EDITORIAL COMMENT
The bubbles and the science of life*
Paolo Voci, MD, PhDa
a Section of Cardiology II, Institute of Cardiac Surgery, "La Sapienza" University of Rome, Rome, Italy
Reprint requests and correspondence: Dr. Paolo Voci, Section of Cardiology II, University of Rome "La Sapienza", Via San Giovanni Eudes, 27, 00163 Roma
Born in 1968, contrast echocardiography has already passed its third decade of life but, after a promising debut (1,2), has never achieved routine clinical use. Differing from two-dimensional echocardiography and color-Doppler, which rapidly became the "prima donna" in cardiac imaging, contrast echocardiography followed a desultory nonlinear evolution, as erratic as the bizarre response of the bubbles themselves to ultrasound, with disillusion often following enthusiasm (3). These alternating fortunes were largely due to the complex physics of the bubbles, and the negative connotation of the word "bubble" itself mirrors our ignorance about the interaction between these agents and ultrasound. It is, therefore, not surprising that we had to wait 25 years before noninvasively obtaining myocardial opacification, first with transesophageal echocardiography and triggered end-systolic imaging (4) and later with transthoracic harmonic imaging (5–7). What basically retarded the technique for a long time was a "complex of stability," inherent in the volatile nature of the bubbles. In the baroque iconography, the vanishing and unstable nature of life is often represented as bubbles between a putto and a skull
(Fig. 1). Fortunately, the stability of the bubbles has been recently improved with the use of gases of low-diffusability instead of air (5). This new generation of bubbles survives the stress of systemic circulation, may be used to trace vital flow, and promises to rehabilitate the discipline of contrast echocardiography.
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Figure 1 "Quis evadet?" (Who can escape?). Copper engraving (1594) by Hendrick Goltzius (Muehlbracht 1558—Haarlem 1617) Allegorie der Vergaenglichkeit (Allegory of fleetness) 193 x 153 mm. Staatliche Museum Preussischer Kulturbesitz, Kupferstichkabinett. Berlin. Courtesy of Judikje Kiers, Rijksmuseum, Amsterdam, Holland.
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The article by Villanueva and associates (8) is a well-conducted experimental study, showing the potential of contrast echocardiography to detect progressive growth of collateral flow during chronic coronary occlusion in the dog. The authors propose contrast echocardiography as a clinical tool to monitor collateral flow growth after therapeutic angiogenesis, a promising new technique to treat chronic ischemia. The results shown in this model, while impressive, demand a note of caution before considering this technique for use in humans. In my opinion there are six points to focus on to define the remaining hurdles to clinical use.
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The complex physiology of collateral flow
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Collateral circulation develops distal to a flow-limiting coronary stenosis and depends on the degree of the stenosis and metabolic requirements of the underlying myocardium. In patients with chronic, stable angina, well-developed collateral vessels ensure homogenous myocardial perfusion at rest. However, collaterals differ in terms of anatomy and flow pattern from normal arterial vessels because they are characterized by marked endothelial cell proliferation and subintimal hyperplasia (9). Thus, a well-developed collateral circulation represents a resistance to blood flow that is functionally comparable with a severe stenosis of a native coronary artery (10). As the microbubbles preferentially follow low-resistance flow, we cannot, a priori, assume that they can accurately depict high-resistance flow.
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Imaging projection
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The authors used a short-axis projection, which has the advantage of including all the three coronary artery beds but excludes the apex, an extremely important region during anterior myocardial infarction. In anterior infarction, apical views provide copious information about reperfusion (7,11) and prognosis. In any case, in humans, myocardial opacification is difficult to achieve in the short-axis view, while it is successful in apical projections (6,7).
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Off-line analysis
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The technique described in this paper requires a time consuming, and possibly biasing, off-line analysis. Ovidius, in his Ars Amandi, wrote, "Medicine is above all the art of timeliness" (Temporis ars medicina fere est). We may paraphrase Ovidius by saying, "Echocardiography is the art of real-time imaging" and should remain this way to provide the best and most reliable results.
