European Journal of Echocardiography Advance Access originally published online on October 9, 2007
European Journal of Echocardiography 2008 9(4):494-500; doi:10.1016/j.euje.2007.08.006
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Quantitative assessment of cardiac allograft vasculopathy by real-time myocardial contrast echocardiography: a comparison with conventional echocardiographic analyses and [Tc99m]-sestamibi SPECT
1 Department of Cardiology, Medizinische Poliklinik, Innenstadt, University of Munich, Ziemssenstrasse 1, 80336 Munchen, Germany
2 Department of Nuclear Medicine, University of Munich, Germany
3 Department of Cardiac Surgery, University of Munich, Germany
4 Department of Cardiology, Asklepios Stadtklinik Bad Tölz, Germany
Received 22 May 2007; accepted after revision 15 August 2007; online publish-ahead-of-print 9 October 2007.
* Corresponding author: Department of Cardiology, Asklepios Stadtklinik Bad Tölz, Germany. Tel: +49 08041 507 1221; fax: +49 08041 507 1223. E-mail address: u.stempfle{at}asklepios.com (H.-U. Stempfle).
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Abstract |
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Aim: To evaluate the additional benefit of visual and quantitative perfusion measurements compared with conventional real-time myocardial contrast echocardiography (MCE) in the detection of CAV.
Methods and results: Thirty patients (26 males, age 58 ± 9.6 years) underwent dobutamine stress echocardiography (DSE) and myocardial perfusion imaging (MPI) as well as coronary angiography (CA) with intravascular ultrasound (IVUS). Ultrasound images were analysed off-line, evaluating (1) wall motion and thickening at high mechanical index (‘conventional evaluation’), (2) the MCE loops stored during continuous infusion of contrast agent with regard to visual changes (stress vs. rest, ‘visual grading’), and (3) the replenishment curves of the contrast agent at low mechanical index after bubble destruction (‘quantitative grading’). CA/IVUS plus MPI showed ischaemia in seven and myocardial scars in nine patients. Sensitivity, specificity, NPV, PPV and accuracy for the detection of ischaemia representing functionally relevant CAV were, respectively, 0.71, 0.83, 0.90, 0.55 and 0.80 for the conventional evaluation alone, 0.71, 0.91, 0.91, 0.71 and 0.87 for additional visual grading and 0.86, 0.91, 0.95, 0.75 and 0.90 for additional quantitative grading.
Conclusion: Real-time MCE including visual and quantitative analysis is feasible for screening patients after HTX and is highly accurate in the diagnosis of haemodynamically relevant CAV.
Keywords: Cardiac allograft vasculopathy; Contrast echocardiography; Myocardial perfusion imaging; Heart transplantation
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Introduction |
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Cardiac allograft vasculopathy (CAV) is a major complication in patients after orthotopic heart transplantation (HTX) and is associated with decreased long-term survival.1,2 As a primarily immune-mediated process, CAV is characterised by a diffuse concentric intimal proliferation affecting both epicardial and intramyocardial coronary arteries.3 Although partial re-innervation of the cardiac allograft is documented, most heart transplant recipients do not experience typical anginal pain associated with myocardial ischaemia or infarction. Hence, first clinical manifestations of CAV frequently are ventricular arrhythmia, congestive heart failure, or sudden cardiac death.1
Coronary angiography (CA) combined with intravascular ultrasound (IVUS) is generally accepted as the gold standard for the detection of CAV. However, various non-invasive tests such as myocardial perfusion imaging (MPI) or stress echocardiography are adding significant prognostic information. MPI delivers perfusion data of both large epicardial vessels and the microcirculation. Additionally, numerous publications have identified MPI as a strong predictor for future cardiac events in patients after HTX.4–7 Like MPI, dobutamine stress echocardiography (DSE) is widely used for the assessment of patients with known or suspected CAV. However, pooled data have shown that the sensitivity of wall motion analysis alone is limited, particularly in patients with single vessel disease.8,9
Real-time myocardial contrast echocardiography (MCE) using power pulse inversion is a recently developed technique for the assessment of myocardial perfusion after intravenous infusion of ultrasound contrast agents. Real-time MCE utilizes a low mechanical index, which both enhances the detection and reduces the destruction of microbubbles, thus enabling simultaneous assessment of both wall motion and perfusion. First published results showed high accuracy of this combined technique for the detection of areas of ischaemia induced by coronary artery stenoses.10,11
The aim of the present study was to evaluate conventional DSE with and without additional real-time MCE and quantitative perfusion evaluation in the detection of haemodynamically relevant cardiac allograft vasculopathy compared to a combined gold standard consisting of [Tc99m]-sestamibi SPECT and coronary angiography with IVUS.
