FormalPara Key Summary Points

The miniaturisation of the electronic circuitry and battery has facilitated new possibilities for a transcatheter-delivered, single, leadless pacing unit.

There is an acute learning curve with respect to the implementation of any new technology, including leadless pacing. As experience has grown, acute complications with single-chamber (RV) pacing are now similar to transvenous pacing. Single-chamber (right ventricular) VVI pacing has been successfully used clinically for several years with accumulating data suggesting a reduction in medium- to long-term complications compared with conventional transvenous devices, due to the lack of intravascular leads and a pocket.

A new single-chamber device (in the right ventricle) can also have the capability to sense signals in the atrium and through VDD pacing, provide atrial sensing and ventricular pacing. This may be suitable for patients with intact sinus node function and AV node conduction disease who require pacing. AV synchrony is not, however, perfect and this can be challenging to maintain especially during patient activity.

The leadless left ventricular endocardial system (WiSE CRT) is a small electrode which works alongside an existing co-implant or right ventricular pacing system (transvenous or leadless). This enables leadless biventricular pacing or cardiac resynchronisation and may be an excellent alternative to conventional transvenous CRT.

With the exponential interest in conduction system pacing, a leadless system to deliver physiological pacing is a very attractive concept and early attempts have shown this can be successfully performed.

Introduction

Since the first implantation of a permanent cardiac pacemaker in 1958, technological iterations have facilitated the introduction of more reliable hardware alongside complex algorithms. Transvenous pacing systems have saved countless lives and improved patient quality of life through the treatment of symptomatic bradycardias. Nevertheless, they come at a cost of potential procedure- and device-related complications, affecting up to 10% of patients [1]. Intravenous leads are considered the Achilles heel of transvenous systems due to the chronic fibrotic and occlusive changes in the venous system, alongside the inevitability of lead dysfunction or damage over time and the clinical consequences of repeated procedures with associated morbidity and mortality [2,3,4,5,6]. Decisions are taken by physicians on a daily basis weighing up the potential benefits of device therapy with the long-term risks of lead-related complications, especially in younger patients. This is particularly pertinent where the device is implanted for a non-bradycardia indication, such as primary prevention defibrillator therapy or cardiac resynchronization therapy (CRT).

The concept of leadless pacing has been considered for several decades. The first self-contained intracardiac pacemakers were conceptualized and implanted in animals over 50 years ago [7, 8]. Since then, the evolution and miniaturisation of technology have led to the development of fully programmable, leadless systems, containing the battery, circuitry and electrodes, all functioning as a single unit.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Leadless Pacemakers Today

The mercury and nuclear batteries in the first experimental devices have been replaced with more patient- and environment-friendly options [9, 10]. According to the European Heart Rhythm Association (EHRA) survey, 86% of EHRA research centres report using leadless pacemakers (LPs) today but most of them implant less than 30 devices per year [11] due to the limitations of single-chamber ventricular pacing when most patients require pacing in both the atria and the ventricle.

Nanostim™ (St. Jude Medical Inc., Saint Paul, MN, USA; now Abbott Medical Inc., IL, USA) was the first self-contained intracardiac pacemaker implanted in a human. At just over 4 cm long, the device had a helix at the distal tip to ensure stable fixation in the right ventricle (RV) (Fig. 1). Almost 1500 devices were implanted since 2013 and three clinical trials confirmed stable performance and acceptable safety results, including at 1-year follow-up, with a rate of device-related serious adverse events of less than 7% [12,13,14]. As a result of rare but serious battery failures, the Nanostim had to be discontinued in 2016 [15], but the concept of leadless pacing has continued to grow. Indeed, the investigational device exemption (IDE) study of a new iteration of this device, the Aveir Leadless Pacing System (Abbott, Fig. 1 [16]), has recently reported preliminary results. The LEADLESS II – phase 2 IDE study [17] recruited 200 patients in North America and Europe. It reported an implant success rate of 98% and met its primary safety endpoint with a 4% rate of device-related complications at a 6-week follow-up. Ninety-six per cent of successfully implanted patients met the primary effectiveness endpoint based on a composite score of RV capture thresholds and R wave amplitude.

