Five-year safety and efficacy of leadless pacemakers in a Dutch cohort.

BACKGROUND: Adequate real-world safety and efficacy of leadless pacemakers (LPs) have been demonstrated up to 3 years after implantation. Longer-term data are warranted to assess the net clinical benefit of leadless pacing. OBJECTIVE: The purpose of this study was to evaluate the long-term safety and efficacy of LP therapy in a real-world cohort. METHODS: In this retrospective cohort study, all consecutive patients with a first LP implantation from December 21, 2012, to December 13, 2016, in 6 Dutch high-volume centers were included. The primary safety endpoint was the rate of major procedure- or device-related complications (ie, requiring surgery) at 5-year follow-up. Analyses were performed with and without Nanostim battery advisory-related complications. The primary efficacy endpoint was the percentage of patients with a pacing capture threshold ≤2.0 V at implantation and without ≥1.5-V increase at the last follow-up visit. RESULTS: A total of 179 patients were included (mean age 79 ± 9 years), 93 (52%) with a Nanostim and 86 (48%) with a Micra VR LP. Mean follow-up duration was 44 ± 26 months. Forty-one major complications occurred, of which 7 were not advisory related. The 5-year major complication rate was 4% without advisory-related complications and 27% including advisory-related complications. No advisory-related major complications occurred a median 10 days (range 0-88 days) postimplantation. The pacing capture threshold was low in 163 of 167 patients (98%) and stable in 157 of 160 (98%). CONCLUSION: The long-term major complication rate without advisory-related complications was low with LPs. No complications occurred after the acute phase and no infections occurred, which may be a specific benefit of LPs. The performance was adequate with a stable pacing capture threshold.

A Dual-Chamber Leadless Pacemaker.

BACKGROUND: Single-chamber ventricular leadless pacemakers do not support atrial pacing or consistent atrioventricular synchrony. A dual-chamber leadless pacemaker system consisting of two devices implanted percutaneously, one in the right atrium and one in the right ventricle, would make leadless pacemaker therapy a treatment option for a wider range of indications. METHODS: We conducted a prospective, multicenter, single-group study to evaluate the safety and performance of a dual-chamber leadless pacemaker system. Patients with a conventional indication for dual-chamber pacing were eligible for participation. The primary safety end point was freedom from complications (i.e., device- or procedure-related serious adverse events) at 90 days. The first primary performance end point was a combination of adequate atrial capture threshold and sensing amplitude at 3 months. The second primary performance end point was at least 70% atrioventricular synchrony at 3 months while the patient was sitting. RESULTS: Among the 300 patients enrolled, 190 (63.3%) had sinus-node dysfunction and 100 (33.3%) had atrioventricular block as the primary pacing indication. The implantation procedure was successful (i.e., two functioning leadless pacemakers were implanted and had established implant-to-implant communication) in 295 patients (98.3%). A total of 35 device- or procedure-related serious adverse events occurred in 29 patients. The primary safety end point was met in 271 patients (90.3%; 95% confidence interval [CI], 87.0 to 93.7), which exceeded the performance goal of 78% (P<0.001). The first primary performance end point was met in 90.2% of the patients (95% CI, 86.8 to 93.6), which exceeded the performance goal of 82.5% (P<0.001). The mean (±SD) atrial capture threshold was 0.82±0.70 V, and the mean P-wave amplitude was 3.58±1.88 mV. Of the 21 patients (7%) with a P-wave amplitude of less than 1.0 mV, none required device revision for inadequate sensing. At least 70% atrioventricular synchrony was achieved in 97.3% of the patients (95% CI, 95.4 to 99.3), which exceeded the performance goal of 83% (P<0.001). CONCLUSIONS: The dual-chamber leadless pacemaker system met the primary safety end point and provided atrial pacing and reliable atrioventricular synchrony for 3 months after implantation. (Funded by Abbott Medical; Aveir DR i2i ClinicalTrials.gov number, NCT05252702.).

NL-EVDR: Netherlands-ExtraVascular Device Registry.

