Leadless Cardiac Pacemakers: Back to the Future
Recently, the results of WiSE-CRT (Wireless Stimulation Endocardially for CRT), a prospective observational feasibility study of leadless ultrasound-based endocardial left ventricular pacing in patients with guideline-directed indication for cardiac resynchronization therapy (CRT) were reported. The WiSE-CRT study used a system intended for chronic use with 2 components: a subcutaneous pulse generator and a small receiver electrode. The subcutaneous pulse generator was surgically implanted in the left lateral thorax (subcutaneous) and generated ultrasonic acoustic energy; the small receiver electrode was implanted directly onto the left ventricular endocardium (using a retrograde aortic approach) and converted the acoustic energy to electric pacing pulses. All patients in WiSE-CRT had existing implantable cardiac devices (pacemakers or defibrillators) and were considered eligible for enrollment if they: 1) had undergone prior failed coronary sinus lead implantation; 2) had undergone previously successful placement of a coronary sinus lead but were clinical nonresponders; or 3) required an upgrade to a CRT system.() From an efficacy perspective, the results of WiSE-CRT were promising: left ventricular function improved at 6 months (mean pre-implantation left ventricular ejection fraction of 25 ± 4.0% vs. mean 6-month post-implantation ejection fraction of 31 ± 7.0%; p < 0.01). However, the study was terminated prematurely for safety reasons. Of the 17 patients enrolled (of an intended 100 patients), the device could be successfully implanted in only approximately three-quarters (n = 13 [76%]). Most important, 3 patients (18%) developed serious procedure-related pericardial effusions due to either delivery sheath or guidewire manipulation; 1 of these resulted in a patient's death. Additionally, 2 patients (11%) required revision of the transmitter position because of loss of biventricular pacing, and in 1 patient, there was unexpected depletion of the battery.
After WiSE-CRT was terminated because of safety concerns, the delivery system was redesigned to permit atraumatic implantation of the receiver electrode onto the left ventricular endocardial surface. Similar to that studied in WiSE-CRT, the redesigned leadless system is also composed of an implanted battery-powered ultrasonic transmitter and a leadless pacing electrode implanted directly onto the left ventricular endocardium (Figure 1). Again, the system detects a right ventricular pacing pulse from a coimplanted pacemaker or defibrillator and delivers ultrasonic energy to the electrode, which transduces the energy to an electric pacing pulse to stimulate the left ventricle synchronously with the right ventricle. The initial evaluation of this redesigned system in the SELECT-LV (Safety and Performance of Electrodes Implanted in the Left Ventricle) study revealed: 1) adequate acoustic windows to permit implantation in the majority of patients (12 of 14 [86%]); 2) significant cardiac resynchronization in all 12 implanted patients, with QRS shortening by 60 ± 24 ms (vs. right ventricular pacing); and, importantly, 3) no instances of intraprocedural adverse events. The SELECT-LV trial continues to enroll patients at multiple centers in Europe.
(Enlarge Image)
Figure 1.
The Leadless Endocardial Left Ventricular Pacing System
Anteroposterior (AP) (A) and lateral (LAT) (B) chest radiograph views of the implanted system, including battery, transmitter, and receiver/pacing electrode (inset).
Although the initial SELECT-LV data suggest that the delivery system modifications have largely addressed the major procedural complication observed in WiSE-CRT, there remain several technology-specific concerns that require consideration. First, although the left ventricular receiver component of this system is indeed leadless, the system does require the use of conventional transvenous leads, because all patients required concomitant conventional implantable right ventricular pacing devices. Second, it is theoretically possible that long-term ultrasound energy exposure to subcutaneous or myocardial tissue in humans may have unintended adverse consequences. Third, there may be untoward effects of external (environmental) interference and changes in the acoustic window on the system's sensing or pacing performance. In some patients, the availability of an adequate acoustic window may limit the response to resynchronization therapy, because of either the location of the endocardial receiver electrode (anterolateral or lateral-apical) or the target location of the transmitter (intercostal space, because acoustic energy is refracted by bone). Fourth, compared with conventional power sources, energy transfer of current ultrasound-mediated pacing systems is inefficient and might result in a comparatively short battery life. In fact, in WiSE-CRT, at the 6-month post-implantation follow-up visit, the remaining battery life projection was a mean of 18 months (range: 9 to 42 months). Finally, the endoluminal left ventricular positioning of the receiver electrode could predispose to thromboembolic complications. Indeed, in SELECT-LV, 1 patient with atrial fibrillation in whom oral anticoagulation was interrupted for the procedure sustained a stroke. In subsequent cases, oral anticoagulation was not interrupted (at operator discretion) for the procedure, and no subsequent strokes were observed; however, the safety of this strategy needs to be validated in a larger cohort of patients. However, it should be noted that in a study that used a different approach to left ventricular endocardial pacing (using a transseptal approach), 14% patients (7 of 51) experienced thromboembolic events (stroke or transient ischemic attack) during follow-up. However, most of these patients had subtherapeutic anticoagulation at the time of the event (the goal international normalized ratio was 3.5 to 4.5), and this risk would certainly be expected to be less with the smaller volume leadless electrodes associated with the multicomponent systems. However, this potential for thromboembolic complications remains important to test in large clinical trials.
