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European Journal of Echocardiography 2007 8(1):19-29; doi:10.1016/j.euje.2005.12.001
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Copyright © 2006, The European Society of Cardiology

Freehand three-dimensional assessment of left ventricular volumes and ejection fraction with ultrasound contrast agent LK565

T. Geislera,e, H.C. Rostb,f, P.S. Wildc,g and R. Zotzd,*

aMedizinische Klinik III, University Hospital Tuebingen, Eberhard-Karls-University, Otfried-Mueller-Strasse 10, 72076 Tuebingen, Germany tobias.geisler{at}med.uni-tuebingen.de
bDepartment of Cardiology, Herzzentrum Leipzig, Germany chri.ro{at}web.de
cMedizinische Klinik II, University Hospital Mainz, Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany
dDepartment of Internal Medicine III, Klinikum Herford, Schwarzenmoorstr. 70, 32049 Herford, Germany

Received 17 May 2005; received in revised form 20 November 2005; accepted after revision 4 December 2005.

* Corresponding author. Tel.: +49 5221 94 2248; fax: +49 5221 94 2148. rainer.zotz{at}klinikum.herford.de


   Abstract
Top
 Notes
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Aims Accurate assessment of left ventricular function by determining left ventricular volumes and ejection fraction is important in evaluating the prognoses of patients with heart failure. Two-dimensional (2D) echocardiography suffers from low correlation with reference methods like ventriculography. Three-dimensionally (3D) assessed data have been proved to have better conformity. Endocardial border delineation remains a problem, however, especially in patients with suboptimal recordings. Few data exist on 3D-echocardiographic volumetry with ultrasound contrast agents (UCAs). We evaluated the second-generation UCA LK565 for its boundary-tracing capacities in freehand 3D echocardiography in a phase II clinical trial. Safety and efficacy of the novel contrast agent were also evaluated.

Methods and results Forty patients between the age of 42 and 77 were included in this trial. Left ventricular end-systolic and -diastolic volume (LVESV, LVEDV) and ejection fraction (EF) were determined by either 2D or 3D freehand second harmonic echocardiography with and without use of LK565. Parameters were compared statistically with ventriculography performed in 35 patients. Immune response to LK565 was evaluated by analysing phagocytosis capacity and kinetics of inflammatory cytokines (TNF-{alpha}, IL-4, IL-10, IFN-{gamma}). Patients were monitored for adverse events up to 72h after application of the UCA.

Calculated values for left ventricular volumes and ejection fraction correlated best for freehand 3D echocardiography in combination with LK565 (r=0.92 for LVEDV; r=0.96 for LVESV; r=0.94 for EF). Excellent left ventricular contrast enhancement was achieved for approximately 8min. A reversible saturation of phagocytosis capacity for monocytes and neutrophils set in with a maximum peak at 6h. No significant increase in cytokine expression was observed.

Conclusion LK565 improves feasibility of endocardial border delineation in 3D echocardiography, leading to better correlation of left ventricular volumetry with reference methods. Efficacy and safety of LK565 are equivalent to those of conventional UCAs.

Keywords: 3D echocardiography; Ultrasound contrast agent; Freehand ultrasound

e Tel.: +49 7071 2983688. tobias.geisler{at}med.uni-tuebingen.de Back

f Klosterstrasse 40a, 97236 Randersacker, Germany. Tel.: +49 931 708608. chri.ro{at}web.de Back