Cardiac implantable electronic device (CIED) therapy is an essential element in treating cardiac arrhythmias. Despite their benefits, conventional transvenous CIEDs are associated with a significant risk of mainly pocket- and lead-related complications. To overcome these complications, extravascular devices (EVDs), such as the subcutaneous implantable cardioverter-defibrillator and intracardiac leadless pacemaker, have been developed. In the near future, several other innovative EVDs will become available. However, it is difficult to evaluate EVDs in large studies because of high costs, lack of long-term follow-up, imprecise data or selected patient populations. To improve evaluation of these technologies, real-world, large-scale, long-term data are of utmost importance. A Dutch registry-based study seems to be a unique possibility for this goal due to early involvement of Dutch hospitals in novel CIEDs and an existing quality control infrastructure, the Netherlands Heart Registration (NHR). Therefore, we will soon start the Netherlands-ExtraVascular Device Registry (NL-EVDR), a Dutch nationwide registry with long-term follow-up of EVDs. The NL-EVDR will be incorporated in NHR's device registry. Additional EVD-specific variables will be collected both retrospectively and prospectively. Hence, combining Dutch EVD data will provide highly relevant information on safety and efficacy. As a first step, a pilot project has started in selected centres in October 2022 to optimise data collection.

Predicted Need for Atrial and Ventricular Pacing Per Indication Group in Patients With Dual-Chamber Pacemakers.

BACKGROUND: Bradyarrhythmias are adequately treated with pacemakers. There are different pacing modes (single-chamber, dual-chamber, cardiac resynchronisation therapy [CRT] and conduction system pacing [CSP]) and a choice between leadless or transvenous pacemakers. The expected pacing need is important for determining optimal pacing mode and device type. This study aimed to evaluate atrial pacing (AP) and ventricular pacing (VP) percentages over time for the most common pacing indications. METHODS: Included patients were aged ≥18 years with a dual-chamber rate-modulated [DDD(R)] pacemaker implantation and ≥1 year of follow-up at a tertiary centre between January 2008 and January 2020. Baseline characteristics, AP and VP at yearly follow-up visits up to 6 years after implantation were retrieved from the medical records. RESULTS: A total of 381 patients were included. Primary pacing indications were incomplete atrioventricular block (AVB) in 85 (22%), complete AVB in 156 (41%) and sinus node dysfunction (SND) in 140 (37%) patients. Mean age at implantation was 71±14, 69±17 and 68±14 years, respectively (p=0.23). Median follow-up was 42 months (25-68 months). Overall, AP was highest in SND with median 37% (7%-75%) versus 7% (1%-26%) in incomplete AVB and 3% (1%-16%) in complete AVB (p<0.001); VP was highest in complete AVB with median 98% (43%-100%) versus 44% (7%-94%) in incomplete AVB and 3% (1%-14%) in SND (p<0.001). Ventricular pacing significantly increased over time in patients with incomplete AVB and SND (both p=0.001). CONCLUSIONS: These results confirm the pathophysiology of different pacing indications, causing clear differences in pacing need and expected battery longevity. They may help guide optimal pacing mode and suitability for leadless or physiological pacing.

Timing and mid-term outcomes of using leadless pacemakers as replacement for infected cardiac implantable electronic devices.

