SEGMENTAL COLOR DOPPLER MYOCARDIAL IMAGING DERIVED PRE-EJECTION VELOCITIES ARE NOT CLINICALLY USEFUL IN THE ASSESSMENT OF POST-INFARCTION SCAR TRANSMURALITY

Introduction. The presence of a velocity in isovolumic contraction phase (Vivc) evaluated using tissue Pulse wave Doppler myocardial imaging (PWDMI) correlates with a transmural extent of scar after myocardial infarction. The possible clinical usefulness of Vivc evaluated using color Doppler myocardial imaging (CDMI) in detection of a scar after myocardial infarction extent in patients with coronary heart disease (CHD) and low LV systolic function remains to be clarified. Patients and methods. 57 patients with CHD (average LVEF 33.5±5%), examined echocardiographicaly (17-segment LV model, 689 segments evaluated) and by cardiac magnetic resonance. All segments were scanned for Vivc presence using CDMI. Vivc presence/absence was correlated with signs of a scar after MI in all segments and in akinetic segments separately. Results. We found significantly larger values of wall thickness (8.2±2,2 vs. 7.1±1.9, p<0.0001), significantly lower values of average late enhancement (LE) extent (1.32±1.78 vs. 1.66±1.98, p=0.041) and LE/wall thickness ratio (20.1±29.8 vs. 29.6±36.7, p=0.008) in segments with present Vivc. Vivc presence in a segment with an abnormal wall motion had a sensitivity of 72.9% and a specificity of 35.7% in recognizing a segment without a transmural scar (LE/ wall thickness ratio ≤75%). Vivc absence in a segment with an abnormal wall motion had a sensitivity of 72.7% and a specificity of 41.2% in recognizing a segment with a transmural scar (LE/wall thickness ratio ≥75%). Conclusions. Isovolumic velocities evaluation assessed using color Doppler myocardial imaging is not applicable in a real-world clinical setting. The presence or absence of a velocity pattern during LV isovolumic contraction is not useful in in the assessment of a post-infarction scar transmurality.


INTRODUCTION
An accurate detection of viable myocardium is of great importance in patients with coronary heart disease (CHD) and impaired systolic function of left ventricle (LV) (ref. 1 ).The presence of a pre-ejection velocity (Vivc -velocity in isovolumic contraction phase) evaluated using tissue Pulse wave Doppler myocardial imaging (PWDMI) correlates with a transmural extent of scar after myocardial infarction (MI) in experimental studies 2 and recently in a clinical study 3 .The possible clinical usefulness of Vivc evaluated using color Doppler myocardial imaging (CDMI) in detection of extent of a scar after myocardial infarction in patients with CHD and low LV systolic function remains to be clarified.

Patient group
57 patients of average age 69.3±15.9 years (50 men, 7 women) were included in the study.The baseline clinical characteristics are listed in Table 1.All patients had chronic ischemic heart disease with a depressed LV ejection fraction (EF) (average LVEF 33.5±5%).They all had stable LV dysfunction.Patients with a history of MI in the last 6 months were excluded.Those with an acute coronary syndrome or any sign of an acute myocardial ischemia as well as patients with a significant valvular disease were not included.All patients had a coronarogra-    phy and were then examined echocardiographicaly and by cardiac magnetic resonance (MR).All patients had sinus rhythm during all examinations.

