Left bundle branch area pacing in patients with atrioventricular conduction disease: A prospective multicenter study.

BACKGROUND: The reported success rate of His-bundle pacing (HBP) in patients with infranodal atrioventricular (AV) conduction disease is only 52%-76%. The success rate of left bundle branch area pacing (LBBAP) in this cohort is not well studied. OBJECTIVE: The purpose of this study was to evaluate the feasibility, safety, and electrophysiological characteristics of LBBAP in patients with AV conduction disease. METHODS: Patients with AV conduction disease referred for pacemaker implantation at 2 centers between February 2019 and June 2021 were considered for LBBAP. Baseline demographic characteristics, procedural success rates, electrophysiological parameters, and complications were assessed. RESULTS: LBBAP was successful in 340 of 364 patients (93%). Mean age was 72 ± 13 years, and mean follow-up was 331 ± 244 days. Pacing indications were Mobitz I in 27 patients (7%), Mobitz II or 2:1 AV block or high-grade AV block in 94 patients (26%), complete heart block in 199 patients (55%), and sick sinus syndrome with isolated bundle branch block in 44 patients (12%). Left bundle branch block and right bundle branch block were present in 57 patients (16%) and 140 patients (38%), respectively. Procedural success rates did not differ between indications (92.6%, 93.6%, 92.9%, and 95%, respectively) or between patients with narrow (<120 ms) vs wide QRS (≥120 ms). Mean LBBAP threshold was 0.77 ± 0.34 V at 0.4 ms at implant and remained stable during follow-up. There were 4 (1.2%) acute LBBAP lead dislodgments. CONCLUSION: LBBAP is safe and feasible with high success rates for patients with AV conduction disease. In contrast to HBP, LBBAP success rates remain high over the entire spectrum of AV conduction disease, and lead parameters remain stable during follow-up.

Atrioventricular junction ablation in patients with conduction system pacing leads: A comparison of His-bundle vs left bundle branch area pacing leads.

BACKGROUND: Single-center studies have shown feasibility of conduction system pacing (CSP) via His-bundle pacing (HBP) or left bundle branch area pacing (LBBAP) in atrial fibrillation (AF) patients undergoing atrioventricular junction ablation (AVJA). OBJECTIVE: The purpose of this study was to compare outcomes in patients with HBP and LBBAP leads undergoing AVJA. METHODS: Consecutive patients with CSP leads referred for AVJA between October 2014 and May 2021 were included. Pacing lead characteristics, procedural characteristics, complications, and long-term outcomes were assessed. RESULTS: One hundred five AVJA procedures (55 HBP, 50 LBBAP) were performed in 98 patients (48 HBP, 50 LBBAP). The acute success rate of the AVJA procedure was 94% vs 100% (P = .11) in HBP vs LBBAP groups. Seven (14%) redo AVJA procedures were required in the HBP group. Mean procedural time (44 ± 24 min vs 34 ± 16 min; P = .02) and mean fluoroscopy time (16 ± 18 min vs 7 ± 6 min; P <.001) were significantly longer in the HBP vs LBBAP group. An acute rise in threshold was noted in 8 cases (14.5%), and 4 (8%) developed exit block after AVJA in HBP patients. Chronic HBP threshold ≥2.5 V was seen in 23 patients (48%), and 4 (8%) HBP leads were deactivated. CSP preserved ejection fraction (EF) in the overall cohort (N = 70; 53% ± 10% vs 55% ± 10%; P = .09) and significantly improved in those with reduced EF <50% at baseline (N = 16; 37% ± 7.6% vs 46% ± 13%; P = .02). CONCLUSION: AVJA in the presence of an LBBAP lead is associated with a higher success rate and fewer acute and chronic lead-related complications. CSP with either HBP or LBBAP preserves left ventricular systolic function in patients with refractory atrial fibrillation post AVJA.

Electrocardiographic characteristics and ablation of ventricular arrhythmias originating from the basal inferoseptal area.

