Prediction of certainty in artificial intelligence-enabled electrocardiography.

BACKGROUND: The 12­lead ECG provides an excellent substrate for artificial intelligence (AI) enabled prediction of various cardiovascular diseases. However, a measure of prediction certainty is lacking. OBJECTIVES: To assess a novel approach for estimating certainty of AI-ECG predictions. METHODS: Two convolutional neural networks (CNN) were developed to predict patient age and sex. Model 1 applied a 5 s sliding time-window, allowing multiple CNN predictions. The consistency of the output values, expressed as interquartile range (IQR), was used to estimate prediction certainty. Model 2 was trained on the full 10s ECG signal, resulting in a single CNN point prediction value. Performance was evaluated on an internal test set and externally validated on the PTB-XL dataset. RESULTS: Both CNNs were trained on 269,979 standard 12­lead ECGs (82,477 patients). Model 1 showed higher accuracy for both age and sex prediction (mean absolute error, MAE 6.9 ± 6.3 years vs. 7.7 ± 6.3 years and AUC 0.946 vs. 0.916, respectively, P < 0.001 for both). The IQR of multiple CNN output values allowed to differentiate between high and low accuracy of ECG based predictions (P < 0.001 for both). Among 10% of patients with narrowest IQR, sex prediction accuracy increased from 65.4% to 99.2%, and MAE of age prediction decreased from 9.7 to 4.1 years compared to the 10% with widest IQR. Accuracy and estimation of prediction certainty of model 1 remained true in the external validation dataset. CONCLUSIONS: Sliding window-based approach improves ECG based prediction of age and sex and may aid in addressing the challenge of prediction certainty estimation.

Feasibility and safety of left bundle branch area pacing in patients with septal hypertrophy.

INTRODUCTION: Left bundle branch area pacing (LBBAP) aims to provide physiological ventricular activation during pacing. Left ventricular septal hypertrophy (LVSH) might be challenging for LBBAP due to the thickness of the interventricular septum and potential presence of septal scar. This study assesses the feasibility, safety, and outcome of LBBAP in patients with LVSH using primarily stylet-driven leads (SDL). METHODS: Adult patients with LVSH who underwent LBBAP between March 2019 and November 2022 were enrolled. Baseline patient characteristics, procedural data and postprocedural results were collected. The feasibility of LBBAP in LVSH patients was compared to a cohort of LBBAP patients with normal septal wall thickness (NST). RESULTS: Seventeen LVSH and 133 NST patients underwent LBBAP with successful implantation achieved in 15 LVSH patients (88%). Mean implant depth was 17.2 ± 1.9 mm, with 53% proven left bundle branch (LBB) capture. Paced QRS duration (146 ± 14 ms) and V6 R-wave peak time (V6 RWPT; 79 ± 20 ms) were comparable between patients with and without septal hypertrophy, although patients with NST had higher rates of proven LBB capture (71% vs. 53%). In LVSH pacing thresholds (0.6 ± 0.3 V at 0.4 ms) and R-wave amplitude (13.9 ± 5.6 mV) were favorable and remained stable at follow-up. At 12 months, 87% of patients had stable or improved left ventricular ejection fraction. CONCLUSION: The results of the study indicate that LBBAP in patients with LVSH is safe and feasible and no lead-related complications were observed despite a mean implant depth exceeding 15 mm. LBBAP using SDL results in favorable pacing and electrocardiographic characteristics in LVSH patients, comparable to patients with NST.

Initial experience of left bundle branch area pacing using stylet-driven pacing leads: A multicenter study.