g Tel.: +49 6131 177250. Back


   Introduction
Top
 Notes
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 
Left ventricular function and structural parameters (ejection fraction, left ventricular end-diastolic and end-systolic volumes, wall motion score) are independent markers for predicting the outcome of cardiovascular patients.1–4 They are important parameters for screening patients with chronic heart failure and left ventricular dysfunction after myocardial infarction. Two-dimensional (2D) echocardiography, while a good method for clinical routine use due to its inexpensiveness and the minimal stress caused to the patient, suffers from low reproducibility and reduced image quality in many cases.5,6 Assessment of the left ventricular wall is restricted to optimal endocardial border delineation, which is often not possible. Improvements in accessibility have been achieved by tissue-harmonic Doppler, thus increasing opacification of the left ventricle and making the myocardium demarkable. Since no geometric assumptions are made, three-dimensional (3D) echocardiography shows higher accuracy for left ventricular volumetry. Good conformity with accepted methods for assessing intraventricular volumes (levocardiography, cardiac magnetic resonance imaging, radionuclide angiography), as well as a low interobserver variability, has been reported for 3D echocardiography.7–10 Freehand imaging techniques show similar good accordance.11 Further advances have been made since the introduction of new ultrasound contrast agents (UCAs). Due to more stable micro-bubbles in these new agents, evaluation of both ventricles with better endocardial delineation is now possible in most patients. However, few data exist on the combination of 3D echocardiography and contrast agents. In this phase II clinical trial, we investigate the accuracy of 3D echocardiography combined with the second-generation intravenous UCA LK565 (Dr. Koehler Chemie, Alsbach-Hähnlein, Germany). LK565 is an air filled contrast agent. It consists of a synthetic polymer of aspartic acid, ethanolamine, and decanoic acid. The beads have an average diameter of 3µm, allowing pulmonary passage of the contrast agent. Due to their surface characteristics, however, the microparticles can mimic microorganisms and thereby cause immunological reactions. The in vivo immune response to LK565 has been described before12 and was also investigated in this trial. A further aim of this study was to evaluate the safety and efficacy of LK565.


   Methods
Top
 Notes
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
The trial was performed in conformity with the declaration of Helsinki and guidelines for good clinical practice. Forty patients were recruited according to the study protocol. Inclusion criteria consisted of written consent and age between 18 and 80 years for male participants and 45 and 80 years for female participants. Exclusion criteria were severe acute disease, hepatic and renal insufficiency, drug abuse, known allergy to contrast agents, antibiotic therapy within the last 7 days before enrolment, and psychiatric illness or mental disability. Twenty-seven men and 13 women entered the study (mean age 64, range between 42 and 77 years). Indications for coronary angiography were assumed coronary artery disease (CAD) in 13 patients, elective control for 21 patients with known CAD, dilatative cardiomyopathy in 2 patients, and severe aortic insufficiency in 1 patient. In another patient, a right catheterisation was performed due to pulmonary hypertension. One patient did not receive any invasive diagnostic at all. Comorbidities and composition of the patient collective are described in Table 1.


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  		Table 1 Demographic data and comorbidities of 40 patients enrolled in the trial

 
The LK565 used was prepared in predescribed manner from a lyophylisate provided by Dr. F. Koehler, Chemie AG, Germany. Ten millilitres of the suspension were injected intravenously after passing a microfilter with a pore width of 200µm. Filling of the right ventricle and left ventricle was recorded using the 4-chamber view. An additional 10ml contrast agent was applied after 10min.

Left ventricular dimensions and ejection fraction were assessed by 2D and 3D echocardiography using an ultrasound scanner with a 2.5MHz transducer (Hewlett-Packard, Sonos 5500). Harmonic imaging was used both for contrast and non-contrast imaging to obtain improved endocardial visualization. In this trial the transmitted frequency was 1.8MHz and harmonic images were generated from echoes with the double frequency (3.6MHz). According to Kasprzak et al. this frequency lies within the optimal range for second harmonic imaging.13 For freehand 3D data acquisition, the transducer was modified by mounting a receiver with six degrees of freedom onto the scanning head. An electromagnetic transmitter (pcBIRD®, Ascension, Burlington, VT, USA) was used to generate an electromagnetic field in which the position of the sensor could be registered. The distance between receiver and transmitter lay within the recommended range of 20.3–76.2cm. Position data were transferred to a personal computer and processed with in vivo software (Medcom, Darmstadt, Germany) for 3D image reconstruction. The investigation was performed according to the technical standards of the American Society for Echocardiography.14 Two-dimensional images were obtained from different apical views by rotation of the ultrasound probe. An ECG trigger was used for adequate 3D image reconstruction during cardiac cycle. Measurements were done both without contrast agent and after each injection of LK565 from two-dimensional 4-chamber views acquired by the same investigator.