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Feasibility of quantitative assessment of flow
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The quantitative assessment of flow has been proposed for many years in experimental models (12–15), but it remained a chimera of contrast echocardiography. The application of the indicator-dilution theory is precluded not only because of microbubble destruction (8) but also because there are many other variables that make the in vivo response to the microbubbles largely unpredictable. Among those, I would like to mention the fluctuant resonance frequency during the cardiac cycle, the wide variation in reflectivity with small changes in bubble diameter, the heterogeneous response to different acoustic fields and the wide variations in backscatter with small changes in the angle of the ultrasound beam.
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Triggering modality
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The microbubbles are destroyed (or most probably change in shape and, therefore, reflectivity) when exposed to an ultrasound field. This is one of the reasons why we have proposed triggered imaging to improve detection of myocardial perfusion (4). However, an improper triggering may produce illusionary normal perfusion in ischemic or even nonviable territories. To detect physiologic changes in microvascular flow, triggering should be restricted to one cardiac cycle, but in most laboratories up to 1:8 triggering intervals are used in an effort to obtain myocardial opacification. The authors of the present study fail to describe triggering interval, and, therefore, we have to assume they have used a 1:4 interval, as in other similar experimental settings. In my opinion this interval may be too long to differentiate normal from pathologic flow. As flow velocity in the capillaries is 0.3 mm/s at rest and the capillaries are 0.3 to 1 mm in length, the microbubbles are likely to traverse the microcirculation in 1 to 3 s. It derives that 1:1 triggering (4,7) (or better, continuous imaging) should better detect temporal heterogeneity in myocardial perfusion. It should also be considered that even nonviable segments maintain a certain degree of vascularization, which is characterized by slow and low flow. The microbubbles may pool in these regions, and prolonged triggered imaging may produce a false positive pattern of adequate perfusion. On the other hand, a 1:1 trigger, producing better "bubble destruction" in slow flow regions, may show false negative perfusion in still-viable segments.
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Technical maze
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The uncertainty about the optimal technique to obtain myocardial opacification involves not only the triggering interval but virtually all the modalities and settings of the ultrasound machine (Table 1). It is still debated whether we have to use an infusion or bolus injection, which transducer frequency, which mechanical index and pulse repetition frequency and which imaging modality (harmonic, power Doppler or pulse inversion). Lastly, attenuation, that is, the shadowing produced by the contrast agent itself, is a major unresolved problem because the dose necessary to obtain optimal perfusion is still too close to that producing the artifact.
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Conclusion and future developments
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In the last six years the clinician has perceived the important message that noninvasive myocardial opacification is a reality, and, recently, a widespread "perfusion fever" has developed with a largely irrational rush to obtain ready-to-use equipment. However, reality is more complex, and the clinician should be aware that a lot of work remains to be done before extending the data obtained in leading centers to routine clinical practice (6).
Nonetheless, there are some important areas in which contrast echocardiography is ready for use and may provide sound clinical information: 1) the evaluation of the infarct zone and reperfusion after acute myocardial infarction (7); 2) improving the accuracy of transesophageal echocardiography in the detection of the left atrial appendage thrombi (16); 3) the noninvasive color-Doppler imaging of the coronary arteries (17,18) with applications to coronary flow reserve, postinfarction reperfusion (11) and coronary vasomotion (19); 4) the early detection of false lumen perfusion during repair of aortic dissection, to decrease risk of intraoperative central nervous system damage and death (20); 5) imaging of intracranial vessels and other unexplored territories such as the arterial supply to the spinal cord (21).
From this perspective, we may re-interpret the apparently negative classical iconography (Fig. 1) and promote the best qualities of the microbubbles as tracers of vital flow, disclosing new secrets of biology, the science of life.