BACKGROUND: Left bundle branch area pacing (LBBAP) has been performed exclusively using lumen-less pacing leads (LLL) with fixed helix design. This registry study explores the safety and feasibility of LBBAP using stylet-driven leads (SDL) with extendable helix design in a multicenter patient population. METHODS: This study prospectively enrolled consecutive patients who underwent LBBAP for bradycardia pacing or heart failure indications at eight Belgian hospitals. LBBAP was attempted using SDL (Solia S60; Biotronik) delivered through dedicated delivery sheath (Selectra3D). Implant success, complications, procedural, and pacing characteristics were recorded at implant and follow-up. RESULTS: The study enrolled 353 patients (mean age 76 ± 39 years, 43% female). The mean number of implants per center was 25 (range: 5-162). Overall, LBBAP with SDL was successful in 334/353 (94%), varying from 93% to 100% among centers. Pacing response was labeled as left bundle branch pacing in 73%, whereas 27% were labeled as myocardial capture. Mean paced QRS duration and stimulus to left ventricular activation time measured 126 ± 21 ms and 74 ± 17. SDL-LBBAP resulted in low pacing thresholds (0.6 ± 0.4 V at 0.4 ms), which remained stable at 12 months follow-up (0.7 ± 0.3, p = .291). Lead revisions for SDL-LBBAP occurred in 5 (1.4%) patients occurred during a mean follow up of 9 ± 5 months. Five (1.4%) septal coronary artery fistulas and 8 (2%) septal perforations occurred, none of them causing persistent ventricular septal defects. CONCLUSION: The use of SDL to achieve LBBAP is safe and feasible, characterized by high implant success in low and high volume centers, low complication rates, and stable low pacing thresholds.

Mitral Annular Disjunction: Associated Pathologies and Clinical Consequences.

PURPOSE OF REVIEW: To provide an overview of mitral annular disjunction (MAD) and to discuss important challenges in diagnosis and management of MAD. RECENT FINDINGS: MAD has regained interest in the context of sudden cardiac death (SCD) in patients with mitral valve prolapse (MVP), coined as the "arrhythmic" MVP syndrome. In addition, MAD in isolation was recently suggested to be associated with severe arrhythmia and SCD. There is a lack of consensus on the definition of MAD and the imaging modality to be used for diagnosing MAD, and the therapeutic implications of MAD remain uncertain. Furthermore, the exact mechanism underlying the association of MAD with SCD remains largely unexplored.

Left bundle branch area pacing using stylet-driven pacing leads with a new delivery sheath: A comparison with lumen-less leads.

INTRODUCTION: Left bundle branch area pacing (LBBAP) aims to achieve physiological pacing by capturing the conduction system in the area of the left bundle branch. LBBAP has exclusively been performed using lumen-less pacing leads (LLLs) with fixed helix design. This study explores the feasibility, safety, and pacing characteristics of LBBAP using stylet-driven leads (SDLs) with an extendable helix design. METHODS: Patients, in which LBBAP was attempted for bradycardia or heart failure pacing indications, were prospectively enrolled at the Ghent University Hospital. LBBAP was attempted with two different systems: 1/LLL with fixed helix (SelectSecure 3830, Medtronic Inc.) delivered through a preshaped sheath (C315His Medtronic Inc.) and 2/SDL with extendable helix (Solia S60, Biotronik, SE & CO) delivered through a new delivery sheath (Selectra 3D, Biotronik). RESULTS: The study enrolled 50 patients (mean age: 70 ± 14 years, 44% females). LBBAP with SDL was successful in 20/23 (87%) patients compared with 24/27 (89%) of patients in the LLL group (p = 0.834). Screw attempts, screw implant depth, procedural, and fluoroscopy times were comparable among both groups. Acute LBBAP thresholds were low and comparable between SDL and LLL (0.5 ± 0.15 V vs. 0.4 ± 0.17 V, p = 0.251). Pacing thresholds remained low at 3 ± 2.1 months of follow up in both groups and no lead revisions were necessary. Postprocedural echocardiography revealed a septal coronary artery fistula in one patient with SDLLBBAP. CONCLUSION: LBBAP using stylet-driven pacing leads is feasible and yields comparable implant success to LBBAP with LLLs. LBBAP thresholds are low and comparable with both types of leads.

Perimembranous ventricular septal defect following His bundle lead implantation.

His bundle pacing (HBP) offers physiologic pacing by placing the pacing lead directly to the His bundle. We present a case in which a HBP lead, implanted at the fragile membranous septum, resulted in a persistent restrictive perimembranous ventricular septal defect (VSD). This complication of HBP has not been reported before but brings new insights in the discussion regarding the optimal position of a pacing lead in the ventricular septum. The fragility of the membranous septum and low rate of spontaneous closure of membranous VSD, might favor lead placement in the muscular septum when aiming for physiologic pacing.

Feasibility of His-bundle pacing in patients with conduction disorders following transcatheter aortic valve replacement.