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Methods |
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Forty consecutive adult patients, who had undergone heart transplantation at least four years previously, were studied. All patients were asymptomatic at the time of the examination and were scheduled for routine CA including IVUS to exclude CAV. Immunosuppressive therapy included a calcineurin-phosphatase inhibitor (cyclosporin or tacrolimus) and an antiproliferative agent (azathioprine or mycophenolate mofetil) in all patients. β-Blocking agents (8 of 30 patients), angiotensin-converting enzyme inhibitors (28/30), calcium channel blockers (20/30), diuretics (20/30) and statins (25/30) were interrupted 48 h before stress test.
Patients were excluded if they had a suboptimum apical acoustic window at baseline (n = 7), and a history of hypersensitivity to albumin or known hypertension with basal systolic blood pressure values of more than 180 mmHg with/without left ventricular hypertrophy. The study protocol was approved by the institutional ethics committee. Thirty-three patients met the above criteria and gave written informed consent.
Dobutamine stress test
Dobutamine was applied intravenously starting at 10 mg/kg/min and increased every 5 min by 5 mg up to a maximum dose of 40 mg/kg/min until the age-predicted submaximum heart rate ([heart rate 
220 – age in years] x 0.85 [min–1]) was achieved. The stress test was interrupted in patients reporting severe chest pain, ST-segment dynamics >0.2 mV, significant ventricular or supraventricular arrhythmia, hypertension (>240/120 mmHg), systolic blood pressure fall by >40 mmHg or any intolerable adverse effect considered to be caused by dobutamine. Twelve-lead ECG and arterial blood pressure were monitored continuously. In a one-step investigation, the MCE contrast agent and the MPI radiopharmaceutical were applied according to the timeline shown in Figure 1.
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Echocardiographic imaging
Contrast was applied at baseline and peak dobutamine stress as a continuous infusion of 1.2 ml/min SonoVue® (BraccoeByk Gulden, Konstanz, Germany) with a gently agitated volumetric pump. SonoVue is a second-generation ultrasound contrast agent that contains phospholipid-stabilized microbubbles filled with sulphur hexafluoride. Particle diameter is less than 8 mm with a mean of 2.5 mm.12 Imaging was performed with a commercially available sector scanner (Vivid5, GE Ultrasound with EchoPac software, Milwaukee, USA) using a broadband 1.5–3.6 MHz transducer. Three echocardiographic views (apical four- and two-chamber view and apical long axis) were acquired at rest and maximum stress in each patient. Colour-coded harmonic power pulse inversion imaging was performed with ultrasound transmitted at 1.7 MHz and received at 3.4 MHz using low-energy real-time imaging (mechanical index 0.12) at 28 frames/s. For each investigation the same instrument settings were chosen. Complete microbubble destruction was produced by an ECG triggered high-energy FLASH, after which low-energy real-time scanning allowed measurement of microbubble replenishment in the ultrasound field. Frames preceding and following the high-energy FLASH were digitally captured and analysed off-line in consensus by two experienced readers in three steps.