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Footnotes
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* Editorials published in Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Reale A, Pizzuto F, Gioffrè PA, et al. Contrast echocardiography: transmission of echoes to the left heart across the pulmonary vascular bed. Eur Heart J. 1980;1:101–106[Abstract/Free Full Text]
2. Feinstein SB, Cheirif J, ten Cate F, et al. Safety and efficacy of a new transpulmonary ultrasound contrast agent: initial multicenter clinical results. J Am Coll Cardiol. 1990;16:316–324[Abstract]
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5. Porter TR, Xie F. Transient myocardial contrast after initial exposure to diagnostic ultrasound pressures with minute doses of intravenously injected microbubbles. Demonstration and potential mechanisms. Circulation. 1995;92:2391–2395[Abstract/Free Full Text]
6. Marwick TH, Brunken R, Meland N, et al. Accuracy and feasibility of contrast echocardiography for detection of perfusion defects in routine practice: comparison with wall motion and technetium-99m sestamibi single-photon emission computed tomography. The Nycomed NC100100 Investigators. J Am Coll Cardiol. 1998;32:1260–1269[Abstract/Free Full Text]
7. Lepper W, Hoffmann R, Kamp O, et al. Assessment of myocardial reperfusion by intravenous myocardial contrast echocardiography and coronary flow reserve following primary PTCA in patients with acute myocardial infarction. Circulation 2000 (in press).
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9. Flameng W, Schwarz F, Hehrlein F. Intraoperative evaluation of the functional significance of coronary collateral vessels in patients with coronary artery disease. Am J Cardiol. 1978;42:187–192[CrossRef][Medline]
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12. Cheirif J, Zoghbi WA, Raizner AE, Minor ST, Winters W. Assessment of myocardial perfusion in humans by contrast echocardiography. I. Evaluation of regional coronary reserve by peak contrast intensity. J Am Coll Cardiol. 1988;11:735–743[Abstract]
13. Rovai D, Lombardi M, Distante A, L’Abbate A. Myocardial contrast echocardiography: from off-line processing to radiofrequency analysis. Circulation. 1991;83:97–103
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15. Wu CC, Feldman MD, Mills JD, et al. Myocardial contrast echocardiography can be used to quantify intramyocardial blood volume: new insights into structural mechanisms of coronary autoregulation. Circulation. 1997;96:1004–1011[Abstract/Free Full Text]
16. Voci P, Caretta Q. Left atrial masses. In: Voci P, Caretta Q, editors. Myocardial Contrast Echocardiography in Cardiology and Cardiac Surgery. University of Rome "La Sapienza" Press, 1996:153–5.
17. Mulvagh SL, Foley DA, Aeschbacher BC, Klarich KK, Seward JB. Second harmonic imaging of an intravenously administered echocardiographic contrast agent: visualization of coronary arteries and measurements of coronary blood flow. J Am Coll Cardiol. 1996;27:1519–1525[Abstract]
18. Caiati C, Zedda N, Montaldo C, Montisci R, Iliceto S. Contrast-enhanced transthoracic second harmonic echo Doppler with adenosine: a noninvasive, rapid and effective method for coronary flow reserve assessment. J Am Coll Cardiol. 1999;34:122–130[Abstract/Free Full Text]
19. Voci P, Testa G, Plaustro G, Caretta Q. Coronary Doppler intensity changes during handgrip: a new method to detect coronary vasomotor tone in coronary artery disease. J Am Coll Cardiol. 1999;34:428–434[Abstract/Free Full Text]
20. Voci P, Testa G, Tritapepe L, Menichetti A, Caretta Q. Detection of false lumen perfusion at the beginning of cardiopulmonary bypass in patients undergoing repair of aortic dissection. Cri Care Med 2000. In press.
21. Voci P, Tritapepe L, Testa G, Caretta Q. Imaging of the anterior spinal artery by transesophageal color Doppler ultrasonography. J Cardiothorac Vasc Anesth. 1999;13:586–587[CrossRef][Medline]
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