Signal quality was evaluated using a standardized score (0=no contrast, 1=regional contrast, 2=moderate contrast, 3=good contrast).15 Endocardial delineation was semiquantitatively described by dividing left ventricular wall into 6 standard segments from 4-chamber view (1=basoseptal, 2=midseptal, 3=apicoseptal, 4=apicolateral, 5=midlateral, 6=basolateral). Left ventricular end-diastolic (LVEDV) and end-systolic volumes (LVESV) were determined using the modified Simpson's method. EF was calculated using the formula


Formula

For 3D volumetric calculation, the longest vertical axis was chosen and the endocardial border was framed at horizontal cross sections with 1cm distance, thus generating truncated cones of 1cm height from apex to mitral level. By adding the volume of each cone, total LV volume was calculated.

Each patient's blood pressure, heart rate, and rhythm were recorded right after second application of LK565 and 24h later. Blood samples for clinical routine were drawn before first injection and 1h and 24h after the second injection of LK565. For clinical safety evaluation, kinetics of immunologic parameters (Table 2) were assessed by flow cytometry and phagocytosis capacity test (Phagotest, Orpegen, Germany) as described elsewhere.16


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  		Table 2 Statistical results

 
Within 48h after contrast echocardiographical investigation, cardiac catheterisation with ventriculography was performed in 35 patients. Left ventricular volumes were measured by planimetry and EF was determined in the usual way.

Statistical analysis was performed using Excel 2000 and SPSS 11.0 software. Null hypothesis assuming a normal distribution of values was rejected (Kolmogorov–Smirnov) for some of the volumetric values. For this reason and for the reason of a small sample size a non-parametric test (Mann–Whitney–Wilcoxon) was used to prove the null hypothesis that claimed no difference between angiography and echocardiography. It was rejected for p<0.05. Spearman rank coefficient r and coefficient of determination (r2) were calculated. Significance level of correlation was tested with p<0.05. Measurement agreement was graphically shown by plotting the differences of the two methods against their mean (Fig. 4A–D). Limits of agreement were estimated according to Bland–Altman17 comparing the mean differences ±2 standard deviations.


Figure 4
Figure 4
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  		Figure 4 (A–C): Plot of differences against means comparing values for end-systolic (ESLVV) and end-diastolic (EDLVV) left ventricular volumes and ejection fraction (EF) obtained by 2D and 3D echocardiography without UCA (2DN, 3DN), and after second injection of LK565 (2DC2, 3DC2) with those obtained by ventriculography as reference (n=35 for 2DN, 2DC2; n=29 for 3DN; n=28 for 3DC2). Horizontal lines represent ±2 standard deviations from mean of differences. LV-volumes are slightly underestimated by echocardiography compared to the reference method.

 

   Results
Top
 Notes
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
Useful contrast enhancement was observed for an average of 36 cardiac cycles after the first injection and 34 after the second injection for the right ventricle, and 137 cardiac cycles after the first injection and 153 after the second for the left ventricle. Pulmonary transit time was 3–8s (mean 4.7s) after the first injection and 3–15s (mean 4.8s) after the second injection (Fig. 1).


Figure 1
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  		Figure 1 Two-dimensional echocardiographic 4-chamber view (harmonic imaging mode; 3.6/1.8MHz, MI 1.6) showing influx of ultrasound contrast agent into the right (RV) and left ventricle (LV). Mean pulmonary transit time was 4.7s.

 
A score value of 3 (good contrast) was achieved in 90% of all patients after application of LK565, whereas in the scout recording a maximum score of 2 could be described only in 11 patients (28%).

Before and after each application of LK565, all 6 segments of the left ventricular wall were evaluated by 2D echocardiography. Significant contrast enhancement was achieved after the first injection (Fig. 2), and slight enhancement after the second. The endocardial border could be excellently delineated in all segments in most of the patients. The difference was greatest in segments 1–4 (basoseptal–apicolateral). Harmonic power Doppler signal was significantly enhanced with the first injection of LK565 (Fig. 3). Left ventricular dimensions, being hardly evaluable after 3D reconstruction due to artefacts, were more easily demarkable with intraluminal contrast agent enhancement.


