Copyright © 2005, The European Society of Cardiology
Tissue Doppler imaging does not show infraclinical alteration of myocardial function after contrast echocardiography
Cardiology Department, Academisch Ziekenhuis - VUB, 101 Laarbeeklaan, 1090 Brussels, Belgium
Received 20 December 2004; received in revised form 14 February 2005; accepted after revision 6 March 2005.
* Corresponding author. Tel.: +32 24776010; fax: +32 24532294. E-mail: bcosyns@skynet.be
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Abstract |
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Background It has been previously suggested that simultaneous exposure of hearts to contrast and ultrasound can damage the myocardium and produce a transient decrease of the contractility in animals. Tissue Doppler imaging (TDI) is a useful tool to quantify the myocardial function with very high temporal resolution.
Aim of the study The aim of the study was to test whether contrast echocardiography (CE) can cause alteration of the myocardial function by using tissue Doppler analysis.
Methods Twenty-eight healthy patients (mean age: 44±22) underwent baseline echocardiography before and after 5min of continuous intravenous infusion of Sonovue from the apical views, using an intermediate mechanical index (MI=1). High frame rate images were acquired in tissue Doppler mode. Data were averaged over 3 cardiac cycles and analysed offline before and after CE.
Results There were no significant changes, before and after CE, in the peak systolic velocity (basal septum (BS): 6.2±2.2 vs 6.4±2.6; basal lateral (BL): 6.2±3.1 vs 6.4±3.3cm/s), in the peak diastolic E velocity (BS: 5.4±1.8 vs 5.3±1.7; BL: 7.3±2.4 vs 7.7±3.2cm/s), in the peak diastolic A velocity (BS: 6.3±1.9 vs 6.9±2.4; BL: 6.1±3.5 vs 6.2±2.5cm/s), in the peak systolic strain (BS: 16±7 vs 17±7; BL: 12.6±5 vs 12.9±5%) and in peak systolic strain rate (BS: 1.3±0.6 vs 1.4±0.6; BL: 1.2±0.5 vs 1.21±0.51 1/sec).
Conclusions Our data suggest that CE does not cause alterations in the myocardial function as assessed by tissue Doppler imaging. CE, even with high MI settings, usually used for left ventricular opacification, can be safely performed.
Keywords: Contrast echocardiography; Tissue Doppler imaging; Toxicity
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Introduction |
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Contrast echocardiography has an established role for left ventricular cavity opacification (LVO). The use of intravenously administered microbubbles to assess myocardial perfusion has been the source of research studies for the recent years. Microbubbles used as ultrasound contrast agents can be destroyed by ultrasound, as described in vitro and in vivo with the demonstration of different bioeffects in animals.1–3 These significant bioeffects consist of a transient and reversible decrease in LV contractile performance, a transient and reversible increase in coronary perfusion pressure, an increase in lactate production, and the occurrence of microvascular damage. Indeed, when the microbubbles are destroyed by ultrasound, they may rupture the microvessel in which they are located with demonstration of nonviable cells at the microvessel rupture sites. The magnitude of bioeffects depends on the mechanical index (MI) applied and the interspecies differences in terms of tissue vulnerability. The incidence of reported adverse events in human trials (mainly investigating LV opacification) has been very low. Whilst serum troponin levels are normal in humans after high MI imaging,4 recent work has demonstrated troponin I and myoglobin in coronary sinus samples of humans after high MI imaging.5
The left ventricular function is commonly evaluated by 2-D and M-mode echocardiography. These modalities have significant limitations and tissue Doppler imaging (TDI) has been introduced as a quantitative and more objective method for assessing myocardial function. Moreover, TDI is a very sensitive test to identify subclinical changes that affect ventricular function in various pathologic conditions.6–8
The aim of our study was to test prospectively whether contrast echocardiography (CE) can cause alteration of the myocardial function by using tissue Doppler imaging analysis.
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Patients |
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We have prospectively included 28 healthy patients. All of them have signed a written informed consent according to the standard ethical guidelines of the Free University of Brussels. The mean age of the patients studied was 44±22 years. The study population comprised 21 men and 7 women.