BACKGROUND: Cardiac implantable electronic device (CIED) infections have a high morbidity and mortality and are an indication of device extraction. As a replacement, leadless pacemakers (LPs) may be preferable due to a low infection risk, but mid-term data on reinfections is lacking. Moreover, early LP reimplantation in pacemaker-dependent patients would circumvent the need for temporary pacemakers. METHODS: We included all patients with LP implantation as a replacement for an infected CIED, between January 2013 and December 2021. The occurrence of reinfection was assessed during standard follow-up visits. RESULTS: Twenty-nine patients (mean age 81 ± 9 years) were included, of which 21 (73%) had a pocket infection, 7 (24%) endocarditis, and 1 (3%) a systemic infection without endocarditis. All LP implantations were successful. LPs were implanted before extraction (n = 4, 13%), simultaneously with extraction (n = 5, 17%) and after extraction (n = 20, 70%). No reinfection occurred during the follow-up of median 32 months (IQR 13-66 months). Repeat blood cultures obtained in 9 (30%) patients and transthoracic echocardiography in all 7 patients with pacemaker endocarditis were negative for reinfection. In a subset of 6 LPs extracted during follow-up due to early battery depletion, prophylactically after the battery advisory or due to non-capture (median 36 months (range 0-67 months) post-implantation), histopathologic examination of tissues around the LPs showed no signs of infection. CONCLUSIONS: After replacing infected CIEDs for an LP, no reinfections occurred in over 2.5 years follow-up. These results confirm that in case of CIED infection, the LP is an appealing replacement device. LP implantation before CIED extraction is feasible.

Preclinical safety and electrical performance of novel atrial leadless pacemaker with dual-helix fixation.

BACKGROUND: Complications associated with transvenous pacemakers, specifically those involving the lead or subcutaneous pocket, may be avoided with leadless pacemakers (LPs). The safety and efficacy of single-chamber right ventricular LPs have been demonstrated, but their right atrium (RA) use poses new design constraints. OBJECTIVES: The purpose of this study was to evaluate the implant success, electrical performance, and safety of a novel RA LP design in benchtop and preclinical studies. METHODS: A new LP was designed with a dual-helix fixation mechanism specific to the RA anatomy. A 12-week preclinical ovine study was conducted to evaluate implant success, electrical performance, mechanical stability, and safety in vivo, with supporting benchtop measurements to quantify the mechanical forces needed for device retrieval and dislodgment. RESULTS: LPs were successfully implanted in all 10 ovine subjects with no complications. The pacing capture threshold improved significantly over time from implant to week 12 (1.1 ± 0.7 V vs 0.4 ± 0.2 V, P = .008). Sensing amplitudes and pacing impedances were stable from implant to week 12 (4.8 ± 1.8 mV vs 6.0 ± 1.9 mV, P = .160; and 393 ± 77 Ω vs 398 ± 65 Ω, P = .922, respectively). Gross pathology and microscopic histology revealed no adverse interactions and no evidence of device dislodgment or clinically significant myocardial perforation. Benchtop ex vivo porcine atrial tissue measurements revealed greater pull forces required to dislodge the LP vs transvenous active fixation lead (0.42 ± 0.18 lbf vs 0.29 ± 0.08 lbf, P = .020), and greater rotational forces required for deliberate extraction (0.28 ± 0.04 lbf vs 0.14 ± 0.07 lbf, P <.001). CONCLUSION: The novel atrial LP demonstrated successful implantation, with acceptable electrical performance, mechanical stability, and safety in a 12-week preclinical study.

Long-term performance of a novel communicating antitachycardia pacing-enabled leadless pacemaker and subcutaneous implantable cardioverter-defibrillator system: A comprehensive preclinical study.

BACKGROUND: Subcutaneous implantable cardioverter-defibrillators (S-ICDs) and leadless pacemakers (LPs) are intended to diminish transvenous lead-related complications. However, S-ICDs do not deliver antibradycardia pacing or antitachycardia pacing, and currently, there is no commercially available coordinated leadless option for patients with defibrillator and (expected) pacing needs. OBJECTIVE: We evaluated the performance, safety, and potential replacement strategies of a novel modular cardiac rhythm management (mCRM) system, a wirelessly communicating antitachycardia pacing-enabled LP and S-ICD in a preclinical model. METHODS: LP implantation was attempted in 68 canine subjects, and in 38 an S-ICD was implanted as well. Animals were evaluated serially up to 18 months. At all evaluations, communication thresholds (CTs) between the devices, LP electrical parameters, and system-related complications were assessed. Different replacement strategies were tested. RESULTS: The LP was successfully implanted in 67 of 68 (98.5%) and the concomitant S-ICD in 38 of 38 (100%). mCRM communication was successful in 1022 of 1024 evaluations (99.8%). The mean CT was 2.2 ± 0.7 V at implantation and stable afterward (18 months: 1.8 ± 0.7 V). In multivariable analysis, larger LP-to-S-ICD angle and dorsal posture were associated with higher CTs. At implantation, the mean pacing capture threshold, impedance, and R-wave amplitude were 0.3 ± 0.1 V, 898.4 ± 198.9 Ω, and 26.4 ± 8.2 mV. The mean pacing capture threshold remained stable and impedance and R-wave amplitudes were within acceptable ranges throughout (0.7 ± 0.4 V, 619.1 ± 90.6 Ω, and 20.1 ± 8.4 mV at 18 months). Different replacement strategies seem feasible. CONCLUSION: This first mCRM system demonstrated excellent performance up to 18 months in a preclinical model.