Figure 2
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  		Figure 2 Left ventricular contrast enhancement after first injection of LK565 (harmonic imaging mode, 3.6/1.8MHz, MI 1.6). Notice the improved endocardial delineation in the apical segments.

 


Figure 3
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  		Figure 3 Enhancement of harmonic power Doppler (3.6/1.8MHz, MI 1.6) signal after injection of LK565 during diastole (A, B) and systole (C, D).

 
Of 35 patients receiving a ventriculography, 20 showed a normal cardiac function. In 7 patients EF was slightly reduced, in 6 patients moderately, and in 2 patients severely. Maximum end-diastolic volume was measured at 421ml (end-systolic, 30ml) in a patient with DCM and severe aortic insufficiency. Utilizable data for 3D reconstruction could be obtained in 32 patients before and in 31 patients after application of LK565.

The null hypothesis of agreement between reference method and echocardiography had to be rejected for left ventricular end-diastolic and -systolic volumes measured by non-contrast 2D- and 3D-echocardiography and end-diastolic volumes measured by non-contrast 3D-echocardiography (p<0.05). For the other methods no significant differences could be tested. Correlation was best between 3D echocardiography with LK565 and ventriculography (r=0.92, r2=0.85 for LVEDV; r=0.96, r2=0.92 for LVESV; r=0.94, r2=0.88 for EF; Table 2).

Limits of agreement were lowest for 3D echocardiography with LK565 (–2.2±32.1ml for LVEDV; –4.4±21.2ml for LVESV; –1.4±10.7% for EF; Fig. 4D).

In general, a slight underestimation for LV volumes was observed for echocardiographic evaluation (Fig. 4A–D).

Safety of LK565
Two patients developed signs of allergic reaction (shivering). These symptoms totally disappeared after a few hours. Clinical inspection showed no pathological findings. During and after application of the UCA, no significant changes in heart rate were registered. No pathological cardiac arrhythmias were documented during ECG monitoring. Blood pressure was stable in all patients.

Immune response
Phagocytosis capacity for monocytes and neutrophils showed transient saturation 6h after application of LK565. Baseline values were reached after 24h (Fig. 5). Intracellular analysis of cytokine synthesis (TNF-{alpha}, IFN-{gamma}, IL-4, IL-10) by immunologic cells was not significantly increased within 48h after injection of the UCA (not shown).


Figure 5
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  		Figure 5 Relative changes in phagocytosis capacity of neutrophils (A) and monocytes (B).

 

   Discussion
Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
In this trial we used the advantages of freehand 3D echocardiography to obtain spatial data on the left ventricle. With 3D computing of left ventricular volumes and ejection fraction, no geometric assumptions are necessary as with 2D echocardiography. Good agreement of three-dimensionally processed values with those from reference investigations has already been reported in the literature; after positive experimental work comparing 3D ultrasound with invasive measurements (intraventricular balloon volumetry) in an animal model,18 a high correlation with clinical accepted methods was confirmed in several trials. Gopal et al. described a correlation with r=0.94 for left ventricular EF between 3D echocardiography and equilibrium radionuclide angiography,10 and similar results were obtained in comparison to magnetic resonance imaging (r=0.9 for left ventricular end-diastolic volume, r=0.88 for end-systolic volume). Interobserver variability was reported between 5 and 10%.8

Limitations of 3D echocardiography, as for 2D recording techniques, consist in the need for manual endocardial border delineation to measure ventricular volumes. Manual tracing carries the danger for over- or underestimating the real volume, depending on the image quality. Three-dimensional reconstruction suffers from high susceptibility to artefacts.19,20 Both 2D and 3D imaging can therefore profit from contrast enhancement. Improvement of endocardial border delineation for all left ventricular segments with 2D echocardiography has been described for contrast enhanced second harmonic imaging.13 Kasprzak et al. could show a good correlation of myocardial mass calculated by rotational 3D contrast echocardiography with weighted mass in open-chested pigs.21 In a study of 15 patients with post-ischemic dysfunction and suboptimal endocardial delineation, combination of harmonic imaging with second-generation UCA levovist showed best results measured by LV-wall segment visualization compared to fundamental and harmonic imaging.22 Changes in visualization of ischemic segmental LV-wall motion were not systematically evaluated in this study.

