The development of pacemaker technology in the 1950 s’ focused on creating an implantable ventricular device to prevent death from asystole. In the following years, technologic developments enabled restoration of sequential activation between the atrium and ventricle in a view to maintain the hemodynamics of bradyarrhythmia patients, preventing heart failure and atrial fibrillation. Eventually, cardiac resynchronization therapy (CRT) devices were developed to treat heart failure (HF) due to systolic left ventricular (LV) dysfunction with a broad QRS [1
]. Furthermore, modern devices are instrumental to patient monitoring, enabling prompt detection of clinical issues and streamlined device follow-up [2
The aim to restore a normal cardiac physiology, despite conduction system disease, is still ongoing after 60 years of cardiac pacing, in a quest of truly physiologic pacing that stems from the occurrence of symptomatic LV dysfunction/heart failure in 12–20% patients treated by right ventricular (RV) pacing, despite maintenance of atrioventricular (AV) coupling [3
An ideal model of stimulation is based on maintenance of the physiologic cardiac activation: atrioventricular, interventricular, and intraventricular. The goal is to achieve the optimal ventricular preload by enabling normal interatrial and atrioventricular (AV) coupling, which portends a normal stroke volume once physiologic ventricular activation ensues. This concept is challenging in the context of bradycardia therapy and unfolds in multiple ways in clinical practice.
The key points stemming out of medical literature and leading into the future of cardiac stimulation are:
Atrial-based pacing and maintenance of atrioventricular (AV) coupling;
The detrimental effect of right ventricular (RV) stimulation;
The role of AV timing and of RV pacing minimization;
His bundle and conduction system pacing to preserve physiologic AV timing and ventricular activation;
Minimization of device related complications by leadless cardiac stimulation.
3. Conduction System Pacing
Indirect evidence from large clinical trials [27
] points to RVPIC as a possible mechanism of LV dysfunction in recipients of AV sequential pacing, this deleterious effect being more prevalent in patients with mild to moderate LV dysfunction prior to pacemaker implantation, or with a > 160 ms paced QRS, and with increased ventricular stimulation percentage (> 20% of time) [55
]. Alternative RV pacing sites, such as the outflow tract or septal pacing, have not shown clinical benefit compared to RVA pacing either in the setting of bradycardia treatment or of CRT, thus prompting more physiologic ventricular activation [56
CRT has been advocated as an effective treatment of RVPIC, but is largely underused, expensive, and technically challenging in several cases. Moreover, it dictates redundancy by implantation of three endocardial leads in many patients. An approach based on CRT to all patients with advanced AVB without left bundle branch block (LBBB) would unnecessarily cause ventricular dyssynchrony in many patients, as reported by Ploux et al. [58
]. In patients with advanced first or second–third degree AVB, and a normal or < 130 ms QRS duration, CRT increases rather than decreases intra- and inter-ventricular activation time. In this perspective, the mortality data of the MADIT-CRT non-LBBB group [59
] and of the Echo CRT trial [60
] are not surprising. The prolongation of ventricular activation time due to biventricular stimulation in patients with narrow QRS may partially limit the benefit observed in non-LBBB patients with a long baseline PR interval > 230 ms observed in MADIT-CRT [50
]. These premises warrant the effort to achieve a higher degree of atrioventricular and inter-intraventricular synchrony when treating brady-arrhythmias, beyond biventricular stimulation. In this scenario, conduction system pacing (CSP, meaning His bundle and left/right branches) offers a unique possibility to restore normal cardiac activation. While being increasingly adopted, CSP has yet to prove its efficacy in randomized trials.
Owing to the variable intertwining of the His-Purkinje with myocardial fibers [61
], CSP can be selective (the pacing stimulus captures the CS only), or nonselective His Bundle Pacing (NS-HBP), where fusion of the CS and of the adjacent ventricular myocardium occurs. Clinical superiority of the former over the latter is uncertain at this stage [62
], although nonselective CSP may yield some technical advantages.