In a first step (conventional evaluation), wall motion and wall thickening were interpreted in consensus by two independent investigators who had no knowledge of the clinical and angiographic data, using an 18-segment model as described previously.13 Wall motion was scored in each of the 18 segments as normal, hypokinetic, akinetic, or dyskinetic. All segments were assigned to a corresponding coronary artery territory. Wall motion analysis was defined as abnormal when wall motion abnormalities in two or more adjacent segments were present.
In a second step (visual grading), myocardial contrast enhancement was graded quantitatively at rest and at peak stress using the 18-segment model with the following segmental scores: 0 (no enhancement of contrast agent), 1 (poor enhancement, incomplete filling), 2 (moderate enhancement, complete filling), 3 (strong enhancement) or x (unsuccessful, e.g. due to artefacts). A difference of 1 between stress and rest was considered to represent ischaemia, when the difference score was 1 in two or more adjacent segments. Myocardial scars were defined when equal abnormal scores at stress and rest were present. Scores of 1 or 2 in basal segments were not considered abnormal due to the fact that contrast attenuation typically occurs in these segments.
In a third step (quantitative grading), myocardial perfusion was quantitatively evaluated using the real-time MCE loops at rest and stress. Images were analysed by placing a region of interest (ROI) within a segment of the myocardium and signal intensity was measured ECG triggered at end systole (Figure 2). The ROI size was determined to minimize image artefacts as well as to assure intramyocardial measurements and adapted to the motion of the myocardium frame by frame. Microbubble replenishment after FLASH was quantitatively measured by fitting to the exponential function Y = A(1–e–βt) to obtain the increase (β) of the plateau level (A) of myocardial contrast intensity in the tested segments13,14 (Figure 2).
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For each segment,
β and A were calculated as the differences of β and A from stress to rest. Multiple ROC analyses were performed for the determination of segmental threshold values for β and A indicating both myocardial ischaemia and scar tissue. On a patient based level ischaemia was defined as the presence of quantitative ischaemic patterns in two or more adjacent segments.
Myocardial perfusion SPECT
All patients received a dobutamine stress/rest MPI according to the one-day protocol mentioned above (Figure 1) using [Tc99m]-sestamibi. Approximately 1 min before the termination of the stress test, an intravenous dose of 4 MBq/kg (at least 300 MBq) of [Tc99m]-sestamibi was administered. For the resting study a dose of 10 MBq/kg (at least 700 MBq) of [Tc99m]-sestamibi was injected. Image acquisition was performed using a triple headed camera system (Philips [formerly Picker] Prism 3000 XP, Cleveland, Ohio) with a 360° rotation in continuous mode. For each study short and long axes were reconstructed, a standardized filter (low pass fourth power, cut-off frequency 0.26) was used.
Scintigraphic images for stress and rest were evaluated semiquantitatively in consensus by two experienced observers blinded to the findings of SE and CA, but aware of size, weight and gender of the patients. The left ventricular myocardium was divided into 18 segments as described above. Each of the 18 segments was scored according to the guideline for semiquantitative analysis (‘semiquantitative scoring system: the fivepoint model’: 0 = normal; 1 = mildly reduced – not definitely abnormal; 2 = moderately reduced – definitely abnormal; 3 = severely reduced; 4 = absent radiotracer distribution).15 The sum of the stress scores of all segments, the summed stress score (SSS) and the sum of the rest scores of all segments, the summed rest score (SRS) were determined. A summed difference score (SDS) was calculated as the difference of SSS and SRS. SDS >1 was defined as reversible perfusion defect indicating ischaemia, and SRS >1 was defined as a fixed perfusion defect.
Coronary angiography and intravascular ultrasound
CA was performed using the Judkins technique.16 Coronary angiograms were analysed visually in consensus by two experienced observers blinded to the results of DSE and MPI. Intravascular ultrasound (IVUS) was additionally acquired in case of ischaemia in MPI without significant stenosis in CA to verify the presence of significant CAV. Measurements were expressed as the percent narrowing in diameter, using either the diameter of the nearest normal appearing region or, if acquired, using the IVUS-measured media/intima border. Diameter reduction of 50% was considered significant.
