Direct epicardial mapping predicts the recovery of left ventricular dysfunction in chronic ischaemic myocardium

Christian Vahlhausa,*, Hans-Jürgen Brunsa, Jörg Stypmanna, Tonny D.T Tjanb, Frauke Janssenb, Michael Schäfersc, Hans H Scheldb, Otmar Schoberc, Günter Breithardta and Thomas Wichtera

a Department of Cardiology and Angiology, Hospital of the University of Münster, Münster, Germany
b Department of Thoracic and Cardiovascular Surgery, Hospital of the University of Münster, Münster, Germany
c Department of Nuclear Medicine, Hospital of the University of Münster, Münster, Germany

* Correspondence to: Dr Christian Vahlhaus, Universitätsklinikum Münster, Medizinische Klinik und Poliklinik C-, Albert-Schweitzer-Str. 33, D-48149 Münster, Germany. Tel: +49-251-83-48370; Fax: +49-251-83-47864
E-mail address: Vahlhaus{at}uni-muenster.de

Received 5 June 2003; revised 30 September 2003; accepted 16 October 2003

Abstract

Aims This study investigated the hypothesis that direct epicardial bipolar mapping is able to predict the recovery of left ventricular (LV) dysfunction in ischaemic myocardium.

Methods and results In 34 patients with CAD, a maximum of 102 bipolar epicardial electrograms per patient (n=3468 electrograms) were simultaneously recorded with a ventricular jacket array intraoperatively immediately prior to revascularization. Only LV electrograms with good myocardial contact (n=1813, 52±14 per patient, mean±SD) were analyzed. In accordance to the position of each electrode, segmental myocardial function was assessed by transthoracic echocardiography before and 7±2 months (mean±SD; range 3–10 months) after CABG using a wall motion score. Preoperatively dysfunctional segments (n=700) were classified as viable (improvement in wall motion score of at least 20% following CABG, n=424) or non-viable (no improvement, n=276). Bipolar voltage was significantly lower in non-viable when compared to viable myocardium (P<0.001, ANOVA) At a cut-off value of 5.9mV, ROC-curve analysis for bipolar voltage (to discriminate between viable and non-viable myocardium) revealed a sensitivity of 83% at a specificity of 83% (area under the ROC-curve of 0.92±0.01, mean±SE).

Conclusion Direct epicardial mapping is able to predict the recovery of chronically ischaemic dysfunctional myocardium and thereby proves the presence of myocardial viability.

Key Words: ECG • Myocardial viability • Mapping

1. Introduction

The discovery of myocardial hibernation, identified in patients with coronary artery disease undergoing coronary artery bypass surgery,1,2has introduced fundamental changes to the treatment of patients with left ventricular dysfunction due to coronary artery disease.3,4If these patients demonstrated myocardial viability during low-dose dobutamine echocardiography, revascularization not only improved myocardial function but also survival.5Therefore, it is of utmost relevance to detect viable regions with the potential to recover before planning the optimal treatment strategy in patients with left ventricular (LV) dysfunction due to ischaemic cardiomyopathy. Refining established modalities and developing new methods may improve diagnostic accuracy of viability detection. Simultaneously, but not at the expense of the diagnostic accuracy, simpler methods are required to save time and money, to increase patients’ acceptance, and to reduce potential risks (i.e. radiation exposure, contrast agents). In pigs, hibernating myocardium has been characterized by preserved electrical activity (endocardial electromechanical NOGA-mapping)6while electrograms from infarct sites had smaller amplitudes and longer durations when compared with control regions (endocardial electroanatomic CARTO-mapping).7In humans, LV mapping showed higher voltage amplitudes in viable when compared with non-viable myocardial segments (endocardial electromechanical NOGA-mapping).8Several investigators tried to detect viable myocardium validated by radionuclide techniques in humans by NOGA-mapping.8,9A great overlap was observed between groups of viable and non-viable myocardial segments with a lot of segments found in a ‘grey zone’ of 5.4mV to 12.3mV10until Perin and coworkers were able to detect subendocardial and transmural myocardial infarction validated by delayed-enhanced magnetic resonance imaging.11