However, there are compelling data indicating a potentially significant clinical benefit to leadless left ventricular endocardial pacing. Endocardial left ventricular pacing is more physiological (endocardial-to-epicardial transmural activation sequence), may enhance left ventricular diastolic and systolic performance, has the potential to be less proarrhythmic (reduced dispersion of ventricular repolarization), and likely requires lower pacing energy outputs compared with optimally placed coronary sinus leads. Furthermore, because it is not limited to those coronary sinus branches able to accommodate a transvenous lead, endocardial pacing offers a larger choice of optimal left ventricular stimulation sites; there is also the added benefit of no phrenic nerve stimulation. Leadless left ventricular endocardial pacing might mitigate these limitations and expand our ability to provide optimal CRT. However, there are other variables, such as endocardial scar and adjacent structures, including the papillary muscles, that may affect the ability to pace at the optimal endocardial location. Finally, and most important, 2 independent randomized controlled trials, TARGET (Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy) and STARTER (Speckle Tracking Assisted Resynchronization Therapy for Electrode Region), demonstrated that better targeting of the left ventricular pacing site (at the site of latest contraction or ventricular activation) leads to improvements in clinical response, including freedom from heart failure hospitalization or mortality. Indeed, because of these various potential advantages to left ventricular endocardial pacing, several investigators have attempted left ventricular endocardial pacing with standard transvenous leads (placed transseptally across the mitral valve directly into the left ventricle) for nonresponders or those with inaccessible coronary sinus anatomy. Although technically feasible, its widespread adoption has been limited by the complexity of the procedure, the need for aggressive chronic oral anticoagulation (with a recommended target international normalized ratio of 3.5 to 4.5), and potential adverse consequences, such as the long-term effect on the mitral valve. Leadless left ventricular endocardial pacing might mitigate these risks and expand our ability to provide optimal CRT.
Leadless pacing using induction (electromagnetic) technology also consists of at least 2 components: a subcutaneous (or submuscular) transmitter unit located just above the heart and a receiver unit implanted into the ventricular endocardium. Briefly, the transmitter generates an alternating magnetic field, of which a fraction is converted to stimulatory voltage pulses by the receiver unit. Although leadless pacing using induction may be feasible, it has been tested only in animal models (porcine and goat), and further work is needed to determine the effects of alignment, distance, and external interferences on this technology.
Multicomponent (Not Self-contained) Leadless Pacing
Ultrasound-mediated Energy Transfer
Recently, the results of WiSE-CRT (Wireless Stimulation Endocardially for CRT), a prospective observational feasibility study of leadless ultrasound-based endocardial left ventricular pacing in patients with guideline-directed indication for cardiac resynchronization therapy (CRT) were reported. The WiSE-CRT study used a system intended for chronic use with 2 components: a subcutaneous pulse generator and a small receiver electrode. The subcutaneous pulse generator was surgically implanted in the left lateral thorax (subcutaneous) and generated ultrasonic acoustic energy; the small receiver electrode was implanted directly onto the left ventricular endocardium (using a retrograde aortic approach) and converted the acoustic energy to electric pacing pulses. All patients in WiSE-CRT had existing implantable cardiac devices (pacemakers or defibrillators) and were considered eligible for enrollment if they: 1) had undergone prior failed coronary sinus lead implantation; 2) had undergone previously successful placement of a coronary sinus lead but were clinical nonresponders; or 3) required an upgrade to a CRT system.() From an efficacy perspective, the results of WiSE-CRT were promising: left ventricular function improved at 6 months (mean pre-implantation left ventricular ejection fraction of 25 ± 4.0% vs. mean 6-month post-implantation ejection fraction of 31 ± 7.0%; p < 0.01). However, the study was terminated prematurely for safety reasons. Of the 17 patients enrolled (of an intended 100 patients), the device could be successfully implanted in only approximately three-quarters (n = 13 [76%]). Most important, 3 patients (18%) developed serious procedure-related pericardial effusions due to either delivery sheath or guidewire manipulation; 1 of these resulted in a patient's death. Additionally, 2 patients (11%) required revision of the transmitter position because of loss of biventricular pacing, and in 1 patient, there was unexpected depletion of the battery.
After WiSE-CRT was terminated because of safety concerns, the delivery system was redesigned to permit atraumatic implantation of the receiver electrode onto the left ventricular endocardial surface. Similar to that studied in WiSE-CRT, the redesigned leadless system is also composed of an implanted battery-powered ultrasonic transmitter and a leadless pacing electrode implanted directly onto the left ventricular endocardium (Figure 1). Again, the system detects a right ventricular pacing pulse from a coimplanted pacemaker or defibrillator and delivers ultrasonic energy to the electrode, which transduces the energy to an electric pacing pulse to stimulate the left ventricle synchronously with the right ventricle. The initial evaluation of this redesigned system in the SELECT-LV (Safety and Performance of Electrodes Implanted in the Left Ventricle) study revealed: 1) adequate acoustic windows to permit implantation in the majority of patients (12 of 14 [86%]); 2) significant cardiac resynchronization in all 12 implanted patients, with QRS shortening by 60 ± 24 ms (vs. right ventricular pacing); and, importantly, 3) no instances of intraprocedural adverse events. The SELECT-LV trial continues to enroll patients at multiple centers in Europe.