BACKGROUND: Conduction disorders requiring permanent pacemaker implantation occur frequently after transcatheter aortic valve replacement (TAVR). This multicenter study explored the feasibility and safety of His bundle pacing (HBP) in TAVR patients with a pacemaker indication to correct a TAVR-induced left bundle branch block (LBBB). METHODS: Patients qualifying for a permanent pacemaker implant after TAVR were planned for HBP implant. HBP was performed using the Select Secure (3830; Medtronic) pacing lead, delivered through a fixed curve or deflectable sheath (C315HIS or C304; Medtronic). Successful HBP was defined as selective or nonselective HBP, irrespective of LBB recruitment. Successful LBBB correction was defined as selective or nonselective HBP resulting in paced QRS morphology similar to pre-TAVR QRS and paced QRS duration (QRSd) less than 120 milliseconds with thresholds less than 3.0 V at 1.0-millisecond pulse width. RESULTS: The study enrolled 16 patients requiring a permanent pacemaker after TAVR (age 85 ± 4 years, 31% female, all LBBB; QRSd: 161 ± 14 milliseconds). Capture of the His bundle was achieved in 13 of 16 (81%) patients. HBP with LBBB correction was achieved in 11 of 16 (69%) and QRSd narrowed from 162 ± 14 to 99 ± 13 milliseconds and 134 ± 7 milliseconds during S-HBP and NS-HBP, respectively (P = .005). At implantation, mean threshold for LBBB correction was 1.9 ± 1.1 V at 1.0 millisecond. Thresholds remained stable at 11 ± 4 months follow-up (1.8 ± 0.9 V at 1.0 millisecond, P = .231 for comparison with implant thresholds). During HBP implant, one temporary complete atrioventricular block occurred. CONCLUSION: Permanent HBP is feasible in the majority of patients with TAVR requiring a permanent pacemaker with the potential to correct a TAVR-induced LBBB with acceptable pacing thresholds.

Progression of incomplete toward complete left bundle branch block: A clinical and electrocardiographic analysis.

BACKGROUND: Complete left bundle branch block (cLBBB) is associated with increased cardiovascular mortality and heart failure. On the contrary, the clinical relevance of incomplete left bundle branch block (iLBBB) is less known. This study investigated the profile and outcome of iLBBB patients and assessed the risk of progression to cLBBB. METHODS: Patients diagnosed with iLBBB between July 2013 and April 2018 were retrospectively included. Subsequently, echo- and electrocardiographic examinations at time of iLBBB diagnosis and during follow-up, as well as progression to non-strict cLBBB and strict cLBBB, were evaluated. RESULTS: The study enrolled 321 patients (33% female, age 74 ± 11 years). During the follow-up of 21 (8;34) months, 33% of iLBBB patients evolved to non-strict cLBBB and 27% to strict cLBBB. iLBBB patients who evolved to non-strict or strict cLBBB were older, had more frequently reduced left ventricular ejection fraction, and had more often QRS notching/slurring in the lateral leads and inferior leads, compared to patients without progression to cLBBB. In multivariate analysis, only QRS notching/slurring in the lateral leads was independently associated with progression to non-strict cLBBB (odds ratio 4.64, p < .001) and strict cLBBB (odds ratio 9.6, p < .001). iLBBB patients with QRS notching/slurring had a progression rate to non-strict cLBBB of 52% and 49% to strict cLBBB. CONCLUSION: Among patients with iLBBB, up to one third of the patients progress to cLBBB within a period of 2 years. The presence of QRS notching/slurring in the lateral leads during iLBBB was the strongest predictor for progression toward cLBBB.

Outcome of degenerative nonprolapse mitral regurgitation using the average pixel intensity method.

BACKGROUND: Primary mitral valve regurgitation (MR) is a comprehensive term that mostly comprises mitral valve prolapse (MVP), while other causes of degenerative MR are often not considered. We describe the echocardiographic characteristics of degenerative nonprolapse mitral regurgitation (DMR) and assess the outcome at medium-term follow-up using the novel average pixel intensity (API) method. METHODS: Of 126 patients with any nonprolapse DMR were consecutively included. MR was graded according to all guideline-recommended parameters and with the API method. MR flow dynamics in DMR were compared to MVP-MR and functional MR (FMR). RESULTS: DMR is associated with moderate-to-severe calcifications of the mitral valve apparatus, and a low event rate was observed at a mean follow-up of 27 months. The API grading method had a higher feasibility (94%) compared to proximal isovelocity surface area (PISA) (60%) method and vena contracta width (VCW) (71%) for assessing MR. The API method was predictive for events. The API method also provides insights into DMR flow dynamics: A triphasic pattern was observed with a midsystolic nadir for both API and PISA-EROA, which is similar to the dynamic flow pattern described in FMR, but distinct from holosystolic MVP-MR. Compared to FMR and MVP-MR patients, DMR is less severe and patients with DMR are generally older than MVP-MR patients. CONCLUSIONS: DMR is a distinct MR pathology and conveys a relatively low event rate. MR grading was feasible with the API method, and flow dynamics demonstrated a similar triphasic pattern compared to FMR but distinct from holosystolic MVP-MR.

