5 1 -mm-diameter, 3.1 -MHz, lithium niobate transducer that had in situ (at the heart) peak rarefactional and compressional pressures of 15.9 MPa and 36.1 MPa, respectively, (1.7-kHz PRF and 1.3-ps pulse duration) was used to expose each heart. Twenty rats were anesthetized, clipped, depilated, and connected to a digital ECG recorder. Electrocardiograms were recorded digitally and continuously during seven experimental intervals: ECG baseline; exposure to pulsed ultrasound without intravenous MUECIA; discontinue ultrasound exposure and then inject intravenous MUECIA; expose to pulsed ultrasound with intravenous MUECIA; discontinue ultrasound exposure; exposure to pulsed ultrasound with intravenous MUECIA; and discontinue ultrasound exposure. Rats had no meaningful conduction abnormalities when exposed to ultrasound alone or contrast agent alone but developed premature atrial (PAC) and ventricular complexes (PVC) and polymorphic ventricular tachycardia (PVT) when contrast agent was administered intravenously and the heart exposed to pulsed ultrasound. When ultrasound exposure was concluded, cardiac arrhythmias ceased but reoccurred when ultrasound exposure was resumed. Necrotic cardiac rhabdomyocytes were observed microscopically in myocardium of rats exposed to ultrasound following injection of contrast agent. Because cardiac arrhythmias were induced only when contrast agent interacted with ultrasound during exposure, the presence of myocardial lesions alone did not appear sufficient to serve as foci for ectopic electrical activity. These results suggest that microbubble contrast agent through its biomechanical interactions with pulsed ultrasound has the potential to induce conduction abnormalities leading to potentially hazardous cardiac arrhythmias.