There are only few data on left ventricular volume quantification by 3D contrast echocardiography. Bae et al. found a similar good correlation between calculated and anatomic volumes (r=0.89) in an animal model.23

We investigated the benefit of contrast enhancement with the second-generation UCA LK565 for freehand 3D echocardiography in a phase II clinical trial. An increased correlation was observed between 3D echocardiography with LK565 and ventriculography as a reference method compared with 2D contrast imaging. Efficacy and safety of the new contrast agent were evaluated. Good contrast of the left ventricle was observed in 87% of the patients after first injection of 30mg LK565 and in 90% after the second injection. Thus similar results were obtained as for other novel UCAs (89% in a phase II trial with perflutren).24–26 The differences in endocardial delineation were greatest in patients with suboptimal baseline recordings and contrast imaging particularly improved visualization of apical segments confirming observations made for contrast imaging with levovist.13 Doses beyond 30mg LK565 did not show additional benefit in contrast enhancement. Immune response analysis revealed no significant reactions to LK565. Mechanical index as a value for power of ultrasound waves was kept within normal range (1.6). For volumetric studies lower values (around 0.5) are preferred to avoid continuous deformation or destruction of micro-bubbles and to obtain micro-bubble harmonic signals enabling maximal differentiation between the myocardium and the opacified blood-pool.27,28 With higher mechanical index apical swirling caused by micro-bubble destruction and lower discrimination of the blood-pool/myocardium border by increased tissue-harmonic signals have been described for other UCA. High mechanical index, however, is used for detection of myocardial perfusion defects.29,30 Despite normal mechanical indices in this trial, no swirling was observed and the opacified blood-pool/endocardial barrier was well definable in most cases. This may be due to high stability of the polymer suggesting an application of LK565 both for myocardial and LV-wall imaging. Evaluation of myocardial perfusion and detection of perfusion defects were possible in a smaller part of the patients. Quantitative measures by means of densitometry were not performed. A systematic investigation of the capacities and stability of LK565 in myocardial perfusion imaging should be conducted in future studies.

Signals in Doppler ultrasound for evaluation of regurgitation jets in valve insufficiency were significantly enhanced even with small doses of LK565. Duration of utilizable contrast enhancement in the left ventricle was approximately 8min and therefore lied within the predescribed range for LK565.31 Assessment of all data needed for 3D reconstruction was possible within this time window. Transient immunological reactions measured by phagocytosis capacity could be confirmed as shown before.12 The nonincrease of cytokine secretion observed gives no support for a severe immune response.


   Conclusion
Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
LK565 provides an excellent contrast enhancement for left ventricular volume analysis. Feasibility of endocardial border delineation with 3D echocardiography is improved by LK565, resulting in a better correlation of reconstructed values to those obtained by ventriculography.

Safety data did not show any severe immune reactions. Regular application of LK565 in 2D and 3D echocardiographic diagnosis is therefore recommended.


   Acknowledgements
 
We would like to thank Dr. Paul Kretchmer (kretchmer@sfedit.net) at San Francisco Edit for his assistance in editing this manuscript.


   Notes
Top
 Notes
Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
e Tel.: +49 7071 2983688. tobias.geisler{at}med.uni-tuebingen.de Back

f Klosterstrasse 40a, 97236 Randersacker, Germany. Tel.: +49 931 708608. chri.ro{at}web.de Back