AIMS: Ventricular arrhythmias (VAs) from the basal inferoseptal (BIS) area are rare and can pose unique challenges during catheter ablation (CA) due to the anatomic complexity. The study sought to describe the electrocardiographic and clinical characteristics of VAs originating from the BIS area. METHODS AND RESULTS: Patients with VAs and successful ablation at the BIS area from 2016 to 2020 were included. The 12-lead electrocardiogram (ECG), intracardiac findings, and outcomes were analysed. Of 482 patients with VAs referred for CA, 17 (3.5%) had successful ablation at BIS area. There were 12 males, mean age was 66.7 ± 9 years, 82% had ejection fraction <50%. Mean baseline premature ventricular complex burden was 28.6 ± 9%. All patients had a leftward superior axis. Left bundle branch block (LBBB) with early transition in V2 was noted in eight patients and right bundle branch block (RBBB) in nine patients. Detailed mapping of the right ventricle (RV) was performed in 15 patients (88%), coronary sinus (CS)/middle cardiac vein (MCV) in 13 (76%), right atrium (RA) adjacent to the inferoseptal process (ISP) of left ventricle (LV) in 5 (29%), ISP-LV in 13 (76%), and epicardium in 2 (12%). Successful ablation site was in LV in 10 (59%), RV in 2 (12%), CS/MCV in 1 (6%), RA in 1 (6%), and epicardium in 2 (12%). Fifteen patients (88%) required mapping in at least two chambers (range 2-5) and seven patients (41%) required ablation in at least two chambers (range 2-3). CONCLUSIONS: Ventricular arrhythmias originating in the BIS are uncommon. The most common ECG patterns were leftward superior axis, LBBB with transition in V2 or RBBB. The VA foci can be endocardial or epicardial and meticulous mapping/ablation from multiple chambers is often required to eliminate these foci successfully.

Safety and feasibility of left bundle branch area pacing following valvular interventions: Multicenter study.

OBJECTIVES: To evaluate the safety and feasibility of left bundle branch area pacing (LBBAP) in patients with valvular interventions. METHODS: Eighty-four patients were included in this study. All patients underwent recent surgical or percutaneous valvular interventions. LBBAP was attempted in all patients. Implant success rates, peri- and postprocedure electrocardiogram, pacing parameters, and complications were assessed at implant, and during follow-up. RESULTS: LBBAP implantation was successful in 80/84 (95%) patients. Mean age was 74.1 ± 13.8 years and 56% patients were male. Prior valvular replacements included: percutaneous aortic (26), surgical aortic (36), combined surgical aortic plus mitral (6), MVR (10), tricuspid (1), and pulmonic (1). Average LVEF was 52.6 ± 11%. Majority of patients underwent LBBAP due to atrioventricular block (76%) and sinus node disease (13%). Total procedure duration was 74.1 ± 12.5 min and fluoroscopic duration was 9.7 ± 6.8 min. Pacing parameters were stable during follow-up period of 10.0 ± 6.3 months. Pacing QRS duration was significantly narrower than baseline QRS duration (131.5 ± 31.4 ms vs. 114.3 ± 13.7 ms, p < .001, respectively). No acute complications were observed. Mean follow-up was 10.0 ± 6.3 months (median: 8.4 months, min: 1 and max: 24 months). During follow-up, there were three device infections and two patients had loss of LBBA capture within 1 month of implant. CONCLUSIONS: LBBAP is a feasible and safe pacing modality in patients with prior interventions for valvular heart disease.

Imaging-Based Localization of His Bundle Pacing Electrodes: Results From the Prospective IMAGE-HBP Study.

OBJECTIVES: This study sought to evaluate the correlation between His bundle (HB) pacing (HBP) implantation characteristics, lead-tip location, and association of intraprocedural His recordings with approximated HB anatomic landmarks using computed tomography (CT) imaging. BACKGROUND: HBP continues to grow in clinical practice due to offering true physiological pacing. However, a clear understanding of HB anatomy and the lead-tip location's influence on pacing characteristics is lacking. METHODS: The IMAGE-HBP study (Imaging Study of Lead Implant for His Bundle Pacing) was a prospective, multicenter study designed to assess implantation characteristics of the SelectSecure Model 3830 lead placed at the HB, evaluate protocol-specified HBP success (His recording present on electrogram and HBP threshold ≤2.5 V at 1 ms), and correlation between lead-tip location by CT imaging and HBP characteristics as well as lead-related complications through 12 months. RESULTS: Sixty-nine patients underwent a lead implantation attempt at the HB. Of these, 61 patients (88%) had a lead successfully implanted at the HB, and 52 patients (75%) met the pre-specified definition of successful HBP. In 51 patients with CT imaging, 11 leads (22%) were placed in the atrial aspect of the HB region (36% selective HBP), and 40 leads (78%) were placed in the ventricular aspect (28% selective HBP). Four of the 51 patients had P-wave oversensing, all with leads in the atrium. Freedom from lead-related complication at 12 months was 93%. CONCLUSIONS: Successful HBP could be achieved at lead-tip locations in the atrium or ventricle but is preferable in the ventricle to eliminate risk of oversensing. The IMAGE-HBP study offers better insight into approximated HB anatomic landmarks, lead-tip location, and correlation with pacing characteristics. (Imaging Study of Lead Implant for His Bundle Pacing [IMAGE-HBP]; NCT03294317).