Ventricular-vascular coupling is predictive of adverse clinical outcome in paediatric pulmonary arterial hypertension.

AIMS: Ventricular-vascular coupling, the ratio between the right ventricle's contractile state (Ees) and its afterload (Ea), may be a useful metric in the management of paediatric pulmonary arterial hypertension (PAH). In this study we assess the prognostic capacity of the ventricular-vascular coupling ratio (Ees/Ea) derived using right ventricular (RV) pressure alone in children with PAH. METHODS: One hundred and thirty paediatric patients who were diagnosed with PAH via right heart catheterisation were retrospectively reviewed over a 10-year period. Maximum RV isovolumic pressure and end-systolic pressure were estimated using two single-beat methods from Takeuchi et al (Ees/Ea_(Takeuchi)) and from Kind et al (Ees/Ea_(Kind)) and used with an estimate of end-systolic pressure to compute ventricular-vascular coupling from pressure alone. Patients were identified as either idiopathic/hereditary PAH or associated PAH (IPAH/HPAH and APAH, respectively). Haemodynamic data, clinical functional class and clinical worsening outcomes-separated into soft (mild) and hard (severe) event categories-were assessed. Adverse soft events included functional class worsening, syncopal event, hospitalisation due to a proportional hazard-related event and haemoptysis. Hard events included death, transplantation, initiation of prostanoid therapy and hospitalisation for atrial septostomy and Pott's shunt. Cox proportional hazard modelling was used to assess whether Ees/Ea was predictive of time-to-event. RESULTS: In patients with IPAH/HPAH, Ees/Ea_(Kind) and Ees/Ea_(Takeuchi) were both independently associated with time to hard event (p=0.003 and p=0.001, respectively) and when adjusted for indexed pulmonary vascular resistance (p=0.032 and p=0.013, respectively). Neither Ees/Ea_(Kind) nor Ees/Ea_(Takeuchi) were associated with time to soft event. In patients with APAH, neither Ees/Ea_(Kind) nor Ees/Ea_(Takeuchi) were associated with time to hard event or soft event. CONCLUSIONS: Ees/Ea derived from pressure alone is a strong independent predictor of adverse outcome and could be a potential powerful prognostic tool for paediatric PAH.

Significantly less inappropriate shocks in ischemic patients compared to non-ischemic patients: The S-ICD experience of a high volume single-center.

BACKGROUND: The subcutaneous cardioverter-defibrillator (S-ICD) continues to be preferentially used in relatively young patients, with less advanced heart disease. OBJECTIVE: We, therefore, studied the short and long-term efficacy and safety of the S-ICD in subgroups of patients, which are underreported at present. METHODS: A total of 218 patients between November 2010 and February 2019 undergoing S-ICD with a follow up of at least 6 months implantation were included in a prospective registry. Mean follow up was 38 months. RESULTS: The most common indication for S-ICD implantation was ischemic cardiomyopathy (n = 106, 49%). Complication rate needing invasive intervention was 9% (n = 21). Appropriate shock rate in patients with an S-ICD was 3.5%/year. A total of 30 inappropriate shocks (IAS) occurred in 19 patients (8.7%; 2.7%/year). The proportion of appropriate and inappropriate shock rates in patients with different cardiomyopathies shows remarkable variances. There were significant more IAS (3.6%/year vs. 1.7%/year, p = .048) in patients with non-ischemic cardiomyopathy versus patients with ischemic cardiomyopathy. Multivariate analysis identified, besides type of cardiomyopathy, atrial fibrillation (AF) as predictor for IAS. CONCLUSION: In this real-world prospective registry we analyzed S-ICD performance in the more traditional ICD patient. Patients with ischemic cardiomyopathy had significantly less inappropriate therapy compared to patients with non-ischemic cardiomyopathy and appear to be appropriate patients for this type of device.