g Tel.: +49 6131 177250. Back


   References
Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Nicod P., Gilpin E., Dittrich H., Chappuis F., Ahnve S., Engler R., et al. Influence on prognosis and morbidity of left ventricular ejection fraction with and without signs of left ventricular failure after acute myocardial infarction. Am J Cardiol (1988 Jun 1) 61(15):1165–1171.[CrossRef]
  2. Ali A.S., Rybicki B.A., Alam M., Wulbrecht N., Richer-Cornish K., Khaja F., et al. Clinical predictors of heart failure in patients with first acute myocardial infarction. Am Heart J (1999 Dec) 138(6 Pt 1):1133–1139.[CrossRef][Web of Science][Medline]
  3. Kober L., Torp-Pedersen C., Pedersen O.D., Hoiberg S., Camm A.J. Importance of congestive heart failure and interaction of congestive heart failure and left ventricular systolic function on prognosis in patients with acute myocardial infarction. Am J Cardiol (1996 Nov 15) 78(10):1124–1128.
  4. Galasko G.I., Basu S., Lahiri A., Senior R. A prospective comparison of echocardiographic wall motion score index and radionuclide ejection fraction in predicting outcome following acute myocardial infarction. Heart (2001 Sep) 86(3):271–276.[Abstract/Free Full Text]
  5. Broderick T.M., Bourdillon P.D., Ryan T., Feigenbaum H., Dillon J.C., Armstrong W.F. Comparison of regional and global left ventricular function by serial echocardiograms after reperfusion in acute myocardial infarction. J Am Soc Echocardiogr (1989 Sep–Oct) 2(5):315–323.[Medline]
  6. Kuecherer R.F., Kee L.L., Modin G., Cheitlin M.D., Schiller N.B. Echocardiography in serial evaluation of left ventricular systolic and diastolic function: importance of image acquisition, quantitation, and physiologic variability in clinical and investigational applications. J Am Soc Echocardiogr (1991) 4:203–214.[Medline]
  7. Sapin P.M., Schroeder K.D., Smith M.D., DeMaria A.N., King D.L. Three-dimensional echocardiographic measurement of left ventricular volume in vitro: comparison with two-dimensional echocardiography and cineventriculography. J Am Coll Cardiol (1993 Nov 1) 22(5):1530–1537.
  8. Gopal A.S., Keller A.M., Rigling R., King D.L. Jr., King D.L. Left ventricular volume and endocardial surface area by three-dimensional echocardiography: comparison with two-dimensional echocardiography and nuclear magnetic resonance imaging in normal subjects. J Am Coll Cardiol (1993 Jul) 22(1):258–270.[Abstract]
  9. Sapin P.M., Schroder K.M., Gopal A.S., Smith M.D., DeMaria A.N., King D.L. Comparison of two- and three-dimensional echocardiography with cineventriculography for measurement of left ventricular volume in patients. J Am Coll Cardiol (1994 Oct) 24(4):1054–1063.[Abstract]
  10. Gopal A.S., Shen Z., Sapin P.M., Keller A.M., Schnellbaecher M.J., Leibowitz D.W., et al. Assessment of cardiac function by three-dimensional echocardiography compared with conventional noninvasive methods. Circulation (1995 Aug 15) 92(4):842–853.
  11. Mannaerts H.F., Van Der Heide J.A., Kamp O., Papavassiliu T., Marcus J.T., Beek A., et al. Quantification of left ventricular volumes and ejection fraction using freehand thransthoracic three-dimensional echocardiography: comparison with magnetic resonance imaging. J Am Soc Echocardiogr (2003 Feb) 16(2):101–109.[CrossRef][Web of Science][Medline]
  12. Funke B., Maerz H., Okorokow S., Polata S., Lehmann I., Sack U., et al. Immunological evaluation of the new stable ultrasound contrast agent LK565: a phase one clinical trial. Cardiovasc Ultrasound (2004 Sep 10) 2(1):16.[CrossRef]
  13. Kasprzak J., Paelinck B., Folkert J., Cate J.T., Vletter W., Nd Jong, et al. Comparison of native and contrast-enhanced harmonic echocardiography for visualisation of left ventricular endocardial border. Am J Cardiol (1999) 83:211–217.[Web of Science][Medline]