3.1. What Do We Already Know? Several Studies Have Shown the Feasibility, Safety, and Positive Clinical Outcomes of His Bundle Pacing (HBP) Compared with Customary RV Apical Pacing
A recent meta-analysis of single-center studies has shown that HBP is feasible with acceptable pacing thresholds (average threshold 1.71 V (95% CI 1.42–2.01 V), most often reported at a pulse width of 0.5–1 ms), which were stable at chronic follow-up, and a low rate of complications in clinical practice [55
In a multicenter experience, the upgrade to HBP after a mean of 6 years of RV apical pacing significantly decreased QRS duration and improved ventricular function, reversing RVPIC [63
]. In a direct comparison with RV apical pacing, HBP showed better clinical outcomes: the primary outcome (death, HF hospitalizations and upgrade to biventricular pacing (BiVP) was reduced significantly (25% during HBP vs. 32% during RVA, p
= 0.02, 25% vs. 36% in patients with VP > 20%, p
= 0.02). A significant improvement of LV function occurred, mostly pronounced in patients with HF [64
Small studies show HBP as an intriguing alternative in CRT candidates, proving to be effective and safe in implementing CRT in CRT-indicated patients [65
]. A crossover study by Lustgarten et al. [70
] compared NS-HBP with CRT in such patients: a Y-adapter connected both HB and LV leads to the LV port. The authors were able to correct QRS duration in 72% of cases. Clinical and echocardiographic responses were similar to those of BIV patients, suggesting that NS-HBP was at least as effective as CRT. The 6-months LVEF improved from 26% to 32% and 31% respectively in NS-HBP and conventional CRT, while functional outcomes were similar [69
]. Right Bundle Branch Block (RBBB) patients have suboptimal response to CRT [71
]: HBP seems to convey the same clinical advantage as true CRT for LBBB patients [72
Though improved ventricular activation by HBP seems to enhance mechanical resynchronization [70
], technical issues in term of implant success rate, stability of the pacing capture and of conduction distally to the His bundle, along follow-up are key points for the planning of a large randomized trial of HBP vs. conventional CRT.
3.2. Which Possible Indications for CSP?
The conduction system is an anatomical-functional continuum that offers the possibility to treat conduction disorders at different levels. HBP may be considered in two populations: those with AV nodal disease (Figure 3
) and those with infra-Hisian disease (Figure 4
In both groups, patients with a coexistent bundle branch block (BBB) can also receive BBB correction and, thus, complete synchronization (Figure 5
), while in those without BBB, HBP simply aims to avoid further desynchronization. The true difference in these two scenarios is the challenge to reach a pacing site distal to the site of block in the latter, to ensure consistent capture of the conduction system at long term follow-up with only minimal excitation of the surrounding muscle, resulting in NS-HBP [74
]. The need of a back-up ventricular pacing lead is also dependent on a preserved His-ventricular conduction distal to the site of pacing, which can be tested during implantation by rapid HBP pacing [74
]. For both groups we can consider the following indications:
Brady-arrhythmia therapy, including SND with 1st, 2nd and 3rd-degree AVB;
“Ablate and pace” strategy for AF;
Cardiac resynchronization therapy in patients with HF and systolic dysfunction, by restoring AV synchrony in those with AVB first and/or BBB, either right or left.
In the CRT setting, a particular scenario is failure to deliver optimal CRT for any reason: failure to access the coronary sinus, inadequate coronary vein anatomy to reach the target site, high pacing threshold, or delayed electrical activation from the LV pacing site, leading to an increased LV activation time. In these clinical scenarios, HBP offers a viable solution to CRT-delivery failure, but is associated with several limitations, such as: high capture thresholds with risk of non-capture at follow-up, low R-wave amplitudes, and failure to correct BBB. Indeed, the recently published His-SYNC trial showed lower success rates with HBP due to a larger number of patients with nonspecific intraventricular conduction defects and high LBBB correction thresholds [75
]. To overcome the challenges of HBP in patients with infra-Hisian block, or in CRT-indicated patients in whom LBBB correction is not successful, CSP has been extended to stimulation of the left bundle branch area. LBBAP (left bundle branch area pacing) is a recent innovation aimed at pacing the conduction system beyond the site of conduction block in the majority of patients with His-Purkinje conduction disease. LBBAP lead, by placement in the deep septal myocardium, offers very low capture thresholds, high R-wave amplitudes, and the ability to bypass conduction blocks in the distal His bundle or proximal left bundle. LBBAP is feasible in the majority of patients and is associated with low and stable capture threshold at mid-term follow-up [76
]; in a study of non-ischemic cardiomyopathy patients, Huang et al. [78
] showed that LBBAP thresholds were 0.5 ± 0.15 V/0.5 ms, and substantially stable at 1-year follow-up. LBBAP was feasible and safe, with clinical outcomes at 1 year similar to those observed with conventional CRT.