Because infarct development starts in the subendocardial layer, viable myocardium is more likely detectable from the epicardium. Indeed, most recently, direct epicardal mapping has been shown to have a good diagnostic accuracy in predicting viable myocardium as compared to the non-invasive gold standard 18F-FDG positron emission tomography (PET).12However, the most appropriate end-point to define myocardial viability in chronically ischaemic dysfunctional myocardium remains functional recovery following myocardial revascularization. Therefore, we hypothesized that direct epicardial bipolar mapping is able to predict the recovery of chronically ischaemic dysfunctional myocardium and thereby proves myocardial viability.

2. Methods

The investigation conforms with the principles outlined in the Declaration of Helsinki.13The study protocol had been approved by the Ethical Review Board of the University of Münster,Germany. Patients gave written informed consent before entering the study.

2.1. Patients
Thirty-four patients (30 male, four female; age: 61±9 years) admitted for elective coronary artery bypass grafting (CABG) without concomitant valvular heart disease were prospectively enrolled in this study. All patients had undergone coronary angiography and biplane LV angiography (global LV-EF-range: 25%–61%; 47±9%, mean±SD) before admission because of angina (n=29) and/or angina equivalents (n=13) with a positive stress test. Only patients with regional LV dysfunction were included. 20 patients had a history of prior myocardial infarction. Patients with acute myocardial infarction within the preceding 4 weeks, former CABG or PTCA, atrial fibrillation, ventricular tachycardia, or left bundle branch block were not included.

Standard clinical tests prior to CABG included physical examination, respiratory function test, chest-X-ray, and standard 12-lead ECG-recording. ECG showed pathologic Q waves in 20 patients, 17 of them with and three patients without a history of acute myocardial infarction. To further objectify the influence of prior myocardial infarction the preoperative ECG was evaluated with the complete 57-criteria/32-point QRS-scoring system developed by Selvester and coworkers14to the resting 12-lead-ECGs of the whole study population (n=34). This scoring system has extensively been validated to estimate infarct size15–19and global left ventricular function after myocardial infarction.20Selvester-score amounted to 3.2±3.1 (range 0–10, n=34). Global left ventricular function estimated with Selvester's formula was comparable with that measured by left ventricular angiography (calculated global LV-EF-range: 30%–60%; 50±9%, mean±SD).

2.2. Protocol
2.2.1. Intraoperative epicardial mapping
After opening the chest and the pericardium, the right atrium and the aorta were connected to the cardiopulmonary bypass. Epicardial mapping was performed using a ventricular jacket array which was carefully fixed around both ventricles without ignoring any part of the left ventricular free wall, especially the true posterior wall. Data were recorded with a commercial system (CardioMapp®, Prucka Engineering Inc., Houston, Texas, USA) as previously reported.12In brief, the ventricular jacket array consisted of 102 gold-plated bipolar electrode pairs, arranged in 12 strips of printed copper layers on flexible plastic material: six strips with 10 pairs of electrodes and six strips with seven pairs of electrodes (Fig. 1). Each electrode measured 1.5mm in diameter. In vertical direction, the distance between electrode pairs was 13mm with an inter-pole distance of 4 mm. In horizontal direction, the 12 electrode strips were connected with elastic fabric to fit the ventricular jacket array to different sizes of the heart and to optimize LV contact. The resulting distance between electrode pairs in horizontal direction measured 10 to 13mm. Spatial resolution of electrical mapping (10 to 13mm) was within easy reach by echocardiography and almost comparable to spatial resolution achieved by PET.