Fig. 1
figure 1

Modified from Ibrahim et al. [16], with permission

Aveir Leadless Pacemaker by Abbott.

Full size image

In 2015 the Micra™ (Medtronic, Minneapolis, MN, USA, Fig. 2 [18]) demonstrated a similar safety profile to that of a transvenous system while providing low and stable pacing thresholds in over 700 patients [19]. Slightly thicker and shorter than Nanostim, it employed four tines for stable fixation in the RV. Duray et al. reported that over a 1-year follow-up the risk of major complications from Micra™ was 4% (n = 726), 48% lower than the 1-year complication rate from a historical cohort of patients with transvenous devices (n = 2667). The rate of cardiac perforation from Micra™ in this cohort was 1.5% [20].

Fig. 2
figure 2

Modified from Ritter et al. [18], with permission

MICRA transcatheter leadless pacing system by Medtronic.

Full size image

Leadless Versus Transvenous Pacing Systems

Multiple real-world clinical registries have demonstrated stable performance and reassuring safety results both acutely and longer term [12, 13]. Implantation success rates are above 99% with a relatively low rate of periprocedural major complications at 1.5–4.0% [20,21,22]. In a propensity-matched comparison of leadless pacing with Micra versus transvenous pacemakers, significantly lower complication rates were noted for the leadless system at medium-term follow-up [2, 23] (Table 1).

Table 1 Comparison of major complications for Micra and transvenous pacemakers (modified from Duray et al. [20])
Full size table

Similar favourable findings were observed with Nanostim, which included fewer infectious and device-related events (compared with Micra), but more pericardial effusions which were uncommon but some with life-threatening consequences [6]. El-Chami et al. observed a low systemic infection incidence of 2.2% with Micra devices in the 720-patient Micra IDE study [24].

The prevalence of complication rates across all transvenous systems (including ICD/CRT) is approximately 10% with a wide range in some clinical series [1, 5]. Intravascular leads, considered the weakest link of the cardiac pacing system, can potentiate venous obstruction and are prone to insulation breaks, conductor fractures, and infection necessitating extraction [3, 4, 25]. One should acknowledge that whilst the initial acute complication rate of pericardial effusion and tamponade was higher with leadless pacing, successive clinical registries with larger numbers of patients have shown low rates of acute complications [22], similar to contemporary transvenous implants. This likely reflects the early clinical experience with the transcatheter delivery system and the learning curve associated with this [26].

Advantages of Leadless Pacing

Infection Risk

Leadless pacing at its inception was proposed as a solution for patients with pre-existing cardiac device infections [27]. Given most of the medium- to long-term complications are related to wound breakdown, erosion, infection (from the presence of a pocket) and transvenous lead attrition, the absence of these appears to contribute to a lower rate of such complications with a leadless pacing system. Additionally, the Micra has a small surface area, a tendency for encapsulation and a parylene coating with antibacterial properties which all help to resist infection [28]. Moreover, leadless pacing is an attractive route for patients with superior central venous occlusion who cannot undergo conventional transvenous pacing, as well as those in whom preservation of central venous access is critical for chronic catheter placement in haemodialysis for end-stage renal disease.

Extraction

Despite the sturdy fixation mechanism to the ventricular myocardium, the leadless pacemaker can be safely extracted percutaneously [29, 30]. In a high-volume, single-centre retrospective analysis of 302 patients, extraction of an LP was performed mainly for an upgrade to cardiac resynchronisation therapy (CRT) and was associated with no procedural or long-term complications [31] which is noteworthy given that transvenous lead extraction may have periprocedural rates of morbidity and mortality of 5–10% in some cases [25]. However, there is not enough data to comment on the extraction of LPs with longer dwelling times as opposed to transvenous pacing systems which have been studied quite well owing to their long presence in clinical practice.