Echocardiography
Echocardiography was performed on a GE Ultrasound Vivid 7 (GE Healthcare; Chalfont St. Giles, UK).A resting echocardiography examination with 1-lead ECG registration was performed in the standard way using 2, 3 and 4-chamber views according to a 17-segments LV model 4 .Individual walls were imaged separately to get a higher frame rate and optimized parallel beam alignment with longitudinal wall motion.The echocardiography machine was set-up to obtain an optimal tissue signal under standard clinical conditions (frame rate above 160 fps, gain 2 dB, scale 1,00 kHz, frequency 2,5 MHz, average smoothing 30 ms).All data were obtained during a calm end-expirium.Color-Doppler sequences superposed on 2D-image (3 cardiac cycles were recorded for every sequence) were saved in the archival program EchoPac 7 Option (version BT 06) and subsequently evaluated offline blindly without knowledge of the clinical status and results of other examinations.A region of interest was set to the middle of an analyzed segment.The pre-ejection phase was defined as an interval between the beginning of QRS complex and onset of flow in aorta evaluated using pulse Doppler wave (PW) signal at LV outflow tract.All segments were scanned for the presence or absence of Vivc.

Feasibility and reproducibility
Apical segments were excluded (57 of 969 segments).Only segments with a very good image quality were included in the analysis.Segments with poor image quality were not scanned for the presence of Vivc and thus excluded from analysis.A sum of 689 LV segments (76% of all possible LV segments) was included in the statistical analysis.
To study the intra-and inter-observer variability, the presence or absence of Vivc was assessed in 87 segments with a very good image quality from 6 patients during one day and subsequently again after one week by two observers with experience with tissue Doppler echocardiography (TDE).Each observer placed a new sample volume in the studied segment.Examinations by two observers were performed 5 min apart.Inter-observer agreement in detection of a present Vivc was 100% (30/30) for basal segments, 100% (29/29) for middle segments and 89% (25/28) for the apical segments.Intra-and inter-observer variability of evaluation of Vivc presence were 8.9±6.1 and 9.7±7.6 in average, 6.7±5.2 and 8.1±7.0 separately for basal segments, 8.2±5,8 and 8.4±7.0 for middle segments and 11.8±7.3 and 12.3±8.7 for apical segments.An evident increase in variability of examinations from basal to apical segments can be explained by an unsatisfying incident angle and diminishing systolic velocities from base to apex.Apical segments were thus not included into statistical analysis.Segmental color Doppler myocardial imaging derived pre-ejection velocities are not clinically useful in the assessment of post-infarction scar transmurality

Magnetic resonance
The cardiac MR was performed on the Siemens Magnetom Avanto (Siemens, Erlangen, Germany), Q engine (33 mT/m), Tim 76x18, installed in 2005, equipped with the Syngo 2004A software and complete cardio-MR equipment (Advanced Cardiac Package, post-processing software Argus).A standard protocol of myocardial viability evaluation included a functional cinematic examination focused on LV using TrueFisp2D-CINE sequence (evaluation of end-diastolic myocardial thickness and LVEF) and late enhancement (LE) with high space resolution sequences CE-IR-MRI.Both types of LV myocardium display were performed at consonant planes (series of layers at short-axis plane, 4-chamber and 2-chamber projection and apical long axis).For LE depiction a paramagnetic extra-cellular contrast agent based on gadolinium was applied in a unified dose of 20 ml (0.5 molar contrast agent) or 10 ml (1 molar contrast agent) respectively.Scanning was started 10 minutes after contrast agent application.Standardly a modern sequence PSIR-TrueFisp2D (PSIR = Phase Sensitive Inversion Recovery) was used.A manual adjustment of inversion time (TI) for viable myocardium signal zero setting was not necessary.Automatically reconstructed images of this sequence were used for the myocardial viability assessment.LV segmentation was performed according to a standard 17-segment model of LV (without evaluation of apical segment 17) (ref. 4).In every segment we evaluated an extent and a transmurality of a scar after MI (maximal and average extent of a scar in the particular segment in mm), an average wall thickness (in mm) and an average extent of a scar in the particular segment (in %).The evaluation was performed by 2 independent, mutually blinded radiologists, without using automated software.

