Abstract: Background. Optimal positioning of the left ventricular (LV) lead at the latest activated part of the left ventricle is one of the major challenges in implantation of cardiac resynchronization therapy (CRT) devices with respect to ascertaining an optimal resynchronization effect resulting in a high responder rate. In the present study, we evaluated the feasibility of transcoronary measurement of LV electrical activation by a coated guidewire in a porcine model. Methods and Results. Transcoronary measurement of ventricular activation was performed in 16 pigs under general anesthesia. Left bundle branch block (LBBB) was induced by transvenous pacing in the right ventricular apex (RVA). A specially coated guidewire (Vision Wire; Biotronik) serving as the different electrode was positioned subsequently in the proximal and distal part of each coronary main vessel. A cutaneous skin patch electrode was placed at the back of the thorax of the animal to act as the indifferent electrode. Both electrodes were connected to a portable electrophysiology lab system (EP Tracer 38; CardioTek). Mean QRS width during transvenous right ventricular pacing was 83 ± 5 ms with a typical LBBB pattern. The measured time interval between the beginning of the QRS complex in the surface electrocardiogram (ECG) and the local signal derived from the tip of the guidewire (QRS-EGM) was 32 ± 9 ms in the distal ramus circumflex (RCX) coronary artery and 51 ± 6 ms in the proximal RCX, yielding a mean delay of 18 ± 8 ms within this vessel. In the left anterior descending (LAD) coronary artery, the local signal was 23 ± 10 ms in the distal part and 41 ± 10 ms in the proximal part of the vessel, with an identical mean delay of 18 ± 8 ms. The QRS-EGM interval within the right coronary artery (RCA) was 14 ± 8 ms in the distal part and 40 ± 9 ms in the proximal part of the vessel, resulting in a mean delay of 25 ± 7 ms. The delay between the activation of the distal RCA and the activation of the distal LAD and RCX was statistically significant (P<.001). Within the proximal guidewire positions, the latest electrical activation of the left ventricle during pacing-induced LBBB could be observed in the RCX with 51.4 ± 6.3 ms (P<.01). Conclusion. Transcoronary measurement of LV excitation by a specially coated guidewire is feasible and could confirm the electrical asynchrony induced by LBBB. Since coronary angiography is a mandatory part of the evaluation of patients for CRT implantation, a “transcoronary mapping procedure” can be easily performed, thereby evaluating the latest activated part of the left ventricle in advance of the implantation procedure, aiming to improve the responder rate in CRT therapy.

Key words: CRT, lead positioning, transcoronary mapping

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Cardiac resynchronization therapy (CRT) is an established therapeutic option for patients with heart failure, reduced left ventricular ejection fraction, and left bundle branch block (LBBB) according to the current international guidelines.^1-4

However, up to one-third of patients with advanced heart failure and LBBB do not exhibit a positive response to CRT.⁵ One of the identifiable reasons for the non-response^5,6 is an inappropriate left ventricular (LV) lead position in about 20% of these patients. The anatomical optimal LV lead position is in a posterolateral cardiac vein.⁷ However, the electrical delay within the left ventricle depends on global and local conduction velocity and the dimensions of the ventricles.⁸ Moreover, local scar tissue due to myocardial infarction or left ventricular hypertrophy with unacceptably high pacing energy requirements as far as phrenic nerve stimulation at the target region can prolong the implant procedure to find an adequate lead position at the latest activated part of the left ventricle with low pacing thresholds without phrenic nerve stimulation.⁷

Therefore, it would be favorable to identify the optimal LV lead position in a specific patient before maneuvering the lead in different veins, which can require the override of several obstacles, such as venous valves and kinking anatomies or local obstructions of the cardiac veins, and not infrequently results in phrenic nerve stimulation, high local pacing thresholds, or only a short delay between the right ventricular (RV) and LV lead (RV-LV delay) if the region with the latest LV activation was not reached. De Cock et al described the use of a coated guidewire for transvenous mapping of the optimal LV lead position during CRT implantation.⁹ They could demonstrate comparable pacing thresholds with the pacing guidewire in use and the LV lead in the same position. 

In our opinion, it would be favorable to evaluate the optimal lead position within the context of the coronary angiography in advance of the implantation procedure without cannulating the coronary sinus system. Because of the concordance of the main coronary arteries and the main coronary veins, this mapping procedure should be possible using the coronary artery system with comparable results. 

Therefore, transcoronary pacing and mapping could be a promising approach. The transcoronary pacing technique was introduced by Meier et al in 1985.¹⁰ More recently, this technique was further developed by our group, when we demonstrated comparable low pacing thresholds as obtained by standard transvenous pacing with an optimal patch position and the use of a balloon catheter for further insulation of the guidewire.¹¹ In addition, the introduction of coated guidewires yielded excellent pacing and sensing results with this method.^11,12

The purpose of the present study was to proof the epicardial transcoronary mapping technique for measurement of left ventricular activation during pacing-induced LBBB.