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Fig. 1 (A) Ventricular jacket array consisting of 102 gold-plated bipolar electrode pairs, arranged in 12 strips of printed copper layers on flexible plastic material: six strips with 10 pairs of electrodes and six strips with seven pairs of electrodes. (B) 102 bipolar epicardial electrograms simultaneously recorded with CardioMapp®.

 
In each patient, a map with the exact position of the 102 electrode pairs was drawn. Atrioventricular groove and left anterior and posterior interventricular arteries served as landmarks. Those electrode pairs overhanging at apical or atrial border or positioned on fatty epicardium were marked on the map to identify all segments without LV contact. Multiple registrations of 8.9s duration were performed while the patients were in stable sinus rhythm during partial normothermic cardiopulmonary bypass and before induction of ventricular fibrillation. Mechanical pulmonary ventilation was interrupted for the time of the recordings and the systolic blood pressure was set to about 100mmHg. Signals were separately band-pass filtered (0.2–300Hz), amplified (dynamic input range ±16mV, gain 63), analogue-to-digital converted (1kHz sampling rate, 12-bit digital resolution, 7.8µV least significant bit) and stored on a hard disk. For reasons of resolution only bipolar electrograms were recorded. In contrast to unipolar mapping, bipolar mapping allows identification of low-amplitude local activity and spatial resolution of unipolar recordings is markedly reduced by large remote components of the electrogram.21

2.2.2. Echocardiography
Segmental myocardial function was assessed by transthoracic echocardiography preoperatively and 7±2 months (range 3–10 months) after CABG. For acquisition and digital storage of parasternal long- and short-axis and apical four-, three-, and two-chamber echocardiograms, commercially available equipment was used (3.5-MHz transducer; SONOS 5500, Agilent Technologies). Two experienced readers, blinded to the clinical results, analysed segmental myocardial function on quadscreen views of the digitally stored echocardiograms. Based on the handmade maps made during direct epicardial mapping the pre- and postoperatively acquired echocardiography data was precisely assigned to the sight of every electrode pair in each patient. In accordance to the number of electrode pairs and strips from atrioventricular groove to apex and from anterior to inferior border of the left ventricular free wall segmental echocardiograms were evaluated. Segments were graded semiquantitatively on a 5-point scoring system (1: normal, 2: mild hypokinesis, 3: severe hypokinesis, 4: akinesis, and 5: dyskinesis). Segmental improvement was defined as a decrease in wall motion score of at least 20%.22Improved segments of a region supplied with a bypass graft were classified as viable (n=424), preoperatively dysfunctional, revascularized segments, that did not improve were classified as non-viable (n=276).

2.2.3. 18F-FDG positron emission tomography (PET)
To test the validity of the individually modelled LV maps used for data fusion, eight of 34 patients underwent 18F-FDG-PET preoperatively as described.23Analysis of the parametric images and correlation to the epicardial mapping data started with an automated contour finding algorithm of the LV myocardium as reported recently.24,25On the defined contour of the LV myocardium, the electrode mapping system was projected as an elastic net array using the sulcus interventricularis anterior (seen on the scintigraphic image as the anteroseptal origin of the right ventricle), the sulcus interventricularis posterior (seenon the scintigraphic image as the inferoseptal origin of the right ventricle) as well as the apex as guiding structures. PET-uptake discriminated between viable and non-viable segments with an accuracy comparable to that found in literature.26Receiver operating characteristic (ROC) analysis (area under the curve: 0.88±0.03; P<0.001) revealed a sensitivity of 82% with a specificity of 73%. The value of epicardial mapping in predicting viable myocardium as compared to the non-invasive gold standard 18F-FDG-PET has been reportedbefore.12The previous findings were highly reproducible in the subset of eight patients in the present study: ROC analysis for bipolar voltage to discriminate between viable and non-viable myocardium revealed a sensitivity and a specificity of 80% at a cut-off value of 5.9mV (area under the curve: 0.89±0.02; P<0.001).