Intermediate-term performance and safety of His-bundle pacing leads: A single-center experience.

BACKGROUND: The short-term safety, feasibility, and performance of His-bundle pacing (HBP) leads have been reported; however, their longer-term performance beyond 1 year remains unclear. OBJECTIVE: The purpose of this study was to examine the intermediate-term performance and safety of HBP. METHODS: All HBP lead implants at Virginia Commonwealth University between January 2014 and January 2019 were analyzed. HBP was performed using a Medtronic SelectSecure 3830-69 cm pacing lead. RESULTS: Of 295 attempts, successful HBP implantation (selective or nonselective) was seen in 274 cases (93%). Mean follow-up duration was 22.8 ± 19.5 months (median 19.5; interquartile range 11-33). Mean age was 69 ± 15 years; 58% were males; and ejection fraction <50% was noted in 30%. Indications for pacemaker included sick sinus syndrome in 41%, atrioventricular block in 36%, cardiac resynchronization therapy in 7%, and refractory atrial fibrillation in 15%. Selective HBP was achieved in 33%. Mean HBP capture threshold at implant was 1.1 ± 0.9 V at 0.8 ± 0.2 ms, which significantly increased at chronic follow-up to 1.7 ± 1.1 V at 0.8 ± 0.3 ms (P <.001). Threshold was ≥2.5 V in 24% of patients, and 28% had an increase in HBP threshold ≥1 V. Loss of His-bundle capture at follow-up (septal right ventricular pacing) was seen in 17%. There was a total of 31 (11%) lead revisions, primarily for unacceptably high thresholds. CONCLUSION: Although HBP can prevent or improve pacing-induced cardiomyopathy, the elevated capture thresholds, loss of His-bundle capture, and lead revision rates at intermediate follow-up are of concern. Longer-term follow-up data from multiple centers are needed.

Initial Experience, Safety, and Feasibility of Left Bundle Branch Area Pacing: A Multicenter Prospective Study.

OBJECTIVES: This study sought to evaluate the safety and feasibility of conduction system pacing by performing left bundle branch area pacing (LBBAP). BACKGROUND: There are limited data from single centers showing that LBBAP may circumvent the technical and electrophysiological challenges encountered with His bundle pacing. METHODS: Patients referred for pacemaker implantation at 2 centers between February 1, 2019, and March 31, 2020, were considered for LBBAP. LBBAP was performed by implanting a lumen-less, exposed helix lead approximately 2 cm distal to the His bundle and deep into the septum using a specialized delivery sheath. Implant success rates, complications, and electrophysiological parameters were assessed. RESULTS: LBBAP was successful in 305 of 341 patients (89%). Mean age was 72 ± 12 years; 45% were women; and 39% had QRS duration (QRSd) >130 ms, 22% right bundle branch block, 11% left bundle branch block, and 6% intraventricular conduction defect. Pacing indications were sinus node dysfunction in 28.7%, atrioventricular block in 52.5%, cardiac resynchronization therapy in 8.8%, and refractory atrial fibrillation in 10% of patients. Procedural duration was 74.7 ± 34 min and fluoroscopic time was 10.4 ± 8.1 min. The mean baseline QRSd and paced QRSd in the overall cohort was 114 ± 29.8 ms versus 112 ± 11.7 ms (p < 0.001) and in patients with infra-Hisian disease was 144.5 ± 19 ms versus 115 ± 12 ms (p < 0.001), respectively. Mean left ventricular activation time was 71.7 ± 11 ms at high output and 74.7 ± 11 ms at low output. LBB potentials were noted in 41% patients. Pacing threshold and R waves were 0.74 ± 0.3 V at 0.4 ms and 10.7 ± 4.9 mV at time of implantation and were stable at 1-, 3-, 6-, and 12-month follow-ups. The only major complications were 3 LBBAP lead dislodgements, 2 within 24 h and 1 at 2 weeks. CONCLUSIONS: LBBA pacing is safe, feasible, and a reliable alternative to His bundle pacing for providing physiological pacing. Randomized controlled studies are needed to confirm the safety, feasibility, and clinical outcomes of LBBAP.