Combination of MPI and coronary angiography/IVUS
The combination of CA plus MPI with or without IVUS was defined as the gold standard in the detection of haemodynamically relevant CAV.
The combined gold standard was rated as ‘ischaemia’, when significant stenosis (50%) at CA with an appropriate, reversible perfusion defect at MPI was present. A fixed perfusion defect at MPI combined with vessel occlusion or stenosis was defined as a ‘myocardial scar’. In case of present perfusion defects in MPI without significant stenosis at CA, additional IVUS was performed. The combination of a perfusion defect at MPI with significant wall irregularities at IVUS was rated as haemodynamically relevant CAV and assessed as ‘positive’ for the ischaemic group.
Data analysis
Statistical analyses were performed using the SPSS software package (version 12.1, SPSS, Inc., Chicago, Illinois). Results are presented as mean ± standard deviation (SD). Student's t-test and the Wilcoxon test were used when appropriate. Statistical significance was tested on the 95% confidence level.
ROC analysis for determining β and A threshold values was performed and the areas under the curves were compared according to the method of Hanley and McNeil.17 Statistical significance was tested on the 5% confidence level.
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Results |
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A complete set of DSE, MPI and CA data was obtained in 30 of 33 patients (26 male, mean age 58 ± 10 years, 90 ± 56 months after HTX) included in the study. In one patient, MPI could not be performed due to a camera defect, in another patient CA was not performed because of a newly diagnosed malignancy, and one patient refused CA after an unremarkable MPI scan.
The combination of CA/IVUS plus MPI detected ischaemia in seven patients and myocardial scars in nine patients, indicating haemodynamically relevant CAV. Four patients showed both ischaemia and scar tissue. Two patients with perfusion defects at MPI showed no stenoses at CA and no vessel irregularities at IVUS. These findings were consequently not rated as significant CAV. Five areas of ischaemia were allocated to the LAD, one to the RCA and one to the LCX vessel. Myocardial scars were allocated to the LAD in three, to the LCX in two and to the RCA in four patients.
Dobutamine stress echocardiography
During stress, patients' heart rate increased from 81 ± 10.5 to 142 ± 9.2 beats/min and systolic blood pressure increased from 126 ± 14.0 to 146 ± 23.6 mmHg at peak stress. Diastolic blood pressure decreased from 75 ± 9.8 to 67 ± 12.7 mmHg. On average, 24 ± 4.9 mg/kg/min of dobutamine was applied to achieve maximum stress (Table 1). All patients achieved the 85% of predicted heart rate.
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A total of 502/540 segments (94%) could be analysed. In 38 segments, a valid interpretation was not possible due to image artefacts or bad image quality. These segments were excluded from analyses.
Conventional evaluation showed 18 wall motion or wall thickening abnormalities detected in 13 of 30 patients. Nine of them rated as ischaemia and nine as scar. Four patients showed both scar and ischaemia. Four areas with scar and two areas of ischaemia were not detected (false negatives); four areas of ischaemia and four areas of scar were rated false positive (Table 2).
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Adding continuous infusion of the contrast agent for visual grading and allocating perfusion defects to myocardial segments, the number of false positive ischaemic findings was reduced by two and true positives and true negatives in the diagnosis of myocardial scar were increased by two (Table 2).
Sensitivity, specificity, negative predictive value, positive predictive value and accuracy for the detection of ischaemia representing haemodynamically relevant CAV were 0.71, 0.83, 0.90, 0.56 and 0.80, respectively, for the conventional evaluation and 0.71, 0.91, 0.91, 0.71 and 0.87, respectively, for additional visual grading (Table 3).
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Quantitative grading failed in five patients due to difficulties with exact ROI placement. These patients were not included in analyses.