Statistical analysis
Statistical analysis was performed on the statistical software SPSS 15.Values of p≤0,05 were evaluated as statistically significant.The chi square test and Mann-Whitney test were used for the statistical analysis: the results of Vivc presence measured echocardiographicaly were compared to magnetic resonance (LE extent/wall thickness ratio parameter) as a reference method.1) Presence or absence of Vivc in all segments was compared with wall thickness, average LE extent and LE/ wall thickness ratio to evaluate correlation of Vivc with the signs of a scar after MI. 2) Of all 689 segments 148 were evaluated as akinetic.
Vivc presence/absence was evaluated in these akinetic segments.A specificity, sensitivity, positive and negative predictive value of Vivc presence or absence respectively in accuracy of detection of a scar after MI were calculated for LE extent/wall thickness ratio in individual LV segments on MR below and above 75%.This cut-off value was based on previous studies 5 chosen to assess the usefulness of Vivc presence/ absence in exclusion/confirmation of a transtmural scar in each individual segment.

RESULTS
1) Nonparametric Mann-Whitney test showed significantly larger values of wall thickness (8.2±2.2 vs. 7.1±1.9,p<0.0001) (Fig. 2) and significantly lower values of an average LE extent (1.32±1.78 vs. 1.66±1.98,p=0,041) (Fig. 3) and LE/wall thickness ratio (20.1±29.8 vs. 29.6±36.7,p=0.008) (Fig. 4) in segments with present Vivc.2) Vivc presence in a segment with an abnormal wall motion had a sensitivity of 72.9% and a specificity of 35.7% in recognizing a segment without a transmural scar (LE/wall thickness ratio ≤75%).The accuracy of Vivc presence in detection of a segment without a transmural scar was 60.2% (Table 2).Vivc absence in a segment with an abnormal wall motion had a sensitivity of 72.7% and a specificity of 41.2% in recognizing a segment with a transmural scar (LE/wall thickness ratio ≥75%).The accuracy of Vivc absence in detection of a segment with a transmural scar was 66.5% (Table 3).

DISCUSSION
In an experimental model of MI a presence of Vivc was linked with the presence of a non-transmural necrosis.An absence of Vivc, on the other hand, pointed to a transmural scar.The pathophysiologic basis for this is the ability of a viable myocardial segment to perform a minimal contraction power during the isovolumic contraction phase, in which the intraventricular pressure rises, but is still low compared to the ejection phase, in which the contraction force of the particular segment is not sufficient enough and it appears as dysfunctional.Nonviable segments are not able to generate contraction even in the pre-ejection phase 2,6 .Pathophysiologicaly the presence of pre-ejection velocities in the isovolumic contraction phase should reflect the presence of a viable myocardium in the particular segment and vice-versa; the absence of pre-ejection velocities should mean that there is not a remarkable amount of viable myocardium in the particular segment.These velocities are detectable on TDE as a shortly lasting positive wave before a subsequent positive wave representing systolic myocardial motion (Fig. 1).
According to a recent clinical study, the evaluation of pre-ejection velocities should be useful as a marker of myocardial viability also under clinical conditions 3 .Penicka et al. 3 evaluated the presence of Vivc using PDWMI.The possible clinical usefulness of Vivc evaluated using CDMI in the detection of the extent of a scar after myocardial infarction in patients with CHD and low LV systolic function remains to be clarified.
MRI was used as a reference method to assess the extent of post-infarction scar presence and transmurality.Late enhancement evaluation corresponds well with the Segmental color Doppler myocardial imaging derived pre-ejection velocities are not clinically useful in the assessment of post-infarction scar transmurality Regarding these results we can not reliably presume a transmural (LE extent ≥75%) scar just from the absence of Vivc in a given segment.We also can not presume a nontransmural (LE extent ≤75%) scar just from the presence of Vivc.Hence viability of myocardium in the particular segment can not be confirmed or disaproved merely from an absence or presence of Vivc evaluated using CDMI.In our patient group, the assessment of presence or absence of Vivc does not represent a clinically useful marker of viability in the particular segment.
The difference of these results from those earlier published could be explainable with limitations of this parameter when evaluated using CDMI.There are several limitations present using CDMI for evaluation of Vivc.CDMI data must be collected at frame rates in excess of 100/s.These are not obtainable if a standard wide sector imaging contralateral walls is used.Optimally to capture such short lived events such as Vivc even higher frame rates (in excess of 400 frames/s) should be used.This is hardly achieved using CDMI and these parameters surely are not part of a standard echocardiographic machine setting in daily praxis.Prior studies used pulsed tissue Doppler which has a higher temporal resolution than color tissue Doppler imaging 3 .Capturing of such brief events as Vivc could also be effected by sampling rate.An average smoothing of 30 ms was employed in this study.This could have limited determination of peak Vivc.Smoothing leads to a possibility of omission of Vivc but on the other hand smaller value of average smoothing results in the presence of a lot of artifacts making proper evaluation of Vivc presence difficult.Another limitation of Vivc detection using CDMI may be influence of deformation of apical and mid segments.This deformation could lead to a velocity trace of basal segments of the same wall and thus possibly render evaluation of velocities in basal segments impossible.The above stated limitations of usefulness of CDMI in myocardial velocities evaluation seem to be the reason why this methodology is according to these results not clinically applicable.Another distortion of the predictive value of Vivc presence can be caused by the presence or absence of resting myocardial ischemia in the particular segment interfering with the regional tissue velocities.A poor echocardiography image quality in some patients is also a limiting factor.Assessment of tissue velocities is also difficult in apical segments considering an unsatisfactory incidence angle and low tissue velocity values when minimal Vivc can be overlooked and thus falsely evaluated as not present.