Since the coated guidewire (VisionWire; Biotronik) used is currently only certified for temporary pacing in the coronary veins,⁹ this study had to be performed in an animal model.

Methods

Transcoronary measurement of the local epicardial electrogram was evaluated in 16 adult pigs in an animal laboratory, as described previously.¹³ The study was conducted according to the regulations of the local animal authorities. 

General anesthesia was induced and maintained in each animal with isoflurane, nitrous oxide, and ketamine (adapted to body weight). Mechanical ventilation was instituted while the animal was placed in the supine position on the table of a monoplane catheter laboratory. Two neck vessels (carotid artery and jugular vein) were chosen for vascular access sites. A 6 Fr sheath was placed in the carotid artery for coronary access and transcoronary mapping. Another 6 Fr sheath was inserted into the internal jugular vein for transvenous pacing in the apex of the right ventricle. To avoid thrombus formation during coronary angiography and transcoronary measurement, anticoagulation was established with unfractionated heparin at 70 units/kg body weight at the beginning of the procedure. Angiography of both coronary arteries was performed using standard 6 Fr Judkins guiding catheters (Cordis Corporation) for visualization of the coronary anatomy. 

The surface electrocardiogram (ECG) of the animal was recorded from the limbs.

Mapping technique. Transcoronary mapping was performed in a unipolar setting. The coronary guidewire served as the different electrode in any case. Therefore, the tip of the specially coated 0.014˝ coronary guidewire (VisionWire)was advanced into the target coronary artery: left anterior descending (LAD) coronary artery; ramus circumflex (RCX) coronary artery; or right coronary artery (RCA). This guidewire has an electrically insulating polytetrafluoroethylene (PTFE) coating except at the distal tip (28 mm) and the proximal end (40 mm). 

This uncoated stiff end of the guidewire was connected by a sterile alligator clamp to a portable electrophysiology (EP) lab system (EP Tracer 38; CardioTek) for recording of the unipolar local electrogram of the guidewire tip positioned in the coronary vessel. A self-adhesive skin electrode with a surface area of about 100 cm² placed at the back of the thorax of the animal served as the indifferent electrode, and was also connected to the portable EP system. Finally, a bipolar transvenous pacing lead was advanced via the jugular vein sheath into the apex of the right ventricle and connected to an external temporary pacemaker (Figure 1).

Mapping protocol. The guidewire was advanced through the guiding catheter into the distal part of the first target vessel and the back of the guidewire (outside the body) was connected to the EP system. Temporary right apical pacing by the bipolar transvenous pacing lead was then initiated at a rate of 10-20 beats/min faster than the intrinsic heart rate, resulting in an LBBB (Figure 2, right panel). The time interval between the beginning of the QRS complex from the surface ECG, the local electrogram derived from the tip of the guidewire in the specific position of the coronary vessel, and the width of the QRS complex from the surface ECG were measured within the EP system. 

Temporary pacing was stopped to avoid prolonged VVI pacing with its potential hemodynamic disadvantages, and the guidewire was pulled back to a more proximal position within the same coronary vessel. The time interval measurements were repeated as described above.

After completion of these measurements within the first coronary artery, the guidewire was advanced subsequently into both remaining coronary vessels. The delay of the local electrogram was derived from a distal and a proximal position of the guidewire in each coronary vessel while temporary right ventricular pacing was reestablished (Figure 3).

Finally, a coronary angiography was performed to exclude any damage of the coronary vessels potentially caused by guidewire manipulation within the coronary artery system.

Statistical analysis. All descriptive analyses describe mean and standard deviations of the data. Mixed models with fixed effects were fitted to describe repeated measurements.  The results from this model are described with mean and 95% confidence interval (CI). Measurements were repeated in the distal and proximal segment of the three coronary vessels (RCA, RCX, and LAD) in each pig. A common correlation among the observations from a single pig was assumed corresponding to the compound symmetry structure. To describe the influence of fixed effects of distal and proximal measurements at different vessels, an ANOVA F-type statistic was used. All reported P-values are two-sided, and P-values <.05 were considered to indicate statistical significance. Calculations were made using IBM SPSS Statistics 21 (SPSS, Inc).

Results

None of the animals has had any signs of coronary artery disease. The guidewires were successfully advanced into all three main coronary arteries without complications, so that we could obtain a full data set according to our mapping protocol in all 16 pigs. 

Transcoronary mapping. Transcoronary mapping with the coated guidewire was feasible in all three coronary vessels. 

The mean QRS width during right ventricular pacing was 84 ± 5 ms with a typical left bundle branch pattern (Figure 2, right panel).