Relation between electrical and mechanical dyssynchrony in patients with left bundle branch block: An electro- and vectorcardiographic study.

BACKGROUND: Current guidelines select patients for cardiac resynchronization therapy (CRT) mainly on electrocardiographic parameters like QRS duration and left bundle branch block (LBBB). However, among those LBBB patients, heterogeneity in mechanical dyssynchrony occurs and might be a reason for nonresponse to CRT. This study assesses the relation between electrocardiographic characteristics and presence of mechanical dyssynchrony among LBBB patients. METHODS: The study included patients with true LBBB (including mid-QRS notching) on standard 12-lead electrocardiograms. Left bundle branch block-induced mechanical dyssynchrony was assessed by the presence of septal flash on two-dimensional echocardiography. Previously reported electro- and vectorcardiographic dyssynchrony markers were analyzed: global QRS duration (QRSDLBBB ), left ventricular activation time (QRSDLVAT ), time to intrinsicoid deflection (QRSDID ), and vectorcardiographic QRS areas in the 3D vector loop (QRSA3D ). RESULTS: The study enrolled 545 LBBB patients. Septal flash (SF) is present in 52% of patients presenting with true LBBB. Patients with SF are more frequent female, have less ischemic heart disease and smaller left ventricular dimensions. In multivariate analysis longer QRSDLBBB , QRSDLVAT and larger QRSA3D were independently associated with SF. Of all parameters, QRSA3D has the best accuracy to predict SF, although overall accuracy remains moderate (59% sensitivity, 58% specificity). The predictive value of QRSA3D remained constant in both sexes, irrespective of ischemic heart disease, ejection fraction and even when categorizing for QRSDLBBB . CONCLUSION: In LBBB patients, large QRS areas correlate better with mechanical dyssynchrony compared to wide QRSD intervals. However, the overall accuracy to predict mechanical dyssynchrony by electrocardiographic dyssynchrony markers, even when using complex vectorcardiographic parameters, remains low.

Biventricular Paced QRS Area Predicts Acute Hemodynamic CRT Response Better Than QRS Duration or QRS Amplitudes.

INTRODUCTION: Vectorcardiographic (VCG) QRS area of left bundle branch block (LBBB) predicts acute hemodynamic response in cardiac resynchronization therapy (CRT) patients. We hypothesized that changes in QRS area occurring with biventricular pacing (BV) might predict acute hemodynamic CRT response (AHR). METHODS AND RESULTS: VCGs of 624 BV paced electrocardiograms (25 LBBB patients with 35 different pacing configurations) were calculated according to Frank's orthogonal lead system. Maximum QRS vector amplitudes (XAmpl , YAmpl , ZAmpl , and 3DAmp ) and QRS areas (XArea , YArea , ZArea , and 3DArea ) in the orthogonal leads (X, Y, and Z) and in 3-dimensional projection were measured. Volume of the 3D vector loop and global QRS duration (QRSD) on the surface electrocardiogram were assessed. Differences (Δ) in VCG parameters between BV paced and LBBB QRS complexes were calculated. An increase of 10% in dP/dt max was considered as AHR. LBBB conduction is characterized by a large ZArea (109 µVs, interquartile range [IQR]:75;135), significantly larger than XArea (22 µVs, IQR:10;57) and YArea (44 µVs, IQR:32;62, P < 0.001). Overall, QRS duration, amplitudes, and areas decrease significantly with BV pacing (P < 0.001). Of all VCG parameters, 3DAmpl , Δ3DAmpl , ZArea, ΔZArea , Δ3DArea , and ΔQRSD differentiate AHR response from nonresponse (P < 0.05). ΔZArea predicted best positive AHR (area under the curve = 0.813) and outperformed any other VCG parameter or QRSD measurement. CONCLUSION: Of all VCG parameters, reduction in QRS area, calculated in Frank's Z lead, predicts acute hemodynamic response best. This method might be an easy, noninvasive tool to guide CRT implantation and optimization.