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Methods |
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Image acquisition
Baseline standard echocardiography was performed in each patient. A high frame rate (>150/s) images were acquired in tissue Doppler mode. All examinations were performed by the same cardiologist using Vivid 7 echo machine (GE Vingmed Ultrasound System) equipped with a matrix array transducer M3S.
After 5min of continuous intravenous infusion of Sonovue® (Bracco), a phospho-lipid shell encapsulating sulphur hexafluoride gas, 0.5cc/min with a dedicated pump and continuous insonification using a high mechanical index (MI=1.0), a new set of images was obtained using the same imaging modalities. All the recordings were digitized and stored in a dedicated server.
Image analysis
Data were averaged over 3 cardiac cycles and analysed offline before and after CE using the Echopac software (v 3.1.3). Due to the protocol and the presence of microbubbles in the left ventricular cavity, the analysis was not blinded (Fig. 1). Only 4-chamber apical views and basal segment samples were taken into account for the analysis in this study.
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Statistics |
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Data were expressed as mean±SD or as a percentage. The difference between baseline and postcontrast examination was obtained using Fisher's exact test. A p<0.05 indicated the statistical difference.
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Results |
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Tissue Doppler parameters
As shown in Table 1, there were no significant changes of the TDI longitudinal parameters before and after simultaneous exposure to contrast and ultrasound. The systolic peak velocity was not different at the level of the basal segments before and after CE. Neither the peak systolic deformation nor the peak systolic deformation rate was altered by simultaneous exposure to ultrasound and Sonovue. In the same way, we did not observe any significant changes in diastolic velocity parameters before and after CE. We did not observe appearance of postsystolic shortening compared to baseline after CE.
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Other potential side effects
The blood pressure was 119±20mmHg at baseline and 121±19mmHg after CE (NS). Heart rate was, respectively, 80±17 and 82±14 before and after CE (NS). None of the patients described any side effect. Continuous ECG monitoring did not detect any ectopic beat.
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Discussion |
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Because of their acoustic properties, the microbubbles considerably enhance the backscattering capabilities of blood, thereby allowing the myocardial capillary bed to be imaged with ultrasound. Microbubbles oscillate (expand and contract) in the ultrasound field, depending on the acoustic power of the transmitted ultrasound field, which is expressed as the mechanical index (MI). This phenomenon is often referred as cavitation. Low mechanical index imaging (0.1–0.3) generates nonlinear oscillation of the microbubble whereby expansion is greater than contraction. This phenomenon is known as stable or noninertial cavitation. When exposed to high mechanical index imaging (MI>0.6, i.e. the MI used for standard imaging) the bubbles oscillate wildly and burst. This second form of activity is known as inertial cavitation. There is accumulating evidence that the process of cavitation, particularly inertial cavitation, may produce capillary damage to organs.1,2,9
Other investigators could demonstrate that simultaneous exposure of isolated rabbit hearts to ultrasound and contrast agents results in transient depression of contractile function, a rise in coronary perfusion pressure, and capillary ruptures.10 Because the alteration of contractile performance was paralleled by an increase in coronary perfusion pressure and a rise in lactate production, it was hypothesized that it was related to the occurrence of transient ischemia.
Porter et al.11 confirmed that intramyocardial cavitational activity is present during ultrasound imaging of perfluorocarbon-containing microbubbles and was evident even at an MI of 0.2.
Despite the fact that TDI is a very sensitive test to identify subclinical changes that affect ventricular function, our results did not show any significant changes before and after CE. Moreover, we have used relatively high MI with a continuous insonification leading to important bubbles destruction. In clinical practice, we actually use much more lower MI (0.2) with a transient flash imaging with higher MI (1.1), decreasing the time of tissue exposure to ultrasound and microbubbles, even during a stress test.
The set of CE images was acquired during contrast infusion in order not to miss a contractile dysfunction of transient nature.