2.3. Signal analysis
A total of 3468 electrograms were sampled. Only LV electrograms with good myocardial contact (n=1813, 52±14 of 102 segments in each patient, mean±SD) were analysed. One thousand six hundred and fifty-five electrode pairs without LV contact were excluded (right ventricular: n=990 overhanging at apical or atrial border: n=277 on fatty epicardium: n=325, with atrial far field signals: n=63).

The recording with the highest signal-to-noise ratio was selected for single-beat analysis. A 200ms window, centred around the maximum amplitude of the limb lead QRS complex, was chosen as ‘raw data set’. Maximum and minimum amplitudes were automatically measured and the maximum amplitude range was calculated. Time domain parameters were measured as described recently.23In brief, the manually marked QRS onset of the limb lead was set as the reference time zero for all local epicardial electrograms. For the detection of amplitude variations in the onset and offset of bipolar deflections indicating local depolarisation, a new highly sensitive method was developed.23The time of local activation onset and offset was defined as the point where amplitudes exceeded a noise level calculated from samples before or after the activation peak, plus a variable threshold level T. The lower the chosen for this threshold level T, the more sensitive this algorithm detected amplitude variations in the onset or offset of local activation. After different threshold levels T were tested to find optimal markers for onset and offset of both deflections, signal duration was measured based on a threshold level of 6%.23

2.4. Statistics
Statistical analysis was performed using SPSS software (Version 10.0 SPSS Inc., Chicago, Illinois, USA). Data were subjected to a one-way analysis of variance (ANOVA) accounting for the segmental classification viable versus non-viable. Linear regression analysis between segmental myocardial function and bipolar voltage was performed. With logistic regression the relation of bipolar voltage, preoperative myocardial function- and ECG-data to functional recovery was analysed. Receiver operating characteristic analysis was used to analyse the diagnostic accuracy of direct epicardial mapping and 18F-FDG-PET in predicting viability and to estimate a bipolar voltage cut-off value at optimized sensitivity and specificity. Receiver operating characteristics-area under the curve is reported as mean±SE. All other data are presented as mean±SD.

3. Results

3.1. Segmental myocardial function
Preoperative echocardiography disclosed 1113 normokinetic (61%) and 700 dysfunctional (39%) segments of a total of 1813 LV segments. Recovery of myocardial function by one or more category was observed in 424 of 700 preoperatively dysfunctional segments, which were therefore classified as viable. The remaining 276 preoperatively dysfunctional segments showed no improvement of wall motion, and were therefore classified as non-viable. While there was no relation between bipolar voltage and preoperative segmental myocardial function, regression analysis revealed a significant relation between bipolar voltage and postoperative segmental myocardial function. The higher the wall motion score, the lower was bipolar voltage (Fig. 2; y=–0.02 x+1.7, r=0.21, P<0.001, n=700). However, with such a low r-value the absolute postoperative wall motion score was not predictable. Analysing the improvement (absolute difference in pre- and postoperative wall motion score) as a function of bipolar voltage, the r-value did not improve (y=–0.03 x+0.13, r=0.23, P<0.001; n=700). Therefore, the extent of improvement was notpredictable.



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Fig. 2 Boxplot distributions of bipolar voltage among normokinetic, mild hypokinetic, severe hypokinetic, akinetic, and dyskinetic segments. Data shown within each box correspond to 25th, 50th (median) and 75th percentile cut points for each group. Error bars indicate the 95% confidence interval.

 
3.2. Electrical data
Non-viable segments were characterized by prolonged bipolar signal duration (22.8±0.5ms vs 15.4±0.4ms, P<0.001 vs viable, ANOVA) and reduced bipolar voltage (3.6±0.3mV vs 13.1±0.3mV; P<0.001 vs viable, ANOVA) when compared to dysfunctional but viable segments (Fig. 3). There was no interaction between segmental myocardial function and bipolar voltage at baseline in predicting functional recovery of preoperatively dysfunctional segments (logistic regression, P=0.536, n=700).