The measured local delays between the beginning of the QRS complex on the surface ECG and the local epicardial signal derived from the tip of the guidewire (QRS-EGM interval) are summarized in Table 1. 

The mixed-model statistics showed a significant influence of the position of the guidewire (distal vs proximal) and the different coronary vessels (P<.001) on the QRS-EGM interval.

The QRS-EGM interval showed lower values in distal measurements compared to proximal, with a mean difference of 20.8 ms (95% CI, 17.6-23.9). As expected during right ventricular pacing, the earliest local electrogram could be measured with the mapping guidewire in the distal RCA with 14.1 ± 7.6 ms after the beginning of the QRS complex, followed by the guidewire position in the distal LAD at 23.5 ± 9.9 ms and the guidewire advanced into the distal RCX with 32.0 ± 8.8 ms. This delay between the activation of the distal RCA and the activation of the LAD and the RCX was statistically significant (P<.05). 

Within the proximal guidewire positions, there was a quite similar local ventricular activation in the proximal RCA and LAD with 39.5 ms (95% CI, 34.6-44.5) and 40.6 ms (95% CI, 36.0-45.1), respectively. Again, the latest activation could be observed in the proximal RCX with 50.8 ms (95% CI, 46.1-55.4) (Table 1).

QRS-EGM shows highest values in distal and proximal measurements of the RCX, with a mean difference of 8.9 (95% CI, 3.5-14.3) and 10.3 (95% CI, 4.5-16.1) to distal and proximal measurements of the LAD (Table 2).

According to the dominant RCA in the pig model, the intravessel delay was longest within the distal to proximal position in the RCA, with 25.0 ± 7.4 ms.  

The differences between the distal to the proximal guidewire position were 18.5 ± 7.5 ms within the LAD and 17.9 ± 7.5 ms within the RCX, respectively.

Complications. No complications of transcoronary mapping were observed. There was no thrombotic material adherent to the guidewires after removal. The final coronary angiography at the end of the mapping procedure could exclude any damage of the coronary vessels potentially induced by guidewire manipulations.

Discussion

The technique of transcoronary pacing and transcoronary recording of local electrograms was introduced in 1985 by Meier et al.¹⁰ Initially, this technique was used for emergency pacing during coronary interventions. More recently, our group further developed the transcoronary pacing concept^13,14 by using a specially coated guidewire.¹² 

In the present study, the guidewire in the coronary artery was used for recording local epicardial electrograms. To our knowledge, this is the first application of transcoronary mapping of LV activation by a coated guidewire. We could clearly demonstrate a significant delay of electrical excitation of the lateral wall of the left ventricle (measured in the RCX) during pacing-induced LBBB.

The concept of epicardial guidewire mapping and pacing within the coronary sinus was reported for the first time by de Cock et al.⁹ Recently, data on prelead implantation testing at different LV sites in cardiac resynchronization therapy procedures by a pacing guidewire were published by Chan et al.¹⁵ In both studies, there was a close relationship between the guidewire and the LV lead with respect to pacing thresholds and R-wave sensing in the lateral and basal sites. However, these mapping and pacing maneuvers were performed during the implantation procedure, and not in advance. 

Given this background, the possibility of a preimplantation mapping and pacing option would have several advantages in patients scheduled for cardiac resynchronization therapy:

• Mapping of the latest activated area of the left ventricle in patients with wide QRS and LBBB;
• Screening for electrical asynchrony in heart failure patients with narrow QRS and LBBB less than 130 ms or in patients with right bundle branch block (RBBB) and left anterior hemiblock;
• Detection of scar tissue in patients with coronary artery disease; and
• Detection of areas with phrenic nerve capture.

Epicardial activation mapping of the LV. Many attempts have been made to evaluate specific echocardiographic parameters for detection of asynchrony and prediction of CRT response.^16-18 However, to date, no specific echocardiographic parameter could be shown to be a reliable predictor of CRT response. Perhaps it will be more reasonable to rely on electrical than on mechanical asynchrony by measuring the local activation of different sites of the left ventricle. 

In patients with wide QRS caused by an LBBB, the latest activated region of the left ventricle can be evaluated by transcoronary mapping as the target position for the transvenous LV lead for CRT implantation.

Later on, transcoronary mapping could become an option to evaluate patients with narrow LBBB below 130 ms and patients with RBBB and left anterior hemiblock for delayed activation of the posterolateral left ventricle, thereby selecting potential responders to CRT.

Mapping in patients with coronary artery disease. The transcoronary epicardial mapping procedure can be limited by severe coronary artery disease, especially in patients with proximal occlusion of the left coronary artery system. However, in the absence of sufficient collateral perfusion, the region distal to the occluded vessel will most likely have scar tissue and therefore be unsuitable for epicardial pacing. In patients with sufficient bypass grafts, the mapping procedure could be performed via these grafts, which should be no problem since bypass graft interventions are common in clinical practice. In addition, an approach via the coronary venous system remains an option in cases with suspected viable myocardium despite a proximal occluded coronary artery.