The electrocardiographic characteristics of septal flash in patients with left bundle branch block.

AIMS: In patients with systolic heart failure and left bundle branch block (LBBB), septal flash (SF) movement has been described by echocardiography. We evaluated the prevalence of SF in LBBB and non-LBBB patients and evaluated whether specific electrocardiographic (ECG) characteristics within LBBB are associated with the presence of SF on echocardiography. METHODS AND RESULTS: One hundred and four patients with probable LBBB on standard 12-lead ECG were selected, 40 patients with non-LBBB served as controls. Left bundle branch block and non-LBBB were defined, according to the most recent guidelines. The presence of SF was assessed by echocardiography. Strict LBBB criteria were met in 93.3% of the patients. Septal flash was present in 45.2% of LBBB patients and was not present in non-LBBB patients. This was more prevalent in patients without anterior ischaemic cardiomyopathy (ICMP) compared with those with anterior ICMP (P = 0.008). The duration of QRS was longer in SF patients compared with that of non-SF patients (P < 0.05). The presence of a mid-QRS notching in more than two consecutive leads was a good predictor for the presence of SF (P = 0.01), and when combined with an absent R-wave in lead V1, the presence of SF is very likely (P = 0.001). CONCLUSION: Our data show that SF is present in 45.2% of LBBB patients, whereas it was absent in patients with non-LBBB. Patients with SF fulfilled more LBBB criteria compared with LBBB patients without SF. Our findings raise the provocative question of whether the presence of SF identifies patients with 'true LBBB' and whether this echocardiographic finding might be considered as a selection parameter in cardiac resynchronization therapy.

The Pixel Variation Score: An Echocardiographic Index to Assess Temporal Variation of Mitral Regurgitant Flow.

BACKGROUND: In mitral regurgitation (MR), temporal variation of MR flow has been considered an important reason for inaccurate MR grading. Current echocardiographic methods for assessing temporal MR flow variation are complex, and their clinical relevance has not been investigated. In this study, we investigated whether assessing MR flow variation using a dimensionless index with echocardiography is feasible, clinically meaningful, and related to patient outcomes. METHODS: Consecutive patients with mitral valve prolapse (MVP, n = 244) and functional MR (FMR, n = 396) underwent comprehensive echocardiography. Mitral regurgitation severity was assessed using an integrated approach advocated by current guidelines. The MR continuous-wave Doppler envelope was divided into 3 segments of equal duration. Each segment's pixel intensity was assessed to calculate the pixel variation score (PVS). RESULTS: The PVS was lower in FMR patients than in MVP patients. Lower PVS was associated with worse MR, larger left atrial and left ventricular dimensions, lower ejection fraction, and higher pulmonary artery pressures. In MVP, PVS was significantly associated with postoperative left ventricular reverse remodeling and was able to reclassify most patients in whom single-frame measures overestimated MR severity. Finally, PVS had incremental prognostic value on top of clinical and echocardiographic predictors of outcome. CONCLUSIONS: Temporal variation in MR flow can reliably be assessed with echocardiography through analysis of the continuous-wave Doppler signal. A high PVS value may alert the echocardiographer to defer from single-frame MR grading and also suggests that the MR is probably not severe.

Lead performance of stylet-driven leads in left bundle branch area pacing: Results from a large single-center cohort and insights from in vitro bench testing.