In animals, the ultrasound energy was delivered directly to the heart, without any interposing medium and hence causing attenuation. The effective MI administered through the chest wall to the human heart is probably lower than that which could be delivered in vitro or in vivo, during open chest surgery. In the clinical setting, tissue attenuation is responsible for a decrease of 0.3dB/cm/MHz in the amount of ultrasound that reaches the focal point of the transducer.1 Even if some damage could be provoked, it would be quite localized and unlikely to induce any functional effects. Although the concentration of microbubbles in the tissue will also determine the magnitude of bioeffects, the concentration used in our study was realistic for clinical routine contrast echocardiography. In a subset of 9 patients, we have used higher concentration of 1cc/min without any significant difference compared to lower concentrations in terms of side effects and TDI measurements.
Our results are in concordance with a previous study that demonstrates the lack of evidence of myocardial damage because of contrast echocardiography in human beings, even with very high MI.4
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Limitations |
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To test whether the absence of bioeffects were specific to the contrast agents, i.e., Sonovue, additional experiments should be conducted in which hearts are exposed to Optison or Levovist. Therefore, the transferability of our results is limited. However, a retrospective study comparing the safety of contrast agents during 500 dobutamine stress echocardiography did not show side effects, with similar results for Optison and Sonovue.12
In our study, the number of patients is relatively small and we studied only longitudinal velocities and deformation (rate).
In conclusion, our data suggest that contrast echocardiography performed in human beings, even with high MI, does not cause alterations in the myocardial function as assessed by tissue Doppler imaging.
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References |
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- Skyba D.M., Price R.J., Linka A.Z., Skalak T.C., Kaul S. Direct invivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue. Circulation (1998) 98:290–293.
[Abstract/Free Full Text] - Price R.J., Skyba D.M., Kaul S., Skalak T.C. Delivery of colloidal particle and red blood cell to tissue through microvessel rupture created by targeted microbubble destruction with ultrasound. Circulation (1998) 98:1264–1267.
[Abstract/Free Full Text] - Lindner J.R., Ismail S., Sponitz W.D., Skyba D.M., Jayarweera A.R., Kaul S. Albumin microbubble persistence during myocardial contrast echocardiography is associated with microvascular endothelial glycocalyx damage. Circulation (1998) 98:2187.
[Abstract/Free Full Text] - Borges A.C., Walde T., Reibis R.K., Grohmann A., Ziebig R., Rutsch W., et al. Does contrast echocardiography with Optison induce myocardial necrosis in humans? J Am Soc Echocardiogr (2002) 15:1080–1086.[CrossRef][Web of Science][Medline]
- Vancraeynest D., Hanet C., Kefer J., Pasquet A., Vanoverschelde J.L. Does contrast echocardiography cause myocardial damage in patients? Circulation (2003) 108:624.
- Mc Mahon C.J., Nagueh S.F., Pignatelli R.H. Characterisation of left ventricular dysfunction by tissue doppler imaging and clinical status in children with hypertrophic cardiomyopathy. Circulation (2004) 109.
- Vinereanu D., Nicolaides E., Tweddel A.C., Madler C.F., Molst B., Boden C.E., et al. Subclinical left venticular dysfunction in asymptomatic patients with type II diabetes mellitus, related to serum lipids and glycated haemoglobin. Clin Sci (Lond) (2003) 105:591–599.[Medline]
- Weidemann F., Breunig F., Beer M, et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease. A prospective strain rate imaging study. Circulation (2003) 108:1299–1301.
[Abstract/Free Full Text] - Dalecki D., Child S.Z., Reaman C.H., et al. Age-dependence of ultrasonically-induced lung hemorrhage in mice. Ultrasound Med Biol (1996) 23:917–925.
- Ay T., Havaux X., Van Camp G., Campanelli B., Gisellu G., Pasquet A., et al. Destruction of contrast microbubbles by ultrasound: effects on myocardial function, coronary perfusion pressure, and microvascular integrity. Circulation (2001) 104:461–466.
[Abstract/Free Full Text] - Porter T.R., Everbach C., Kricsfeld D., Xie F. Myocardial cavitational activity during continuous infusion and bolus intravenous injections of perfluorocarbon-containing microbubbles. J Am Soc Echocardiogr (2001) 14:618–625.[CrossRef][Web of Science][Medline]
- Timperley J., Mitchell A.R.J., Thibault H., Becher H. Safety of contrast agents during dobutamine stress echocardiography: a single center experience. Eur J Echocardiogr (2004) 5–S111.
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