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Fig. 3 Comparison of (A) bipolar signal duration and (B) bipolar voltage from 700 dysfunctional segments classified as non-viable (no recovery, n=276) and viable (recovery, n=424). Data shown within each box correspond to 25th, 50th (median) and 75th percentile cut points for each group. Error bars indicate the 95% confidence interval (*P<0.001 vs recovery, ANOVA).

 
3.3. Accuracy of bipolar voltage in predicting functional myocardial recovery
Bipolar voltage discriminated well between viable and non-viable segments. At a bipolar voltage of 5.9mV, ROC analysis (Fig. 4, area under the curve: 0.92±0.01, mean±SE) revealed a sensitivity of 83% with a specificity of 83%. Positive and negative predictive values were 88% and 76% respectively. Taking the dependence of a patient's data into account, logistic regression still revealed bipolar voltage as a significant (P=0.005) predictor of functional recovery. Receiver operating characteristic-analysis was used in every single patient. That resulted in 34 ROC-curves for 34 patients. On a per patient basis, sensitivities ranged from 38 to 100% (83±17%, mean±SD, n=34) with a specificity ranging from 50 to 100% (85±14%, mean±SD, n=34) at a bipolar voltage of 5.9mV. There was no difference of results when the diagnostic accuracy was analysed separately with respect to prior myocardial infarction: Excluding patients with prior myocardial infarction sensitivity and specificity were 85% and 78% respectively. Area under the curve was 0.91±0.02 (mean±SEM, ROC analysis, n=14). Analysis of only those patients with prior myocardial infarction (ROC analysis, n=20) did not show different results: Sensitivity was 82% and specificity was 84% at a bipolar voltage of 5.9mV. Area under the curve was 0.93±0.01 (mean±SEM). In addition, further sub analysis did not lead do different results, neither separate analysis with respect to the presence of Q waves in preoperative ECGs, nor with respect to the severity of preoperative dysfunction. Logistic regression revealed an interaction between bipolar voltage derived directly from the epicardial surface and the Selvester-score obtained from body surface measurement in predicting functional recovery (P=0.024). While bipolar voltage was highly significant in predicting functional recovery (P<0.001) the Selvester-score did not reach the significance level.



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Fig. 4 Plot of receiver operating characteristics (ROC) for bipolar voltage to predict viability. At a bipolar voltage of 5.9mV, sensitivity was 83% with a specificity of 83% (area under ROC curve: 0.92±0.01, mean±SE).

 
4. Discussion

This study demonstrates for the first time that direct epicardial bipolar mapping is able to predict functional recovery, the most appropriate endpoint to define myocardial viability in chronically ischaemic dysfunctional myocardium and thereby proves myocardial viability.

4.1. Is electrical mapping for myocardial viability superior to conventional methods?
At present, conventional methods for assessing myocardial viability including radionuclide techniques,27,28low-dose dobutamine echocardiography,29and contrast enhanced magnetic resonance imaging30are superior to direct epicardial mapping because they all are non-invasive. There is consensus that only radionuclide techniques such as 18F-FDG-PET represent the gold standard for detection of myocardial viability.2718F-FDG-PET identified viability in a relatively high percentage of segments with even less than 25% of viable myocardium.31Therefore, the specificity of 18F-FDG-PET in predicting the recovery of LV dysfunction is limited, while the sensitivity is high. In contrast, in hypokinetic regions, elicitation of a contractile response by dobutamine stimulation requires at least 50% of the myocytes within a segment to be viable.31Therefore, low-dose dobutamine echocardiography shows the highest specificity32and the best accuracy of a positive test33in predicting recovery of myocardial contractile function following revascularization. In regions of severely dysfunctional segments, even the transmural extent of viable myocardium can be assessed by contrast enhanced magnetic resonance imaging (late enhancement), which is a strength of this method.30However, these conventional methods are sometimes impracticable due to claustrophobia, implanted pacemakers or defibrillators, due to low-image quality in patients with emphysema or those suffering from diabetes.