  14. Schnittger I., Gordon E., Fitzgerald P., Popp R. Standardized intracardiac measurements of two-dimensional echocardiography. J Am Coll Cardiol (1983) 2:934–938.[Abstract]
  15. Erbel R., Kneissl G., Schweizer P., Lambertz H., Engberding R. Qualitätsleitlinien in der Echokardiographie. Z Kardiol (1997) 86:387–403.[Web of Science][Medline]
  16. Hirt W., Nebe T., Birr C. Phagotest and Bursttest (Phagoburst), test kits for study of phagocyte functions. Wien Klin Wochenschr (1994) 106:250–252.[Web of Science][Medline]
  17. Bland J.M., Altman D.G. Statistical methods for assessing between two methods of clinical measurement. Lancet (1986 Feb 8) 1(8476):307–310.
  18. Siu S.C., Rivera M., Guerrero L., Handschumacher M.D., Lethor J.P., Weyman A.E., et al. Three-dimensional echocardiography: in vivo validation for left ventricular volume and function. Circulation (1993) 88(Pt 1):1715–1723.[Abstract/Free Full Text]
  19. Handke M., Schäfer D., Müller G., Schöchlin A., Magosaki E., Geibel A. Dynamic changes of atrial septal defect area: new insights by three-dimensional volume-rendered echocardiography with high temporal resolution. Eur J Echocardiogr (2001) 2:46–51.[Abstract/Free Full Text]
  20. Schäfer D., Wollschläger H., Handke M. Structural analysis, spatial and temporal resolution of cardiac structures – comparison of 3D- vs 2D-echocardiography. Eur Heart J (1998) 19(Suppl.):480.
  21. Kasprzak J.D., Vletter W.B., Van Meegen J.R., Nosir Y.F., Johnson R., Ten Cate F.J., et al. Improved quantification of myocardial mass by three-dimensional echocardiography using a deposit contrast agent. Ultrasound Med Biol (1998) 24:647–653.[CrossRef][Web of Science][Medline]
  22. De Castro S., Agati L., Cartoni D., Papetti F., Beni S., Adorisio R., et al. Harmonic imaging with Levovist for transthoracic echocardiographic reconstruction of left ventricle in patients with post-ischemic left ventricular dysfunction and suboptimal acoustic windows. J Am Soc Echocardiogr (2000) 13:139–145.[Web of Science][Medline]
  23. Bae R.Y., Belohlavek M., Tanabe K., Greenleaf J.F., Seward J.B. Rapid three-dimensional myocardial contrast echocardiography: volumetric quantification of nonperfused myocardium after intravenous contrast administration. Echocardiography (1999) 16:357–365.[CrossRef][Web of Science][Medline]
  24. Kitzman D., GolDMan M., Gillam L., Cohen J., Aurigemma G., Gottdiener J. Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Cardiol (2000) 68:669–674.[CrossRef]
  25. Grayburn P., Weiss J., Hack T., Kloda E., Raichlen J., Vannan M., 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. J Am Coll Cardiol (1998) 32:230–236.[Abstract/Free Full Text]
  26. Cohen J., Cherif J., Segar D. Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent: results from a phase III multicenter trial. J Am Coll Cardiol (1998) 32:746–752.[Abstract/Free Full Text]
  27. Stewart M.J. Contrast echocardiography. Heart (2003 Mar) 89(3):342–348.[Free Full Text]
  28. Moir S., Marwick T.H. Combination of contrast with stress echocardiography: a practical guide to methods and interpretation. Cardiovasc Ultrasound (2004 Aug 26) 2(1):15.[CrossRef]
  29. Wei K., Jayaweera A.R., Firoozan S., Linka A., Skyba D.M., Kaul S., et al. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation (1998) 97:473–483.[Abstract/Free Full Text]
  30. Hirayama H., Ishikura F., Okuda K., Hirano T., Kobayashi H., Beppu S. Efficacy of intravenous myocardial contrast echocardiography for assessment of perfusion area of the heart in mice. J Cardiol (2003 Nov) 42(5):213–219.[Medline]
  31. Zotz R., Schenk S., Kuhn A., Schlunken S., Krone V., Bruns W., et al. Untersuchungen zur Sicherheit und Effizienz von LK565 – einem neuen Polymer-Ultraschallkontrastmittel. Z Kardiol (2001) 90:419–426.[CrossRef][Web of Science][Medline]

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