(Enlarge Image)
Figure 1.
The Leadless Endocardial Left Ventricular Pacing System
Anteroposterior (AP) (A) and lateral (LAT) (B) chest radiograph views of the implanted system, including battery, transmitter, and receiver/pacing electrode (inset).
Although the initial SELECT-LV data suggest that the delivery system modifications have largely addressed the major procedural complication observed in WiSE-CRT, there remain several technology-specific concerns that require consideration. First, although the left ventricular receiver component of this system is indeed leadless, the system does require the use of conventional transvenous leads, because all patients required concomitant conventional implantable right ventricular pacing devices. Second, it is theoretically possible that long-term ultrasound energy exposure to subcutaneous or myocardial tissue in humans may have unintended adverse consequences. Third, there may be untoward effects of external (environmental) interference and changes in the acoustic window on the system's sensing or pacing performance. In some patients, the availability of an adequate acoustic window may limit the response to resynchronization therapy, because of either the location of the endocardial receiver electrode (anterolateral or lateral-apical) or the target location of the transmitter (intercostal space, because acoustic energy is refracted by bone). Fourth, compared with conventional power sources, energy transfer of current ultrasound-mediated pacing systems is inefficient and might result in a comparatively short battery life. In fact, in WiSE-CRT, at the 6-month post-implantation follow-up visit, the remaining battery life projection was a mean of 18 months (range: 9 to 42 months). Finally, the endoluminal left ventricular positioning of the receiver electrode could predispose to thromboembolic complications. Indeed, in SELECT-LV, 1 patient with atrial fibrillation in whom oral anticoagulation was interrupted for the procedure sustained a stroke. In subsequent cases, oral anticoagulation was not interrupted (at operator discretion) for the procedure, and no subsequent strokes were observed; however, the safety of this strategy needs to be validated in a larger cohort of patients. However, it should be noted that in a study that used a different approach to left ventricular endocardial pacing (using a transseptal approach), 14% patients (7 of 51) experienced thromboembolic events (stroke or transient ischemic attack) during follow-up. However, most of these patients had subtherapeutic anticoagulation at the time of the event (the goal international normalized ratio was 3.5 to 4.5), and this risk would certainly be expected to be less with the smaller volume leadless electrodes associated with the multicomponent systems. However, this potential for thromboembolic complications remains important to test in large clinical trials.
However, there are compelling data indicating a potentially significant clinical benefit to leadless left ventricular endocardial pacing. Endocardial left ventricular pacing is more physiological (endocardial-to-epicardial transmural activation sequence), may enhance left ventricular diastolic and systolic performance, has the potential to be less proarrhythmic (reduced dispersion of ventricular repolarization), and likely requires lower pacing energy outputs compared with optimally placed coronary sinus leads. Furthermore, because it is not limited to those coronary sinus branches able to accommodate a transvenous lead, endocardial pacing offers a larger choice of optimal left ventricular stimulation sites; there is also the added benefit of no phrenic nerve stimulation. Leadless left ventricular endocardial pacing might mitigate these limitations and expand our ability to provide optimal CRT. However, there are other variables, such as endocardial scar and adjacent structures, including the papillary muscles, that may affect the ability to pace at the optimal endocardial location. Finally, and most important, 2 independent randomized controlled trials, TARGET (Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy) and STARTER (Speckle Tracking Assisted Resynchronization Therapy for Electrode Region), demonstrated that better targeting of the left ventricular pacing site (at the site of latest contraction or ventricular activation) leads to improvements in clinical response, including freedom from heart failure hospitalization or mortality. Indeed, because of these various potential advantages to left ventricular endocardial pacing, several investigators have attempted left ventricular endocardial pacing with standard transvenous leads (placed transseptally across the mitral valve directly into the left ventricle) for nonresponders or those with inaccessible coronary sinus anatomy. Although technically feasible, its widespread adoption has been limited by the complexity of the procedure, the need for aggressive chronic oral anticoagulation (with a recommended target international normalized ratio of 3.5 to 4.5), and potential adverse consequences, such as the long-term effect on the mitral valve. Leadless left ventricular endocardial pacing might mitigate these risks and expand our ability to provide optimal CRT.
Induction Technology
Leadless pacing using induction (electromagnetic) technology also consists of at least 2 components: a subcutaneous (or submuscular) transmitter unit located just above the heart and a receiver unit implanted into the ventricular endocardium. Briefly, the transmitter generates an alternating magnetic field, of which a fraction is converted to stimulatory voltage pulses by the receiver unit. Although leadless pacing using induction may be feasible, it has been tested only in animal models (porcine and goat), and further work is needed to determine the effects of alignment, distance, and external interferences on this technology.