BACKGROUND: Left bundle branch area pacing (LBBAP) requires deep septal lead deployment for left-sided conduction stimulation. Advancing leads toward deep septal positions might add mechanical stress on these leads. Concerns about lead performance and reliability remain an unanswered question. OBJECTIVE: The purpose of this study was to analyze lead performance and integrity of stylet-driven pacing leads (SDLs) for LBBAP. METHODS: This study assessed lead fracture rates of SDL in a large single-center cohort of adult LBBAP patients. Fluoroscopic analysis of lead bending angulations at the septal insertion point and in vitro bench testing of lead preconditioning were performed to simulate clinical use conditions. Lead performance was compared between LBBAP and conventional right ventricular apical pacing (RVp) sites. RESULTS: The study included 325 LBBAP patients (66% male; age 71±15 years). During median follow-up of 18 months, 2 patients (0.6%) experienced conductor fracture between tip housing and ring electrode, whereas no such fractures occurred with RVp patients (n = 149; P = .22). X-ray analysis revealed that high lead bending angulations occurred in 1.3% of the patients. Accelerated bench testing of excessive preconditioned leads showcased a higher probability of early conductor fracture compared to standard preconditioned leads. CONCLUSION: The incidence of early conductor failure in LBBAP seems higher than with conventional RVp sites. The most vulnerable lead part seems to be the interelectrode space between the tip housing and ring electrode. Excessive angulation and preconditioning might contribute to early fatigue fracture.

Physiologic effects of dry needling.

During the past decades, worldwide clinical and scientific interest in dry needling (DN) therapy has grown exponentially. Various clinical effects have been credited to dry needling, but rigorous evidence about its potential physiological mechanisms of actions and effects is still lacking. Research identifying these exact mechanisms of dry needling action is sparse and studies performed in an acupuncture setting do not necessarily apply to DN. The studies of potential effects of DN are reviewed in reference to the different aspects involved in the pathophysiology of myofascial triggerpoints: the taut band, local ischemia and hypoxia, peripheral and central sensitization. This article aims to provide the physiotherapist with a greater understanding of the contemporary data available: what effects could be attributed to dry needling and what are their potential underlying mechanisms of action, and also indicate some directions at which future research could be aimed to fill current voids.

Color Doppler Splay in Mitral Regurgitation: Hemodynamic Correlates and Outcomes in a Clinical Cohort.

BACKGROUND: Recently, an artifactual horizontal extension of the color Doppler signal was described in patients with mitral regurgitation (MR), called color Doppler splay (CDS). This side-lobe artifact was shown to be associated with concealed and significant MR. In the present study, the authors assessed the prognostic significance of CDS and its hemodynamic correlates. METHODS: Consecutive patients with primary and secondary MR underwent comprehensive transthoracic echocardiography. Machine settings were fixed for all patients. MR severity was assessed using an integrated approach, as advocated in current international guidelines. The presence of CDS and CDS width and duration were assessed. The outcome measures included the incidence of major adverse cardiac events (a composite of cardiovascular mortality, hospitalization for decompensated heart failure, mitral valve surgery, or percutaneous mitral intervention). RESULTS: One hundred twenty-seven of 469 patients (27%) with MR demonstrated CDS. The presence of CDS was associated with worse MR, and CDS width correlated with effective regurgitant orifice area, regurgitant volume, and vena contracta width. Mitral annular or leaflet calcification was inversely associated with the presence of CDS. Patients with CDS experienced worse event-free survival. For CDS width, a cutoff of >29 mm was identified as optimal regarding outcome prediction in our cohort and termed "severe CDS." In multivariate Cox regression, the presence of severe CDS was associated with adverse outcome, independent of MR etiology or severity and other clinical and echocardiographic predictors of outcome, and provided incremental prognostic value on top of these parameters. CONCLUSIONS: In patients with MR, the presence of CDS is associated with more severe MR and worse outcomes. Severe CDS provides incremental prognostic value on top of traditional MR metrics and should alert the echocardiographer that MR severity may be underestimated.

An Electrocardiographic Characterization of Left Bundle Branch Area Pacing-Induced Right Ventricular Activation Delay: A Comparison With Native Right Bundle Branch Block.

Background: Left bundle branch area pacing (LBBAP) induces delayed RV activation and is thought to be harmless, since the electrocardiographic signature is reminiscent to native RBBB. However, to what extent the delayed RV activation during LBBAP truly resembles that of native RBBB remains unexplored. Methods: This study included patients with incomplete RBBB (iRBBB), complete RBBB (cRBBB) and patients who underwent LBBAP. Global and right ventricular activation times were estimated by QRS duration and R wave peak time in lead V1 (V1RWPT) respectively. Delayed RV activation was further characterized by duration, amplitude and area of the terminal R wave in V1. Results: In patients with LBBAP (n = 86), QRS duration [120 ms (116, 132)] was longer compared to iRBBB patients (n = 422): 104 ms (98, 110), p < 0.001, but shorter compared to cRBBB (n = 223): 138 ms (130, 152), p < 0.001. V1RWPT during LBBAP [84 ms (72, 92)] was longer compared to iRBBB [74 ms (68, 80), p < 0.001], but shorter than cRBBB [96 ms (86, 108), p < 0.001]. LBBAP resulted in V1 R' durations [42 ms (28, 55)] comparable to iRBBB [42 ms (35, 49), p = 0.49] but shorter than in cRBBB [81 ms (68, 91), p < 0.001]. During LBBAP, the amplitude and area of the V1 R' wave were more comparable with iRBBB than cRBBB. V1RWPT during LBBAP was determined by baseline conduction disease, but not by LBBAP capture type. Conclusion: LBBAP-induced delayed RV activation electrocardiographically most closely mirrors the delayed RV activation as seen with incomplete rather than complete RBBB.