Disadvantages of Leadless Pacing

Atrioventricular Dyssynchrony

Currently available LPs only offer single-chamber ventricular pacing. It is well recognized that VVIR pacing is inferior to atrioventricular (AV) synchronous pacing as a result of patients developing pacemaker syndrome and a significant increase in the risk of atrial fibrillation in patients with intact sinus node function [32]. Furthermore, a sizeable minority of patients with AV nodal block will go on to develop, or indeed already have the presence of sinus node disease, necessitating dual-chamber (atrial and ventricular) pacing. As such, the ESC 2021 pacing guidelines advocate for dual-chamber systems for patients with either sinus and AV node disease [33], precluding them from receiving single-chamber leadless devices. The successful use of an accelerometer in the recent generation of Micra pacemakers to overcome this problem is described in the next section of the article.

Management at End of Battery Life

Although battery life may vary, the estimated average longevity for the Micra pacemaker is about 12 years from implantation based on device settings observed in the Micra clinical trial [19]. Of course, this estimate will depend on the pacing parameters and the burden of RV pacing. Of note, there is also a limit of accessible ventricular endocardium where several leadless units can be safely placed in the right ventricle without interference with each other [34]. Whilst options for the extraction of leadless devices have been demonstrated [30], some physicians and patients may opt for an additional leadless device implant without extraction. Through this approach, a limited number of implants are permissible and they may not be suitable especially for young patients who will require multiple new devices throughout their lives.

Interference with Cardiac Magnetic Resonance Imaging

Leadless pacemakers are approved for scanning in a magnetic field up to 3 T. Cardiac magnetic resonance (CMR) imaging in patients with LP is feasible and offers good image quality allowing an accurate evaluation of LV function, cardiac structures and valves. However, an inevitable area of artefact in proximity to the leadless implant (broadly but not exclusively septal segments) may limit the diagnostic utility of this investigation. The use of scanners with lower magnetic field strength, i.e. 1.5 T, may help improve the image quality in this area [35, 36].

Atrioventricular Synchronous Pacing

In patients with preserved sinus node function, AV synchronous pacing is superior to ventricular pacing alone [37]. Therefore, whilst the overall complication rates appear lower with leadless devices [38] (mostly due to lower medium- to long-term complications in the leadless cohort), the majority of patients who require pacing have AV block, and therefore losing AV synchrony would have deleterious effects.

Using a three-axis accelerometer within the Micra pacemaker enables the sensing of atrial systole and a sequential response with synchronised ventricular pacing. It uses four-point detection of mechanical activity of the atria and ventricles which is translated into signals recognized by the device. There are two programmable intervals (post‐ventricular atrial blanking period or PVAB and passive ventricular filling period) and two programmable thresholds (passive ventricular filling threshold and atrial contraction threshold) to troubleshoot and optimize the pacemaker function.

AV synchrony was demonstrated 87% of the time in the MARVEL study [39]. In further sub-analysis, the MARVEL Evolve substudy showed stable performance of the algorithm over time, including during atrial arrhythmias [40]. MARVEL 2 confirmed good discrimination of atrial contractions in patients with preserved atrial function [41] (Fig. 3). However, AV synchrony achieved using this method is not without limitations; most notably AV synchrony dropped to 70% when patients stood up and began to walk. Clearly filtering out patient motion is an important design feature to enable high percentages of AV synchrony and this may be a limitation of VDD sensing using this method.

Fig. 3
figure 3

Modified from Steinwender et al. [41], with permission

a Atrioventricular synchronous pacing percentage between VVI 50 bpm and VDD mode with Micra AV in 40 patients with complete heart block. b Change in left ventricular outflow tract velocity–time integral (LVOT-VTI) during VDD relative to VVI 50 bpm pacing with a Micra AV device.

Full size image

Whilst a VDD mode for atrial sensing and ventricular pacing is feasible as already described in the Micra AV, many patients with conduction disease exhibit both features of the sinus node and AV node disease; as such many will require some degree of atrial pacing. Animal data already exists demonstrating the clinical efficacy of two separate leadless devices, one atrial and the other ventricular with wireless communication between the two [42]. Furthermore, LPs implanted in an atrial position have shown excellent chronic pacing performance and easy retrieval at 6 months [43]. However, the current target for fixation in the atrium (the right atrial appendage) has a far thinner myocardial layer as compared with its ventricular counterpart; implantation safety data on perioperative complications, particularly perforation and pericardial effusion and tamponade, will be no doubt closely scrutinised in the clinical data which will follow. Another important issue relates to wireless transmission and programmability between two separate structures; this process inevitably requires energy expenditure and will likely be the next hurdle for device engineers to navigate. A dual-chamber AV synchronous leadless pacing is currently being tested in Aveir DR i2i clinical trial (NCT05252702) and will soon provide further insight into the feasibility of migrating the mature algorithms which exist within current conventional device generators to the miniaturised leadless systems.

