All pacing leads are associated with complications such as infection, fracture, failure and dislodgement. Lead extraction is a high-risk procedure. With new device systems that often require implantation of multiple leads and with patients living longer, the incidence of lead complications is becoming compounded over time.1 Therefore, there is a strong demand to develop a pacing system that eliminates the pacing lead as a conduit for energy transfer. Randomised clinical trials on cardiac resynchronisation therapy have demonstrated the clinical benefits of such a system. Access to the left ventricle is achieved with the use of a pacing lead that is advanced into the coronary sinus and positioned in a coronary vein branch. Implantation of this lead is technically demanding and associated with a significant incidence of failure to implant, implantation in a suboptimal location and complications.2,3 Compared with epicardial pacing, endocardial left ventricular stimulation that minimises the conduction delay from the epicardium to the endocardium may be more physiological and therefore may give rise to greater haemodynamic benefits.4,5 Leadless pacing will enable endocardial left ventricular stimulation without the risks of systemic thromboembolism and mitral regurgitation. It will also avoid diaphragmatic stimulation and right ventricular apical pacing, enable multisite pacing and allow almost free choice of stimulation location within the left or right ventricle. It may also address challenges in paediatric pacing and allow the development of a truly magnetic resonance imaging (MRI)-compatible pacing system.
Leadless Pacing with Acoustic Energy
Many concepts have been patented for the development of a leadless pacing system. With a long history and wide application in medical technology, ultrasound energy is considered safe and was chosen to prove the concept of energy transfer. The use of ultrasound-mediated energy to drive a remotely positioned electrode for direct myocardial stimulation is the first to be reported in the medical literature. This new technology uses the mechanical-to-electrical properties of piezoelectric materials for transformation of energy.
The experimental set-up includes an ultrasound-transmitting transducer connected to an ultrasound generator and a steerable bipolar electrophysiology catheter incorporating a receiver electrode at the distal tip. Ultrasound energy was amplitude-adjusted and transmitted at around 330kHz. The lower frequency used in this application achieves better tissue penetration. Ultrasound pulses generated from the transmitting transducer travelled through the chest wall to reach the receiver electrode, which has circuitry to transform the pulses into electrical energy for myocardial stimulation. The feasibility and safety of this novel technology was first demonstrated acutely in animals.6 In the acute safety study, histological examination was performed in pigs that were exposed to continuous ultrasound transmission from the investigational system for two hours. No mechanical or thermal bioeffect was identified in these animals. In the acute feasibility study, the receiver electrode incorporated into a transvascular catheter was selectively positioned and in contact with various heart chambers of a pig. An external transmitter was placed on the chest wall of the animal, with acoustic gel used for coupling. Ultrasound energy was then transmitted through the chest to the receiver, the acoustic energy was converted to electrical energy and the electrodes contacting the endocardium stimulated pacing. The electrode catheter was a modified steerable bipolar electrophysiology (EP) catheter with receiver transducers incorporated near the tip between the bipolar pacing electrodes. Proximal connections on the catheter allowed either direct electrical pacing using a pacing system analyser or monitoring of the receiver output during ultrasound-mediated pacing.
The catheter itself was not directly involved in or required for ultrasound-mediated pacing. The acute porcine study demonstrated the feasibility of leadless ultrasound-mediated pacing in five animals at 30 selected sites in the right atrium, right ventricle, left ventricle and simultaneously in both left and right ventricles.6
Following the animal experiments, human studies were performed.7 Twenty-four patients were tested during or after completion of clinical EP procedures. A total of 80 pacing sites in the right atrium, right ventricle and left ventricle were tested. The transmit-to-receive distance was 11.3±3.2cm. Ultrasound-mediated pacing was achieved at all 80 sites, with consistent capture at 77 sites. There were no adverse events related to ultrasound-mediated pacing. No patients experienced discomfort during pacing.
This novel technology targeting cardiac resynchronisation therapy was also tested in heart failure patients.8 In these patients, the acoustic window on the chest wall that allows efficient ultrasound transmission was defined and found to be large and sufficient for subcutaneous implantation of the ultrasound generator, even after accommodating changes with respiratory movement and body positioning.
