Adverse bioeffects of ultrasound contrast agents used in echocardiography: true safety issue or "much ado about nothing"?

Ultrasound contrast agents, consisting of gas-filled microbubbles, have long been used to enhance ultrasonographic imaging of various organs and in several settings. In echocardiography, after their first use for Doppler signal enhancement, their applications have expanded and several studies, combining a range of stress modalities with myocardial contrast echocardiography have shown the clinical utility of these agents. In experimental isolated heart animal models, the interaction of ultrasound with echo-contrast microbubbles was shown to have significant biologic effects when the acoustic energy of the beam exceeded a threshold, leading them to rupture and causing cavitation phenomena; the observed consequences in the experimental setting included microvascular damage, transient decrease of contractile performance and increased lactate production. From the clinical point of view, the reporting of a number of serious adverse events - whose association with the echo-contrast agents was debated - has led to the addition of warning boxes in the prescribing documentation of these preparations. On the other hand, clinical studies including high numbers of patients have shown good safety and tolerance of contrast use during stress echocardiography, both for left ventricle opacification and myocardial perfusion imaging. The present review aims at presenting a balanced account of the existing data regarding the mechanisms and clinical implications of echo-contrast bioeffects, in order to make an informed assessment of their safety in clinical practice.