The present study demonstrates that direct epicardial mapping is able to predict the recovery of chronically ischaemic dysfunctional myocardium and thereby indicates the presence of myocardial viability. Therefore it encourages further investigation as to whether or not body surface potential mapping may develop as a non-invasive tool to identify regional myocardial viability in the future. We have proved that local epicardial bipolar electrograms allow the identification of myocardial viability. To further develop a non-invasive mapping technique, a 3-dimensional -inverse calculation technique is required to reconstruct or recalculate virtual epicardial electrograms based on body surface potential mapping data. With such inverse solutions the accuracy of reconstructed epicardial potentials was evaluated in dogs34by direct comparison to the electrograms measured simultaneously with 134 epicardial electrodes and in pigs.35Therefore, the spatial resolution that can be achieved appears to be high enough to enable correct identification of regional or even segmental viability with non-invasive ECG techniques.

4.2. Does electromechanical mapping lack diagnostic accuracy?
In pigs, endocardial voltage was not affected in hibernating myocardium6but in scarred myocardium.7However, the scatter of endocardial ECG amplitudes was of a magnitude that endocardial mapping failed to establish cut-off values that allowed useful distinction between viable and non-viable areas.8,9Using bipolar voltage, which may be superior to unipolar voltage in detecting local electrical myocardial status diagnostic accuracy did not improve.9Only when delayed-enhanced magnetic resonance imaging, an excellent predictor of functional recovery36was used to validate the transmurality of myocardial infarction, electromechanical mapping precisely detected subendocardial and transmural scar.11Ischaemia is more severe in the subendocardial when compared to the epicardial layer. In consequence, myocardial infarct development starts from the subendocardial layer before expanding transmurally. Areas of subendocardial infarction with viable but dysfunctional mid- and/or epicardial layers may have low endocardial ECG amplitudes but normal epicardial ECG amplitudes, thus more easily indicating potential functional recovery only from the epicardial site.

4.3. Does direct epicardial mapping have the potential of clinical use?
In contrast to endocardial mapping, which can be performed during left-heart catheterization, epicardial mapping requires cardiac surgery. Therefore, the data provided by the present study may be useful to understand the pathophysiology of chronically ischaemic dysfunctional myocardium but is obviously obtained too late to help in preoperative decision making. It is not the aim of the present study to implement direct epicardial mapping for clinical use. As a first step the present study shows that viability is detectable by epicardial electrocardiography. Epicardial electrograms correlated with electrograms from the body surface in dogs34and pigs.35Our study provides a basis for future developments: Inverse-solutions have to be generated, because electrical mapping from the body surface may develop into a very promising tool for non-invasive viability detection in the future. future. However, inverse solutions would also require magnetic resonance imaging. Therefore, further investigations should focus on the potential of body surface potential mapping in detecting regional viability without the need of magnetic resonance imaging—regional ischaemia for instance was detectable by the single use of body surface potential mapping.37

4.4. Study limitations
One limitation of the study is that not the entire LV can be mapped from the epicardium. The septum wasexcluded from the analysis, since no epicardial signal can be obtained intraoperatively by the ventricular jacket array. Because of epicardial fatty tissue, not all segments could be included in the analyses in all patients.

Another limitation is that image fusion of two-dimensional echocardiographic data with electrical data localized by handmade maps does not allow an exact spatial assignment for every segment analyzed.

Recovery of segmental myocardial function depends on successful coronary revascularization and restoration of perfusion. However, segmental myocardial perfusion was not measured.

Acknowledgments

This study was supported by the Interdisciplinary Center for Clinical Research (IZKF; B1, BMBF-01KS 9604) andthe German Academic Exchange Program (DAAD;313/sf-ppp-kr).

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