Incorporating this novel technology, the future implantable leadless pacing system is being designed. The system includes an ultrasound generator to be implanted subcutaneously in the acoustic window of the chest wall and an endocardial receiver electrode. The receiver electrode is delivered by a steerable transvascular catheter to the target heart chamber, and can be detached and implanted onto the endocardium directly. The receiver and transmitter are programmed to operate at the same frequency of ultrasound pulses to avoid external interference. The ultrasound beam will be optimised and focused onto the receiver electrode in order to improve the efficacy of energy transfer. The estimated device longevity will need to be comparable to that of a conventional pacemaker to make it commercially viable. The acoustic window suitable for implant on the patient's chest wall can be localised pre-operatively by conventional echocardiography, a convenient method that has been shown to predict efficient ultrasound transmission for leadless pacing.8
There are of course other unresolved issues that ongoing research is aiming to answer.9,10 For example, many will doubt the long-term safety of continuous ultrasound exposure. Although the lack of effect of short-term ultrasound-mediated pacing has been shown histologically in animal experiments, tissue injury secondary to heating with continuous exposure is theoretically possible. Similar studies on long-term exposure when ultrasound energy is applied in continuous pacing will address the safety concern. Another challenge of this technology is environmental interference, which may be ubiquitous. Although precise formatting and fine-tuning of the device can be performed, little is known about its actual performance in the real world. This is another big safety issue that requires extensive evaluation. Apart from energy delivery, transmission of sensed endocardial electrograms is an important function of a pacing lead.
There is so far no available information on how the sensing circuit of the future leadless pacemaker is going to operate. As for the risk of infection, the receiver electrode is small, and is embedded in the endocardium followed by complete endothelialisation. It is expected to carry a minimal risk of infection, probably comparable to that of coronary stents and atrial septal defect occluders.
Alternative Energy Sources
In addition to ultrasound, an alternating magnetic energy source has been tested in a pig model for leadless cardiac stimulation.11 The system consists of two components: an external transmitter unit and a receiver unit in contact with the myocardium. The subcutaneous primary coil generates an alternating magnetic field, which is converted by the secondary coil inside the heart to a voltage pulse for pacing stimulation. In the pig experiment described, an alternating magnetic field of approximately 0.5mT was generated by the transmitter unit across a distance of 3cm. Voltage pulses with a duration of 0.4ms and voltage amplitude of 0.6-1.0V were generated. Continuous stimulation of the heart was demonstrated for 30 minutes. The advantage of this technology is that the efficiency of energy conversion is relatively high, making device longevity less of a problem. However, the transmitter coil is of considerable size - 60mm in diameter, 10mm in width and 80g in weight, while the receiver is 15mm in length and 2.5mm in diameter. Apart from the size of the device, another major concern with this technology is potential external interference by environmental magnetic fields. The long-term safety with heat production in the receiver unit generated by continuous exposure is also uncertain.
Other wireless energy sources have been used for stimulation to a limited extent. Radiofrequency energy transmission is employed in an implantable microstimulator device currently under clinical investigation for neuromodulation applications.12 However, the implant incorporates a battery, which requires frequent recharging using an inductive link from an external device. In general, the use of radiofrequency power for wireless applications in the body has the disadvantages of being unfocused and having a shallow depth of penetration. Therefore, it is less efficient than ultrasound energy. It also requires the transmitter and receiver to be in close proximity, which essentially precludes its use for many applications, including cardiac pacing.
Ultrasound energy transduction is currently being used in a clinical application of a wireless sensor.13 In this application, the receiver is coupled to a pressure transducer implanted within an abdominal aortic aneurysm graft for post-procedure monitoring after endovascular repair. The transmitter is an external device placed on the anterior abdomen to communicate with the implanted receiver to acquire realtime intrasac pressure data.
Future of Leadless Pacing
Leadless pacing with ultrasound-mediated energy has been demonstrated in animals and humans in acute studies. This is by far the most advanced development, with proven technological feasibility. More scientific data will be collected from ongoing animal and human research. With refinement of the technology, the challenges identified will be addressed. Currently, a prototype device and the implantation equipment are being developed, and a clinical trial of the permanent implantable system is being planned (personal communication). At the same time, various competing technologies are being developed and evaluated. Although it is not certain whether the intended progress will be accomplished, the favourable result achieved has aroused significant interest in the field of cardiac pacing. Many, including those in the device industry, are keen to be involved in the development of a commercially viable leadless implantable pacemaker. When this materialises, lead complications and lead extractions will be minimised.