CONCLUSION
Isovolumic velocities evaluation assessed using color Doppler myocardial imaging is not applicable in a realworld clinical setting.The presence or absence of a velocity pattern during LV isovolumic contraction is not useful in in the assessment of a post-infarction scar transmurality.presence and extent of a scar after MI according to several studies.In myocadial segments with LE/wall thickness ratio on MR ≥75% a transmural scar is known to be present and a contractile recovery is unlikely 7 .
We have found a significant correlation of Vivc with the signs of a scar after MI (wall thickness, average LE extent, LE/wall thickness ratio) generaly in all evaluated segments.This finding supports the above mentioned pathophysiological relation of Vivc presence/absence and post-infarction scar presence and transmurality.
The question is in which segments it is useful to evaluate Vivc presence?There is no need to assess myocardial viability in segments with normal wall motion, because these segments are by definition viable.Hence for further analysis we included only the segments evaluated as akinetic on echocardiography.These segments could have a transmural scar or they could be hibernated due to a prolonged ischemia with a nontransmural scar or a no scar at all.The clinical question is whether Vivc presence or absence can help us to distinguish these clinical units in individual segments.
The Vivc presence in akinetic segments had in our study a sensitivity of 72.9% and a specificity of 35.7% in recognizing a segment without a transmural scar (LE/ wall thickness ratio ≤75%).The accuracy of Vivc presence in detection of a segment without a transmural scar was 60.2%.
On the other hand Vivc absence in a segment with an abnormal wall motion had a sensitivity of 72.7% and a specificity of 41.2% in recognizing a segment with a transmural scar (LE/wall thickness ratio ≥75%).The accuracy of Vivc absence in detection of a segment with a transmural scar was 66.5%.

Fig. 2 .Fig. 3 .
Fig. 2. Correlation of Vivc presence/absence with wall thickness.(thick line inside of the box = median, bottom of the box = 1 st quartile, upper edge of the box = 3 rd quartile, horizontal line above the box = minimal and maximal proximal value, circle = distant value, star = extreme)

Fig. 4 .
Fig. 4. Correlation of Vivc presence/absence with average LE.(thick line inside of the box = median, bottom of the box = 1 st quartile, upper edge of the box = 3 rd quartile, horizontal line above the box = minimal and maximal proximal value, circle = distant value, star = extreme)