Significantly reduced threshold values were found for β at rest compared to stress in patients with proven perfusion defects (0.030 vs. 0.118). Multiple ROC analyses identified a cut-off value for β of 0.100/s, which was used for the quantitative grading evaluation. No such cut-off value was found for DA as well as for [A x β] (Table 4).
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Comparing quantitative grading results with the combined gold standard without knowledge of conventional evaluation and visual grading data, sensitivity and specificity were 58% and 67%, respectively.
However, adding this technique to the conventional evaluation plus visual grading, one additional patient with ischaemia was identified (Table 2). Additionally, one of the formerly false negatives (minor changes in CA but positive MPI and IVUS, consequently rated as diffuse CAV) was considered abnormal (Table 2). Sensitivity, specificity, negative predictive value, positive predictive value and accuracy increased to 0.86, 0.91, 0.95, 0.75 and 0.90, respectively (Table 3).
Sensitivity, specificity, negative predictive value, positive predictive value and accuracy for the detection of myocardial scars in 30 patients after heart transplantation were 0.56, 0.81, 0.81, 0.56 and 0.73, respectively, for the conventional evaluation and 0.78, 0.90, 0.90, 0.78 and 0.87, respectively, for visual grading (Table 3).
Multiple ROC analyses could not identify a feasible cut-off value for Db or DA to identify myocardial scars. In the presence of scared and thinned myocardial tissue an exact ROI placement is frequently hampered when the standardized ROIswere partly placed in the cavum of the left ventricle, resulting in heterogenous replenishment curves.
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Discussion |
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This prospective study showed an accuracy of 80% for conventional dobutamine stress echocardiography in the detection of significant CAV after orthotopic heart transplantation which could be further improved by using real-time myocardial contrast echocardiography. MCE visual grading of myocardial segments increased the accuracy to 87% with a further increase to 90% by adding quantitative assessment of the myocardial perfusion.
Dobutamine stress echocardiography has been proven to be a sensitive non-invasive technique for the assessment of known or suspected coronary artery disease as well as for the detection of CAV.18,19,9 Several studies have shown that, in patients with suspected coronary artery disease, the addition of myocardial contrast imaging could further improve the accuracy of dobutamine stress echocardiography. 9,20,21 Recently Rodrigues et al. evaluated intermittent harmonic imaging with visual MCE grading in 35 patients after heart transplantation. The authors reported a sensitivity and specificity for the detection of CAV of 70% and 96%, respectively. Although our study showed comparable results, both study design and echocardiography techniques differed in three major aspects.
Firstly, a combined gold standard consisting of CA, IVUS and SPECT was used for detecting functionally relevant CAV. Because CAV is characterised by diffuse concentric intimal proliferation affecting both epicardial and intramyocardial coronary arteries, the combined gold standard reflects both macro- and microvascular flow information. Weis et al. described endothelium-independent microvascular dysfunction and its prognostic importance for deterioration of left ventricular function in cardiac transplant recipients without angiographically visible coronary artery stenoses, supporting the concept that microvascular and epicardial vessel disease after transplantation are two distinct entities with different functional consequences.22 It is also known that coronary angiography alone is a less sensitive method for detecting CAV in comparison to IVUS in patients after heart transplantation.23–25
Secondly, real-time MCE, which can simultaneously assess LV contractility and myocardial perfusion, was used for the first time in patients after heart transplantation. In contrast to intermittent harmonic imaging, real-time MCE using power pulse inversion provides perfusion data over the full cardiac cycle without loss of information and, thus, is preferable, particularly in patients with suspected CAV.20
Thirdly, the present study for the first time evaluated the diagnostic value of quantitative MCE grading in a clinical setup. Adding this complex technique to the visual perfusion evaluation, one additional ischaemic area was rated as true positive. This patient showed no significant stenoses in CA, but a reversible anteroapical perfusion defect in MPI. IVUS detected CAV in the LAD vessel. Additionally, the combination of different echocardiography techniques seems to reduce equivocal findings, which frequently appear in patients with small segmental perfusion defects due to small vessel disease or CAV and might be strengthened by adding a quantitative evaluation method. Otherwise, applying the quantitative grading method as a standalone technique delivered limited sensitivity and specificity of 58% and 67% in the present study. Consequently, in terms of clinical routine diagnostics the application of a quantitative software tool should always be combined with at least a visual analysis of present wall motion and thickening patterns.