Leadless pacing will also open up a new arena for cardiac resynchronisation therapy. Some non-responders may be converted to responders with optimisation of the left ventricular stimulation site. Multisite pacing will no longer be limited by problems of vascular access or coronary venous anatomy. Responders may obtain maximal benefit from cardiac resynchronisation therapy with endocardial left ventricular stimulation.
Subcutaneous Implantable Defibrillators
Although leadless pacing is only in the proof-of-concept stage, subcutaneous implantable defibrillators have been developed and tested in clinical trials.14,15 The preliminary results are encouraging. The first human implant of an implantable cardioverter-defibrillator (ICD) was reported in 1980 by Mirowski. In 1985, the ICD was approved by the US Food and Drug Administration.
Over the years, the ICD has evolved from a sizable non-programmable shock-box with epicardial patches that required thoracotomy for implantation to a much smaller programmable device with tiered therapy and an endocardial lead system suitable for subcutaneous pectoral implant. Furthermore, advances in technology have enabled ICDs to offer electrical therapy for common co-existent conditions such as atrial arrhythmias and congestive heart failure. Over the past decade, large-scale randomised clinical trials have provided consistent evidence of the clinical efficacy of device therapy. The ICD has been proved to be superior to antiarrhythmic drugs in patients with structural heart diseases who suffer from haemodynamically significant ventricular arrhythmias. In postinfarct patients at risk of arrhythmic death, prophylactic ICD implantation confers a survival benefit. Other randomised trials have further expanded the role of the ICD in primary prevention of sudden death in patients with poor left ventricular function of both ischaemic and non-ischaemic aetiologies.
Compared with pacing leads, ICD leads are prone to developing complications and failure, with reported ICD lead 'survival' rates varying from 85 to 98% at five years and from 60 to 72% at eight years.16 ICD lead problems are more common in the paediatric age group because of limited venous access, smaller heart size, future growth of the heart and the relatively longer life expectancy. In primary prevention patients, implantation of a totally subcutaneous system without any hardware inside the heart appears attractive, as patients need not be concerned about major lead complications and lead extraction.
A permanent subcutaneous ICD that delivers electrical shock from subcutaneous electrodes has been developed. Different electrode configurations were evaluated in an acute defibrillation trial.14 The components of the best device configuration consisted of a parasternal electrode and a left lateral thoracic pulse generator. The requirement for electrical defibrillation energy with this subcutaneous system was compared with a transvenous system in a second acute study. With patients serving as their own control, it was shown that the defibrillation threshold of the subcutaneous system was approximately three-fold that of the transvenous system (36.6±19.8 versus 11.1±8.5J). Although this may mean devices will have a maximum shock energy between 60 and 80J, it has the advantage of having a very short implantation time and no need for fluoroscopy and lead manipulation.
In two small non-randomised studies involving six and 55 patients, an entirely subcutaneous permanent ICD (Cameron Health) was demonstrated to be feasible for detecting and converting electrophysiologically induced ventricular fibrillation.15 Twelve episodes of spontaneous sustained ventricular tachyarrhythmia were also successfully detected and treated. The implantable system evaluated consisted of a 3mm tripolar parasternal electrode that was connected to an electrically active pulse generator. The electrode was positioned 1-2cm laterally to the mid-sternal line, and the pulse generator was implanted over the sixth rib between the anterior and mid-axillary line. The device settings were automated except for a few settings on on/off of shock, pacing, supraventricular tachycardia discrimination and rate cut-off. The limitations of this subcutaneous system include lead migration, lead dislodgement, inappropriate sensing and the lack of bradycardia pacing, antitachycardia pacing and post-shock pacing. Continuous modification and improvement of the system is required to make the device comparable or superior to conventional transvenous ICD. The capability of integrating a leadless pacemaker and a subcutaneous implantable defibrillator is important as heart failure patients frequently require cardiac resynchronisation therapy in combination with an implantable defibrillator.
Despite all the advances achieved, much more work needs to be carried out before we can accomplish this major breakthrough in the development of leadless implantable cardiac devices. When that breakthrough occurs, implanting a pacing lead will become a procedure of the past.