Novel Method for Assessment of His Bundle Pacing Morphology Using Near Field and Far Field Device Electrograms.

BACKGROUND: The 12-lead ECG is considered the gold standard to differentiate between selective (S), nonselective (NS) His bundle pacing (HBP), and right ventricular septal capture in routine clinical practice. We sought to assess the utility of device EGM recordings as a tool to identify the type of HBP morphology. METHODS: One hundred forty-eight consecutive patients underwent HBP with a 3830 Select Secure lead (Medtronic, Inc) at 3 centers between October 2016 and October 2017. The near field V-EGM morphology (NF EGM), near field V-EGM time to peak (NFTime to peak), and far-field EGM QRS duration (QRSd) were recorded while pacing the His lead with simultaneous 12-lead ECG rhythm strips. RESULTS: Indications for HBP were sinus node dysfunction, atrioventricular conduction disease, and cardiac resynchronization therapy in 68 (46%), 56 (38%), and 24 (16%) patients, respectively. Baseline QRSd was 108±38 ms with QRSd >120 ms in 57 (39%) patients (27 right bundle branch block, 18 left bundle branch block, and 12 intraventricular conduction delay). S-HBP was noted in 54 (36%) patients. A positive NFEGM and NFTime to peak >40 ms were highly sensitive (94% and 93%, respectively) and specific (90% and 94%) for S-HBP irrespective of baseline QRSd. All 3 parameters (+NFEGM, NFTime to peak >40 ms, and far-field EGM QRSd <120 ms) had high negative predictive value (97%, 95%, and 92%). A novel device-based algorithm for S-HBP was proposed. EGM transitions correlated with ECG transitions during threshold testing and can help accurately differentiate between S-HBP, NS-HBP, and right ventricular septal pacing with a cumulative positive predictive value of 91% (positive predictive value =100% in patients with baseline QRSd <120 ms). CONCLUSIONS: We propose a novel and simple criteria for accurate differentiation between S-HBP, NS-HBP, and right ventricular septal capture morphologies by careful analysis of device EGMs alone. This study paves the way for future studies to assess autocapture algorithms for devices with HBP.

Profound Sinoatrial Arrest Associated with Ibrutinib.

BACKGROUND: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor approved for second-line treatment for mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenström macroglobulinemia. Ibrutinib use has been linked to increased incidence of atrial fibrillation and hypertension in multiple studies. Other forms of cardiac toxicities have also been reported in isolated case reports. Bradycardia and asystole have not been associated with ibrutinib use in the past. CASE REPORT: We present a case of a 76-year-old female with no prior cardiac history, who initiated treatment with ibrutinib for relapsing mantle cell lymphoma and was noted to have symptomatic bradycardia, greater than 20 second long pauses on her cardiac monitor requiring placement of a permanent pacemaker. CONCLUSION: This is the first case associating bradycardia and asystole with tyrosine kinase inhibitor use. Irreversible inhibition of certain cardioprotective tyrosine kinases has been a growing topic of research in oncology therapeutics.

Repetitive nonreentrant ventriculoatrial synchrony: An underrecognized cause of pacemaker-related arrhythmia.

Similar to endless loop tachycardia (ELT), repetitive nonreentrant ventriculoatrial synchrony (RNRVAS) is a ventriculoatrial (VA) synchrony pacemaker-mediated arrhythmia. RNRVAS was first described in 1990 and can only occur in the presence of retrograde VA conduction and dual-chamber or cardiac resynchronization devices with tracking (P-synchronous ventricular pacing such as DDD, DDDR) or nontracking pacing modes that allow AV-sequential pacing (DDI, DDIR). RNRVAS is promoted by (1) high lower rate limit or any feature that allows rapid pacing, (2) long AV intervals, or (3) long postventricular atrial refractory period (PVARP). In contrast to ELT, RNRVAS is a less well-recognized form of pacemaker-mediated arrhythmia; thus, unlike ELT, there are no specific device algorithms to prevent, recognize, and terminate RNRVAS. However, RNRVAS has been recently shown to occur frequently. We present a series of cases, some of which were found fortuitously. Owing to its clinical implications, we propose that algorithms should be developed to prevent, identify, and terminate RNRVAS.

Thoracic Sympathectomy for Severe Refractory Multivessel Coronary Artery Spasm.