In patients with advanced cardiomyopathy and intraventricular conduction delay (IVCD) and/or BBB and variable extent of LV scarring, the use of HBP remains uncertain. In about 10–30% of patients, LBBB may not be correctable by permanent HBP [79
]; thus, residual intraventricular conduction delay due to scar or peripheral conduction disease may persist. In these cases, more complete resynchronization can be achieved by CSP together with sequential LV pacing in peripheral myocardial areas lately activated (His Optimized CRT, HOT-CRT). A small observational series of patients with advanced HF showed QRS narrowing and reverse LV remodeling rates by HOT-CRT superior to those reported in CRT studies [77
]. Whether this translates into additional hemodynamic and clinical benefits needs to be proven in controlled studies.
4. Leadless Cardiac Stimulation: Another Step into the Future?
Leadless stimulation concept dates to the middle seventies, to overcome the risks of device surgery. This aspect is pivotal in frail patients and in young patients who face multiple surgeries in lifetime. Freedom from long-term lead related issues and cosmetic needs are additional advantages.
The first VVIR leadless systems (Nanostim Leadless Cardiac Pacemaker, St. Jude Medical; Micra Transcatheter Pacing system, Medtronic) entered clinical practice in a view to avoid short-term (incidence 8–12%) pacemaker complications: pneumothorax, cardiac perforation, upper extremity deep vein thrombosis, lead dislodgement, pocket hematomas, and surgical wound issues [80
]. Long-term complications include central vein obstruction, endocarditis, lead failure, tricuspid valve regurgitation, and pocket erosion or infection, and are quite rare in VVIR recipients (0.2–2.4%) [82
The first human trial of leadless pacing [84
] enrolled 33 patients implanted with a Nanostim device (Table 1
). Aside one cardiac perforation and tamponade, the complication free rate at 90 days was 94% with stable electrical performance and no device complications at three months. The LEADLESS II trial [85
] enrolled 526 patients in three countries (Table 1
) with a successful implant rate of 96%, a 6.7% rate of major adverse effects had been observed at six months (1.3% perforation; 1.3% elevated pacing threshold requiring reintervention, 1.2% of vascular complications and 1.7% of device dislodgement). Regretfully, significant serious events and a device battery recall led to termination of Nanostim implantation, with several indications to pacemaker retrieval. Among 1423 cases of Nanostim implantation worldwide, there were 34 battery failures due to increased battery resistance [86
]. In a long-term series of 14 consecutive patients, device failure was higher than 40% after 3 years [87
]. Moreover, the manufacturer halted Nanostim implantation in 2016 with the indication of replacement in pacemaker-dependent patients. Feasibility of implantation of another transvenous or leadless pacemaker, with or without extraction of the previous one, was demonstrated [88
The Micra Transcatheter Pacing Trial [89
] was an international prospective multicenter study that demonstrated the efficacy and safety of Micra system with a 3.4% rate of complications at six months in 725 patients (1.5% perforation; 0.7% vascular complications), the majority of whom with adequate six-month pacing capture threshold (Table 1
). The safety results were compared with an historical 2667 patients control cohort who received transvenous pacemakers in a post hoc analysis, with similar results obtained in the propensity-matched analysis. A real-life ongoing analysis [90
], reporting around 1.5% of major complications, seems to confirm the previously reported data. A small study of transvenous VVIR vs. leadless VVIR reported no difference in terms of overall complications [91
] (Table 2
). A real comparison of transvenous and leadless VVIR pacemakers in adequately trained centers is not available, and it seems that the premises of leadless technology await confirmation in the clinical arena.
According to two contemporary registries [92
], VVIR pacemakers are indicated in around 10% of pacemaker recipients [1
]. As reported by a recent EHRA (European Heart Rhythm Association) survey [94
] involving 52 high-volume European centers, anticipated difficult vascular access, history of complicated conventional PM implantation, permanent atrial fibrillation, and an anticipated higher risk of infections were the features that dictated the choice of a leadless pacemaker. Interestingly, the main reason reported for not implanting these devices included limited availability and economic issues, such as lack of reimbursement or high cost of the device. The longevity of leadless batteries is an important aspect: expected life-service is strongly dependent on the effective pacing settings, being estimated as 10 years for Micra [95
]. Moreover, the computational work is decreased, and remote monitoring is not available to minimize current drain.