The transcoronary mapping approach could be used in patients with coronary artery disease for detection of scar tissue by demonstrating low R-wave amplitude and high local pacing thresholds, so these regions can be avoided when targeting the LV lead for CRT.

Detection of areas with phrenic nerve stimulation. Phrenic nerve stimulation at the lateral wall is a common problem in CRT implantations. Unfortunately, this phenomenon arises in areas commonly used for LV lead positioning.^19-25 Several attempts have been made to overcome this problem, including the option of electronic repositioning or the use of quadpolar leads.^26-31 Alternatively, the most suitable electrode with special curves or kinkings that allow a stable lead position without the need to wedge the lead in a small distal branch (in the area of extensive phrenic nerve stimulation) can be selected before starting the implantation procedure. Finally, active fixing leads³² or fixing the lead by a coronary stent (even if this would be an off-label use of coronary stents in the cardiac venous system) in a more proximal position, which would have an unavoidably high risk of dislodgment otherwise, could be considered for the implantation. Since epicardial high-voltage pacing in the cardiac veins by a pacing guidewire^9,15 can predict phrenic nerve capture by an LV lead in the same position, this should be possible by transcoronary pacing in advance of the implantation procedure, thereby reducing the implantation time as long as areas of phrenic nerve capture can be avoided and futile attempts to place the lead in this area can be skipped.

Potential clinical work-up for patients scheduled for a CRT implantation. Coronary angiography is mandatory in all patients intended to receive a CRT device for exclusion (and if present for therapy) of an underlying coronary artery disease. By recording the venous phase after injection of the contrast medium, the anatomy of the coronary sinus and its main side branches can be recorded, hence facilitating the planning of the implantation procedure. In addition, a transcoronary mapping procedure should be performed just in the marginal side branches of the RCX (reaching the posterolateral region of the left ventricle) as far as the diagonal side branches of the LAD (reaching the anterolateral region of the left ventricle) for evaluation of the electrically latest activated region of the LV. Phrenic nerve capture could be tested by a short transcoronary pacing maneuver. In case of an underlying coronary disease, areas of concern could be detected by high transcoronary pacing thresholds and low-amplitude R-wave signals. 

Taking all of this information into consideration, the optimal region for the LV lead position can be selected (latest activation, low pacing threshold, no phrenic nerve capture) by matching the measured data from transcoronary mapping and pacing with the anatomy of the cardiac venous system. For practical reasons, the storage of the fluoroscopic image with the guidewire in the preferred area is recommended. 

Study limitations. Since the VisionWire is currently only certified for temporary pacing in the coronary veins,⁹ this study could only be performed in an animal model. Therefore, these data from our small animal study cannot be transferred into humans without proof.  However, even with the relatively small QRS width in the pacing-induced LBBB in the pig model (84 ± 5 ms), significant differences in the ventricular excitation propagation between the three main vessels could be detected as far as within the proximal and distal parts of the vessel. The human heart is larger than the pig heart, and according to the current international guidelines,^1-4 the QRS width in the target patient population will at least exceed 130 ms (ideally, 150 ms), so a more subtle mapping of LV excitation propagation is reasonable to expect. Moreover, in patients with normal or left dominant coronary systems, at least a first and second marginal and diagonal side branch are present, and could be used for more detailed transcoronary activation mapping.

Conclusion

Transcoronary mapping of asynchronous LV excitation caused by LBBB is feasible and safe. This procedure can be performed within minutes during the mandatory coronary angiography before each CRT implantation in patients with heart failure and LBBB who are eligible for cardiac resynchronization therapy according to the current guidelines.^2-4

If these animal data could be reproduced in humans, transcoronary mapping of LV activation in patients scheduled for CRT implantation could become the method of choice for evaluation of electrical asynchrony in patients with LBBB (especially in borderline cases with a QRS width between 120-150 ms and intermediate heart failure) and for selecting the optimal (and maybe the second best) position for the permanent LV lead in case of unavoidable phrenic nerve stimulation at the most delayed LV area.

Finally, in patients with previous myocardial infarction, areas of scar tissue could be identified by low-amplitude local epicardial electrograms and high local pacing thresholds.  

The transcoronary mapping technique could help to increase the responder rate to CRT and decrease both the implantation duration and radiation exposure. n

Acknowledgment. The authors wish to thank the colleagues of the IMTR GmbH Rottmersleben for their support in performing this study. 

Funding: This study was supported by a restricted grant from Biotronik Corporation (Biotronik SE, Berlin, Germany). No author has any affiliation with this company. Data analysis and interpretation were performed completely independent from this company.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

This article was reprinted with permission from the Journal of Invasive Cardiology 2014;26(10):520-526.

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