Coronary artery spasm is a rare but potentially fatal disease. Herein, we report a case of recurrent ST-segment myocardial infarctions and ventricular fibrillation complicating severe multivessel coronary artery spasm successfully treated with bilateral thoracic surgical sympathectomy.

Characteristics of ventricular tachycardia ablation in patients with continuous flow left ventricular assist devices.

BACKGROUND: Left ventricular assist devices (LVADs) are increasingly used as a bridge to cardiac transplantation or as destination therapy. Patients with LVADs are at high risk for ventricular arrhythmias. This study describes ventricular arrhythmia characteristics and ablation in patients implanted with a Heart Mate II device. METHODS AND RESULTS: All patients with a Heart Mate II device who underwent ventricular arrhythmia catheter ablation at 9 tertiary centers were included. Thirty-four patients (30 male, age 58±10 years) underwent 39 ablation procedures. The underlying cardiomyopathy pathogenesis was ischemic in 21 and nonischemic in 13 patients with a mean left ventricular ejection fraction of 17%±5% before LVAD implantation. One hundred and ten ventricular tachycardias (VTs; cycle lengths, 230-740 ms, arrhythmic storm n=28) and 2 ventricular fibrillation triggers were targeted (25 transseptal, 14 retrograde aortic approaches). Nine patients required VT ablation <1 month after LVAD implantation because of intractable VT. Only 10/110 (9%) of the targeted VTs were related to the Heart Mate II cannula. During follow-up, 7 patients were transplanted and 10 died. Of the remaining 17 patients, 13 were arrhythmia-free at 25±15 months. In 1 patient with VT recurrence, change of turbine speed from 9400 to 9000 rpm extinguished VT. CONCLUSIONS: Catheter ablation of VT among LVAD recipients is feasible and reasonably safe even soon after LVAD implantation. Intrinsic myocardial scar, rather than the apical cannula, seems to be the dominant substrate.

Conduction disorders after transcatheter aortic valve implantation: a focused review.

OPINION STATEMENT: Transcatheter aortic valve implantation (TAVI) is a less invasive approach to aortic valve replacement than traditional open chest surgery. It has been very successful in elderly and sick patients who might have otherwise been turned down for surgery. However, many patients who have the procedure develop conduction disease, including new LBBB or complete heart block, and may need permanent pacing or ongoing follow-up to monitor for worsening conduction problems. Here we discuss the risk for conduction disease with TAVI, identifying which patients may need a pacemaker or long-term rhythm follow-up, and methods to decrease the risk of worsening conduction.

Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed.

Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X7 receptor.

The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X(7) receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd(ss). Multi parametric optimization led to identification of pyrazole 39 as a viable lead with excellent potency and oral bioavailability. Further attempts to improve the low Vd(ss) of 39 via introduction of amines led to analogs 40 and 41 which maintained the favorable pharmacology profile of 39 and improved Vd(ss) after iv dosing. But these analogs suffered from poor oral absorption, probably driven by poor permeability.

The CD40 agonist antibody CP-870,893 enhances dendritic cell and B-cell activity and promotes anti-tumor efficacy in SCID-hu mice.

CD40 is a member of the TNF family of receptors that has been shown to play a crucial role in enhancing dendritic cell activity and fostering anti-tumor immune responses. In this study, we demonstrate the in vitro properties and in vivo efficacious activity of the CD40 agonist antibody, CP-870,893. CP-870,893 is a fully human, IgG2 antibody that selectively interacts with CD40 at a site distinct from its ligand-binding region with a KD of 0.4 nM. It enhances the expression of MHC class II, CD54, CD86, and CD23 on human B cells in vitro. CP-870,893 also enhances dendritic cell activity as evidenced by cytokine secretion (IL-12, IL-23, IL-8), the upregulation of CD86 and CD83, and the ability to prime T cells to secrete IFNγ. In SCID-beige mice, a single parenteral injection of CP-870,893 was therapeutically effective against several CD40(pos) human tumors (B-cell lymphoma, breast, colon, and prostate) indicating direct effects on tumor cell survival and/or growth. When mice were co-implanted with human T cells and dendritic cells, the activity of CP-870,893 against CD40(pos) tumors increased, and efficacy was also observed against CD40(neg) and CD40(low) tumors demonstrating the ability of CP-870,893 to enhance anti-tumor immune function in vivo. These studies suggest that CP-870,893 has the potential to be efficacious against a wide range of tumor types through both direct and immune-mediated effects.