In an open-chest model, Masugata et al. have shown that parameters derived from microbubble refilling curves by real-time MCE correlate well with myocardial blood flow and can identify coronary artery stenoses.14 However, no reference or threshold values were available in patients to differentiate between normal and pathological contrast refilling curves to assess myocardial perfusion.
In the present study, β- and A-values as well as the product of [β x A] showed a high variability between the 18 myocardial segments investigated. Using multiple ROC analyses, a β of 0.100/s could be identified as the best threshold value to differentiate patients with and without CAV by the rise of myocardial contrast intensity.
The high variability of the microbubble refilling curves might be caused by intraindividual differences regarding the extent of microbubble destruction due to the small distance between the sector scanner and the microbubbles and, for example, higher applied ultrasound energies in the apical segments. However, there are discrepant published results regarding the accuracy of MCE perfusion studies in apical myocardial segments. While some authors reported increased image artefacts in those segments,8,26 Elhendy et al. recently reported a high accuracy in the LAD vessel territory.9 In the present study, ischaemia in an apical segment was rated true positive due to a significant decrease of the β-value.
Clinical MCE studies are often limited by the number of myocardial segments that cannot be evaluated due to motion artefacts or weak MCE conditions. Yip et al.26 reported that up to 30% may be impossible to evaluate in patients with CAD. In contrast, only 6% of segments could not be evaluated in the present study, probably due to a careful pre-selection. Seven of 40 patients (18%) were not included because of unsatisfactory echocardiography conditions. The main problem in this manner is an atypical thoracal position of the transplanted heart, which complicates the application of a strictly apical window.
Limitations
Twelve of the 40 patients were excluded for quantification evaluation due to poor echocardiographic window or because of difficulties in placing the ROIs adequately. Exact ROI placement is particularly hampered in the presence of myocardial scars, so that quantitative analyses delivered no suitable results in the present study. The preselection of cardiac transplants is necessary to interpret MCE results. However, this is a main limitation of this method for implementation in clinical routine.
The lack of algorithms for automatic quantification of MCE film loops makes easy adoption of this method for routine clinical use difficult. It also has to be considered that image acquisition and postprocessing of the data, particularly manually fitting the regions of interest frame by frame to respective myocardial segments, are time consuming. This is especially the case with the use of all three echocardiography techniques.
Additionally, IVUS was solely performed in patients with perfusion defect on myocardial SPECT and angiograms without significant stenosis. Therefore, there is a possibility of missing patients without perfusion defect or those with abnormal myocardial contrast echo but with a negative SPECT and negative angiogram who may have had evidence of vasculopathy by IVUS. This may have resulted in a higher false negative and/or lower true positive rate and hence, may potentially have influenced the results.
Other well-recognised problems are the correct allocation of perfusion defects to respective coronary vessels as well as the interobserver variability of the various stress echocardiography applications.
Conclusions
Real-time myocardial contrast echocardiography including visual and quantitative analysis is feasible for screening patients after heart transplantation and provides high accuracy in the diagnosis of haemodynamically relevant cardiac allograft vasculopathy. Therefore, MCE has the potential to reduce the number and costs of routine coronary angiography for CAV in cardiac transplants. However, even if semiquantitative analysis is practicable, further tools for quantitative analysis are required for implementation in routine clinical use.
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Acknowledgement |
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A substantial part of this work originated from the doctoral theses of cand. med. Christopher Übleis.
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Notes |
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5 Drs Hacker and Hoyer share equally the authorship of this paper.
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References |
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