In 2020, both FDA and CE approved Micra AV, a leadless pacing system, which aims to synchronize ventricular stimulation with atrial activity, featuring a VDD software in the same VVIR Micra. This single-chamber VDD is equipped with a 3-axis accelerometer, which enables to detect four blood flow accelerations in the right ventricle corresponding to the heart sounds. The fourth signal (A4) of each cycle represents the atrial contraction (the A wave of Doppler trans-mitral flow); thus, triggering ventricular stimulation. Diastolic ventricular filling (or E wave) is recorded as the A3 signal. Feasibility and efficacy of AV synchrony (AVS) delivered by Micra AV in patients with high degree AV block have been demonstrated in acute studies with a downloaded software: MASS (Micra Accelerometer Sensor Sub-Study), MASS2, MARVEL (Micra Atrial Tracking using a Ventricular Accelerometer), and MARVEL2 studies. In the latter, 38/40 patients with variable extent of AVB achieved ≥ 70% AV synchronous pacing, defined as the presence of a ventricular paced event within 300 ms of an intrinsic P wave. MARVEL and MARVEL2 studies showed that stroke volume, assessed with echocardiography, was improved by AVS compared to VVI pacing. In MARVEL2, patients had lower sinus rates in VDD mode than in VVI mode, meaning a decreased sympathetic activity when more physiological-pacing is achieved. However, studies on long-term benefits of Micra AV are lacking [96
]. Sensing atrial activity via its mechanical counterpart may pose some issues, atrial undersensing being a major concern in several scenarios. In the event of ineffective atrial contraction, no A4 is detected: an E/A > 1.5 is predictive of A4 undersensing. Fusion between A3 and A4 may occur during sinus tachycardia; thus, limiting rate increase and exercise tolerance. Body movement can interfere with A4 sensing, as well as frequent PVCs [98
]. Rate smoothing can mitigate transient atrial undersensing: assuming a regular atrial activation, pacing occurs for a brief period also when A4 signal is hampered. This produces a typical variability of the AV delay at 1-lead ECG (Figure 6
) In the event of A4 undersensing, the device switches to VVIR mode producing appropriate rate-responsiveness: older patients with AVB typically engage in physical activity for short periods of time, and rate-responsiveness is thought a reasonable compromise.
It is known that right ventricular pacing, with or without AV synchrony, may promote RVPIC [99
]. Micra AV aims to transfer AV coupling in the leadless world, but still provides only non-physiologic right ventricular stimulation with unreliable and often non-physiologic AV intervals. Indeed, the electromechanical delay between electrical P wave and A4 signal may cause long AV intervals (Figure 6
), that warn about the incidence of new-onset AF, HF, and mortality. This pitfall is partially mitigated by the intact AV conduction mode switch algorithm, which periodically checks for intrinsic conduction and reduces unnecessary pacing. Further studies are warranted to evaluate long-term implications of leadless AV pacing on cardiac function.
After a thorough analysis of all different pacing modes, we suggest below a brief guidance to select the most appropriate one based on specific patients’ characteristics (Table 3
The complex interplay of interatrial, atrioventricular and inter-ventricular conduction dictates that restoration of the normal activation along Bachmann bundles, AV node, and His Purkinje network, should be the preferred pacing modality (Figure 7
). Convincing evidence of such a pacing strategy awaits confirmation of appropriately designed clinical trials, which stand on the availability of dedicated tools and technology to enable broad application of CSP and leadless pacing in all clinical settings. While these latter are technically successful only in a minority of patients nowadays, specific patient characteristics and therapeutic goals to be achieved are key elements to consider in selecting the most appropriate pacing modality.
In clinical practice, the most physiologic settings are achieved with available technologies in a view to the best possible individualized treatment:
Avoid unnecessary atrial stimulation to prevent interatrial dyssynchrony and excessive prolongation of the AV interval;
Avoid unnecessary ventricular stimulation until mild prolongation of the PR interval;
Treat advanced AV block by His bundle pacing in patients with <130 ms QRS duration;
Correct BBB by CSP at any level or CRT in broad QRS complex patients;
Apply ventricular stimulation to correct intraventricular conduction delay residual to CSP, or CRT when CSP is not effective/not feasible.
Though the ideal stimulation pattern aims to mimic the normal conduction to restore electro-mechanical coupling in all patients, individualized medicine can dictate different therapeutic choices, depending on the clinical scenario and on the priority of patient needs.