Clinical and Experimental Evidence for a Strain-Based Classification of Left Bundle Branch Block-Induced Cardiac Remodeling.

BACKGROUND: Septal strain patterns measured by echocardiography reflect the severity of left bundle branch block (LBBB)-induced left ventricular (LV) dysfunction. We investigated whether these LBBB strain stages predicted the response to cardiac resynchronization therapy in an observational study and developed a sheep model of LBBB-induced cardiomyopathy. METHODS: The clinical study enrolled cardiac resynchronization therapy patients who underwent echocardiographic examination with speckle-tracking strain analysis before cardiac resynchronization therapy implant. In an experimental sheep model with pacing-induced dyssynchrony, LV remodeling and strain were assessed at baseline, at 8 and 16 weeks. Septal strain curves were classified into 5 patterns (LBBB-0 to LBBB-4). RESULTS: The clinical study involved 250 patients (age 65 [58; 72] years; 79% men; 89% LBBB) with a median LV ejection fraction of 25 [21; 30]%. Across the stages, cardiac resynchronization therapy resulted in a gradual volumetric response, ranging from no response in LBBB-0 patients (ΔLV end-systolic volume 0 [-12; 15]%) to super-response in LBBB-4 patients (ΔLV end-systolic volume -44 [-64; -18]%) (P<0.001). LBBB-0 patients had a less favorable long-term outcome compared with those in stage LBBB≥1 (log-rank P=0.003). In 13 sheep, acute right ventricular pacing resulted in LBBB-1 (23%) and LBBB-2 (77%) patterns. Over the course of 8-16 weeks, continued pacing resulted in progressive LBBB-induced dysfunction, coincident with a transition to advanced strain patterns (92% LBBB-2 and 8% LBBB-3 at week 8; 75% LBBB-3 and 25% LBBB-4 at week 16) (P=0.023). CONCLUSIONS: The strain-based LBBB classification reflects a pathophysiological continuum of LBBB-induced remodeling over time and is associated with the extent of reverse remodeling in observational cardiac resynchronization therapy-eligible patients.

Generation of T cells from human embryonic stem cell-derived hematopoietic zones.

Human embryonic stem cells (hESC) are pluripotent stem cells. A major challenge in the field of hESC is the establishment of specific differentiation protocols that drives hESC down a particular lineage fate. So far, attempts to generate T cells from hESC in vitro were unsuccessful. In this study, we show that T cells can be generated in vitro from hESC-derived hematopoietic precursor cells present in hematopoietic zones (HZs). These zones are morphologically similar to blood islands during embryonic development, and are formed when hESC are cultured on OP9 stromal cells. Upon subsequent transfer of these HZs on OP9 cells expressing high levels of Delta-like 1 and in the presence of growth factors, cells expand and differentiate to T cells. Furthermore, we show that T cells derive exclusively from a CD34(high)CD43(low) population, further substantiating the notion that hESC-derived CD34(high)CD43(low) cells are formed in HZs and are the only population containing multipotent hematopoietic precursor cells. Differentiation to T cells sequentially passes through the physiological intermediates: CD34(+)CD7(+) T/NK committed, CD7(+)CD4(+)CD8(-) immature single positive, CD4(+)CD8(+) double positive, and finally CD3(+)CD1(-)CD27(+) mature T cell stages. TCRalphabeta(+) and TCRgammadelta(+) T cells are generated. Mature T cells are polyclonal, proliferate, and secrete cytokines in response to mitogens. This protocol for the de novo generation of T cells from hESC could be clinically and scientifically relevant.