Leadless Pacing and ICD Options

The subcutaneous ICD (S-ICD, Boston Scientific) is a well-established fully extravascular alternative to the transvenous ICD with increasing data on the safety, efficacy of shocks and similar inappropriate therapy deliveries compared with their transvenous counterparts [44]. Given higher attrition rates for transvenous ICD leads than those of pacing leads and the morbidity/mortality associated with percutaneous lead extraction, the argument for an extravascular ICD option is increasingly attractive. A significant drawback of the S-ICD, however, is the inability to deliver AV synchronous bradycardia pacing, which a sizeable proportion of patients would require. In addition, the lack of ventricular stimulation (anti-tachycardia pacing, ATP) to overdrive arrhythmias is also a disadvantage and an area currently being addressed by the industry. A combination of an S-ICD with a leadless unit (with VVI pacing and ATP as an option) was tested in both animal and human models with the Nanostim LP [45, 46]. Whilst this initially provided some promise with excellent communication between devices, the discontinuation of the Nanostim LP derailed this development for some time. A similar concept has been successfully tested by a new device, the EMPOWER/EMBLEM unit (Boston Scientific, Marlborough, MA, USA), which uses their S-ICD in addition to an LP implanted in the right ventricle which can deliver both VVI pacing and ATP and demonstrated excellent performance up to 18 months in a preclinical model [46, 47]. Furthermore, a case report of a Micra AV pacemaker implanted along with an S-ICD showed the feasibility of AV synchronous pacing alongside an extravascular ICD [48]; however, the lack of cross-communication between the two devices (made by different companies) highlights the complexity and the need for further clinical research. An alternative extravascular ICD (Medtronic) is currently being tested in a clinical study, the EV ICD study (NCT04060680); this device comprises a substernal, extravascular lead which, in addition to defibrillation, can enable epicardial ATP and pacing owing to the proximity to the heart [49].

Wireless Left Ventricular Pacing

A combination of a transvenous pacemaker/ICD along with a leadless ultrasound-based technology for endocardial LV resynchronization has been proposed as an alternative to a coronary sinus lead in cardiac resynchronisation therapy (CRT) in the form of the WiSE-CRT device (EBR Systems Inc., Sunnyvale CA, Fig. 4) [50]. The system consists of three components: a submuscular transmitter under the left breast connected to a subcutaneous battery on the left side of the chest wall and an endocardial left ventricular receiver electrode. The system needs a co-implant that can pace the right ventricle.

Fig. 4
figure 4

Reproduced from Wijesuriya et al. [50], with permission

The WiSE CRT system.

Full size image

An early feasibility study has shown good acute outcomes in patients who could not receive a conventional CRT device [51]. Subsequently, the SELECT-LV study showed that 84.8% of patients had improvement in the clinical composite score at 6 months, and 66% demonstrated a positive echocardiographic CRT response (> 5% absolute increase in LV ejection fraction) with the WiSE-CRT system [52]. Imaging-guided endocardial implants were associated with a higher degree of chronic LV reverse remodelling [53]. A multicentre registry comprising 90 patients with implanted WiSE-CRT system confirmed technical feasibility and a high success rate [54]. A recent meta-analysis of the current data for WiSE-CRT (n = 181) reported a procedural success rate of over 90%, and a mean increase in LV ejection fraction of 6.3%, in a high-risk population including a significant number of non-responders to conventional CRT [55]. Initial complication rates were reasonably high, including vascular injury (5%), cardiac tamponade (3%) and procedure-related death (3%). However, whilst the learning curve for operators undertaking these procedures was initially quite steep, cumulative clinical experience has shown a significant reduction in complication rates [54]. This may be in part due to the development of a transseptal delivery method for the LV endocardial electrode (very common clinical practice for most electrophysiologists) as compared with large bore femoral arterial access and a retrograde aortic approach [56]. In addition, after initially high rates of pericardial effusions in the WiSE-CRT study [51], the delivery sheath was modified to subvert this complication. The most recently published prospective series reported no pericardial effusions in a cohort of 31 patients [57].