Tissues attached to retrieved leadless pacemakers: Histopathological evaluation of tissue composition in relation to implantation time and complications.

BACKGROUND: Leadless pacemakers (LPs) have proven safe and effective, but device revisions remain necessary. Either replacing the LP or implanting a new adjacent LP is feasible. Replacement seems more appealing, but encapsulation and tissue adhesions may hamper the safety and efficacy of LP retrieval. OBJECTIVE: We determined the incidence and cellular characteristics of tissue adherent to retrieved LPs and the potential implications for end-of-life strategy. METHODS: All 15 consecutive successful Nanostim LP retrievals in a tertiary center were included. We assessed the histopathology of adherent tissue and obtained clinical characteristics. RESULTS: Adherent tissue was present in 14 of 15 retrievals (93%; median implantation duration 36 months; range 0-96 months). The tissue consisted of fibrosis (n = 2), fibrosis and thrombus (n = 9), or thrombus only (n = 3). In short-term retrievals (<1 year), mostly fresh thrombi without fibrosis were seen. In later retrievals, the tissue consisted of fibrosis often with organizing or lytic thrombi. Fibrosis showed different stages of organization, notably early fibrocellular and later fibrosclerotic tissue. Inflammatory cells were seen (n = 4) without signs of infection. Tricuspid valve material was retrieved in 1 patient after 36 months, resulting in increased tricuspid regurgitation. CONCLUSION: Our results suggest that fibrosis and thrombus adherent to LPs are common and encapsulate the LP as seen in transvenous pacemakers. LPs may adhere to the tricuspid valve or subvalvular apparatus affecting retrieval safety. The end-of-life strategy should be optimized by incorporating risk stratification for excessive fibrotic encapsulation and adhesions.

The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension.

OBJECTIVE: To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes. STUDY DESIGN: Children (n = 70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9, and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations. RESULTS: Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n = 7, TBX4 n = 8, ACVRL1 n = 1, KCNK3 n = 1, and EIF2AK4 n = 2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome, and various copy number variations). Survival rates differed between groups and was most favorable in TBX4 variant carriers. CONCLUSIONS: Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk-stratified care management in pediatric PAH.

Leadless cardiac pacing systems: current status and future prospects.

Introduction: Permanent transvenous pacemaker therapy is an essential management option in patients with symptomatic bradyarrhythmias, but harbors a concomitant risk of serious complications. As most complications are lead- or pocket-related, intracardiac leadless pacemaker therapy has the potential to positively impact patient outcome. Since the first leadless pacemaker implant in 2012, many studies have been conducted to evaluate the effectiveness, safety, and applicability of this novel pacing approach.Areas covered: This review will cover the current status of leadless pacemaker technology. Available safety and efficacy outcomes, current area of indication, and end-of-life management will be evaluated. Furthermore, future perspectives for clinical practice and new pacing modalities are discussed.Expert opinion: The first-generation leadless pacemakers are a promising innovation that provide safe and efficient single-chamber pacing therapy without the use of transvenous pacemaker leads. Yet, broad implementation of this technology is hampered by limitations of the current leadless devices, such as end-of-life management and its single-chamber pacing indication. Further innovations such as leadless dual-chamber pacing therapy, leadless cardiac synchronization therapy, energy-harvesting leadless pacemakers, communicating leadless pacemakers with subcutaneous implantable cardiac defibrillators, and minimally invasive completely extracardiac pacemakers are currently being developed that have the potential to become major game changers in pacing therapy.