Impact of myocardial contrast echocardiography on vascular permeability: an in vivo dose response study of delivery mode, pressure amplitude and contrast dose.

An in vivo rat model of myocardial contrast echocardiography (MCE) was defined and used to examine the dose range response of microvascular permeabilization and premature ventricular contractions (PVCs) with respect to method of imaging, peak rarefactional pressure amplitude (PRPA) and agent dose. A left ventricular short axis view was obtained on anesthetized rats at 1.7 MHz using a diagnostic ultrasound system with simultaneous ECG recording. Evans blue dye, a marker for microvascular leakage, and a bolus of Optison were injected i.v. Counts of PVCs were made from video tape during the 3 min of MCE. Hearts were excised 5 min after imaging and petechial hemorrhages, Evans blue colored area and Evans blue content were determined. No PVCs or microvascular leakage were seen in rats imaged without contrast agent followed by contrast agent injection without imaging. When PVCs were detected during MCE, petechial hemorrhages and Evans blue leakage were also found in the myocardium. Triggering 1:4 at end-systole produced the most PVCs per frame and most microvascular leakage, followed by end-systole 1:1, continuous scanning and end-diastole triggering 1:1. All effects increased with increasing Optison dosage in the range 25 to 500 microL kg(-1). Ultrasound PRPA was important, with apparent thresholds for PVCs at 1.0 MPa and for petechiae at 0.54 MPa. PVCs, petechial hemorrhages and microvascular leakage in the myocardium occur as a result of MCE in rats.

[1]  F J Ten Cate,et al.  Safety and efficacy of a new transpulmonary ultrasound contrast agent: initial multicenter clinical results. , 1990, Journal of the American College of Cardiology.

[2]  B B Goldberg,et al.  Ultrasound contrast agents. , 1993, Clinics in diagnostic ultrasound.

[3]  D. Dalecki,et al.  Thresholds for premature contractions in murine hearts exposed to pulsed ultrasound. , 1997, Ultrasound in medicine & biology.

[4]  F Forsberg,et al.  Ultrasound contrast agents: a review. , 1994, Ultrasound in medicine & biology.

[5]  J. Gottdiener,et al.  Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. , 2000, The American journal of cardiology.

[6]  J B Fowlkes,et al.  Mechanical bioeffects from diagnostic ultrasound: AIUM consensus statements. American Institute of Ultrasound in Medicine. , 2000, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[7]  J. Murgo,et al.  Benefits of reducing the cardiac cycle-triggering frequency of ultrasound imaging to increase myocardial opacification with FSO69 during fundamental and second harmonic imaging. , 1997, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[8]  S. Kaul,et al.  Hemodynamic characteristics, myocardial kinetics and microvascular rheology of FS-069, a second-generation echocardiographic contrast agent capable of producing myocardial opacification from a venous injection. , 1996, Journal of the American College of Cardiology.

[9]  J. Weiss,et al.  Phase III multicenter trial comparing the efficacy of 2% dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents in patients with suboptimal echocardiograms. , 1998, Journal of the American College of Cardiology.

[10]  S. Kaul,et al.  Myocardial contrast echocardiography. , 2004, Circulation.

[11]  T. Porter,et al.  Myocardial cavitational activity during continuous infusion and bolus intravenous injections of perfluorocarbon-containing microbubbles. , 2001, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[12]  Martin H Kroll,et al.  Bioeffects of Myocardial Contrast Microbubble Destruction by Echocardiography , 2002, Echocardiography.

[13]  J. Murgo,et al.  Myocardial contrast echocardiography: reliable, safe, and efficacious myocardial perfusion assessment after intravenous injections of a new echocardiographic contrast agent. , 1996, American heart journal.

[14]  S. Rajagopalan,et al.  Ultrasound-mediated transfection of canine myocardium by intravenous administration of cationic microbubble-linked plasmid DNA. , 2002, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[15]  Michael D. Menger,et al.  Clinically Applied Microcirculation Research , 1995 .

[16]  H. Movat,et al.  Simple Method for Quantitation of Enhanced Vascular Permeability 1 , 1970, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[17]  Francis A. Duck,et al.  The Safe Use of Ultrasound in Medical Diagnosis , 2000, Z Ultraschall in der Medizin.

[18]  S. Iliceto,et al.  Echocardiographic contrast imaging of the human right heart: A multicenter study of the efficacy, safety, and reproducibility of intravenous SHU‐454 , 1991, Journal of clinical ultrasound : JCU.

[19]  G. V. Van Hare,et al.  Contrast two-dimensional echocardiography in congenital heart disease: techniques, indications and clinical utility. , 1989, Journal of the American College of Cardiology.

[20]  J G Miller,et al.  Contrast Echocardiography: Current and Future Applications , 2000 .

[21]  D S Segar,et al.  Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent. Results of a phase III Multicenter Trial. , 1998, Journal of the American College of Cardiology.

[22]  P. Grayburn,et al.  Safety and efficacy of QW7437, a new fluorocarbon-based echocardiographic contrast agent. , 1997, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[23]  G Van Camp,et al.  Destruction of Contrast Microbubbles by Ultrasound: Effects on Myocardial Function, Coronary Perfusion Pressure, and Microvascular Integrity , 2001, Circulation.

[24]  D. Miller,et al.  Diagnostic Ultrasound Activation of Contrast Agent Gas Bodies Induces Capillary Rupture in Mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[25]  R Gramiak,et al.  Echocardiography of the aortic root. , 1968, Investigative radiology.

[26]  T C Skalak,et al.  Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound. , 1998, Circulation.

[27]  J. Kisslo,et al.  Detection and Exclusion of Interatrial Shunts by Two-dimensional Echocardiography and Peripheral Venous Injection , 1979, Circulation.

[28]  R. M. Thomas,et al.  Ultrasound contrast agents nucleate inertial cavitation in vitro. , 1995, Ultrasound in medicine & biology.

[29]  A. Weyman,et al.  Negative Contrast Echocardiography: A New Method for Detecting Left-to-Right Shunts , 1979, Circulation.

[30]  H. Becher,et al.  In vitro, animal, and human characterization of OPTISON infusions for myocardial contrast echocardiography. , 1999, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[31]  Ji Song,et al.  Stimulation of Arteriogenesis in Skeletal Muscle by Microbubble Destruction With Ultrasound , 2002, Circulation.

[32]  N. Silverman,et al.  Two-dimensional echocardiography in congenital heart disease , 1982 .

[33]  P A van Der Wouw,et al.  Premature ventricular contractions during triggered imaging with ultrasound contrast. , 2000, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[34]  A. DeMaria,et al.  Assessment of Coronary Stenosis Severity and Transmural Perfusion Gradient by Myocardial Contrast Echocardiography: Comparison of Gray-Scale B-Mode With Power Doppler Imaging , 2000, Circulation.

[35]  L. Crouse,et al.  Opacification and border delineation improvement in patients with suboptimal endocardial border definition on routine echocardiography: Results of a phase III trial of sonicated albumin microspheres , 1991, Clinical cardiology.

[36]  William D O'Brien,et al.  Arrhythmias in Rat Hearts Exposed to Pulsed Ultrasound After Intravenous Injection of a Contrast Agent , 2002, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[37]  T C Skalak,et al.  Direct In Vivo Visualization of Intravascular Destruction of Microbubbles by Ultrasound and Its Local Effects on Tissue. , 1998, Circulation.