SOLVE-CRT is an international multicentre trial currently underway that aims to implant the WiSE-CRT system in 300 patients who have previously failed an attempt at conventional LV lead implant, or those considered high risk for implant [58].

Completely leadless biventricular pacing in patients with chronic atrial fibrillation can be achieved with the WiSE-CRT system in combination with a Micra leadless pacemaker in the right ventricle [59]. The use of the Micra AV leadless pacemaker may allow atrioventricular synchrony to extend use to patients in sinus rhythm. The addition of an S-ICD has been reported, achieving a completely leadless CRT-defibrillator system [60]. At present, this can only be delivered using devices from three separate vendors, which are not designed to function as a single unit. This leads to complex programming requirements, with the potential for complications related to communication between the devices [61].

Conduction System Pacing

His bundle pacing was described many decades ago, with the knowledge that maintenance of intrinsic conduction of the myocardium leads to a more physiological ventricular activation, as compared with right ventricular pacing which inevitably leads to left ventricular electromechanical delay (recognisable on the surface ECG as left bundle branch block-like QRS morphology). However, the tools to deliver and implant pacing leads to the His bundle region have taken longer to develop and in the last 5 years there has been an exponential rise in their development. Whilst initially, many studies reported improved electrical parameters and more physiological activation of the ventricles as compared with conventional RV pacing, recent analyses of medium-term data has suggested up to one-third of patients with a His bundle pacing lead have high thresholds at follow-up, with 17% demonstrating loss of His bundle capture [62]. Alongside this, data has accumulated on the ability to directly capture the conduction system through left bundle branch pacing. This involves directing (and screwing) a pacing lead through the right ventricular septum to capture the deep septal conduction tissue thus directly activating the myocardium through rapid conducting tissue. More consistent capture, lower thresholds and a shorter learning curve appear to be the main headline features of the clinical studies which describe this method [63]. However, medium- to long-term data will be needed to provide confidence to the pacing community that this route is a reasonable strategy for patients going forward [64]. Of note, transvenous pacing leads are made for attachment to the ventricular endocardium; however, the capture of the left bundle requires a direct screw into the myocardial tissue which may create high torque forces within a lead which is not designed for this purpose. Conduction system pacing certainly presents an attractive option for physiological pacing; coupled with the leadless technology described above, this may expand the options for the pacing physician. Recently, implantation of the WiSE-CRT electrode on the LV aspect of the interventricular septum was reported, demonstrating the feasibility of delivering leadless conduction system pacing [65].

Future Directions and Summary

Demonstration of the feasibility and reliability of leadless RV pacing devices was the first important step in a long journey for leadless technology. There have been ongoing efforts towards achieving AV synchrony using leadless pacing, and it will be exciting to follow the trajectory of this over the next decade. Advances in S-ICD technology, leadless LV endocardial pacing, and the possibility of a leadless device providing ATP would enable a completely leadless system with a full array of CRTD functionality. Whilst this is an extremely attractive concept, especially in younger patients who are currently exposed to a lifetime of lead-related complications, several challenges must be overcome for this to be translatable in a real-world setting: these include miniaturisation of technology to allow complex programming within leadless units; enabling communication between devices from different manufacturers; and how to manage devices at the end of battery life.

Indeed, battery drain and finite capacity is one limitation which surrounds both transvenous and leadless devices. Wireless charging which now exists with smartphones may be possible with pacemaker batteries in the future. Other concepts include complete disruption of the battery concept; harvesting of the kinetic energy generated by the cardiac movement to drive electrical current and pace the heart; feasibility models have been tested and will inevitably undergo numerous further iterations over the coming years [66, 67].

With the indications for device therapy increasing in recent years, leadless pacing has the potential to provide safe long-term treatment options for a large cohort of patients with cardiovascular disease. If rapid innovation and development continue at their current trajectory, it is plausible that leadless technology may become a first-line treatment option in decades to come.