Electrical Delay Research Articles

Macrophages enhance sodium channel expression in cardiomyocytes.

Cardiac macrophages facilitate electrical conduction through the atrioventricular-node (AV) in mice. A possible role for cardiomyocyte-macrophage coupling on the effect of antiarrhythmic therapy has not been investigated yet. Holter monitoring was conducted in LysMCrexCsf1rLsL-DTR mice (MMDTR) under baseline conditions and after an elctrophysiological stress test by flecainide. In vivo effects were recapitulated in vitro by patch-clamp experiments. The underlying mechanism was characterized by expression and localization analysis of connexin43 (Cx43) and voltage-gated-sodium-channel-5 (Nav1.5). ECG monitoring in MMDTR mice did not show any significant conduction abnormalities but a significantly attenuated flecainide-induced extension of RR- and PP-intervals. Patch-clamp analysis revealed that the application of flecainide to neonatal rat ventricular cardiomyocytes (CMs) changed their resting-membrane-potential (RMP) to more negative potentials and decreased action-potential-duration (APD50). Coupling of macrophages to CMs significantly enhances the effects of flecainide, with a further reduction of the RMP and APD50, mediated by an upregulation of Cx43 and Nav1.5 surface expression. Macrophage depletion in mice does not correlate with cardiac electric conduction delay. Cardiac macrophages amplify the effects of flecainide on electrophysiological properties of cardiomyocytes in vivo and in vitro. Mechanistically, formation of macrophage-cardiomyocyte cell-cell-contacts via Cx43 facilitates the recruitment of Nav1.5 to the cell membrane increasing flecainide effects.

Multipoint pacing is associated with improved prognosis and cardiac resynchronization therapy response. MORE-CRT MPP randomized study secondary analyses.

Cardiac resynchronization therapy (CRT) via biventricular (BIV) pacing is indicated in patients with heart failure (HF), reduced ejection fraction and prolonged QRS duration. Quadripolar leads and MultiPoint Pacing (MPP) allow multiple left ventricle (LV) sites pacing. We aimed to assess clinical benefit of MPP in patients who do not respond to standard BIV pacing. Overall 3724 patients were treated with standard BIV pacing. After 6 months, 1639 patients were considered as CRT non-responders (echo-measured relative reduction in LV end-systolic volume (LVESV) < 15%) and randomized to MPP or BIV. We analysed 593 randomized patients (291 MPP, 302 BIV), who had BIV pacing >97% of time before randomization and complete 12-months clinical and echocardiographic data. The endpoint, composed by freedom from cardiac death and HF hospitalizations, and by LVESV relative reduction ≥15% between randomization and 12 months, occurred more frequently in MPP (96/291 (33.0%)) vs. BIV (71/302 (23.5%), p = 0.0103), also confirmed at multivariate analysis (hazard ratio = 1.55, 95% confidence interval = 1.02-2.34, p = 0.0402 vs. BIV). HF hospitalizations occurred less frequently in MPP (14/291 (4.81%)) vs. BIV (29/302 (9.60%), incidence rate ratio = 50%, p = 0.0245). Selecting patients with large (>30 ms) dispersion of interventricular electrical delay among the 4 LV lead dipoles, reverse remodeling was more frequent in MPP (18/51 (35.3%)) vs. BIV (11/62 (17.7%), p = 0.0335). In patients who do not respond to standard CRT, despite high BIV pacing percentage, MPP is associated with lower occurrence of HF hospitalizations and higher probability of reverse LV remodeling, compared with BIV pacing.

Characterization of cardiac resynchronization therapy response through machine learning and personalized models

Introduction: The characterization and selection of heart failure (HF) patients for cardiac resynchronization therapy (CRT) remain challenging, with around 30% non-responder rate despite following current guidelines. This study aims to propose a novel hybrid approach, integrating machine-learning and personalized models, to identify explainable phenogroups of HF patients and predict their CRT response. Methods:The paper proposes the creation of a complete personalized model population based on preoperative CRT patient strain curves. Based on the parameters and features extracted from these personalized models, phenotypes of patients are identified thanks to a clustering algorithm and a random forest classification is provided. Results:A close match was observed between the 162 experimental and simulated myocardial strain curves, with a mean RMSE of 4.48% (±1.08) for the 162 patients. Five phenogroups of personalized models were identified from the clustering, with response rates ranging from 52% to 94%. The classification results show a mean area under the curves (AUC) of 0.86 ± 0.06 and provided a feature importance analysis with 22 features selected. Results show both regional myocardial contractility (from 22.5% to 33.0%), tissue viability and electrical activation delays importance on CRT response for each HF patient (from 55.8 ms to 88.4 ms). Discussion:The patient-specific model parameters’ analysis provides an explainable interpretation of HF patient phenogroups in relation to physiological mechanisms that seem predictive of the CRT response. These novel combined approaches appear as promising tools to improve understanding of LV mechanical dyssynchrony for HF patient characterization and CRT selection.

Selection of candidates for cardiac resynchronization therapy and implantation management: an Italian survey promoted by the Italian Association of Arrhythmology and Cardiac Pacing.

Cardiac resynchronization therapy (CRT) represents an effective heart failure treatment, associated with reduction in mortality and heart failure hospitalizations. This Italian survey aimed to address relevant CRT issues. An online survey was administered to AIAC members. One hundred and five electrophysiologists participated, with a median of 40 (23-70) CRT implantations/year (33% in high-volume centres). Forty-five percent of respondents (especially working in high-volume centres) reported an increase in CRT implantations in the last 2 years, in 16% a decrease, and in 38% CRT remained stable. Seventy-five percent of respondents implanted CRT only in patients with European Heart Rhythm Association (EHRA) class I indications. All operators collected ECG and echocardiography before implantation. Eighty-five percent of respondents selected coronary sinus target vein empirically, whereas 10% used mechanical and/or electrical delay techniques. Physicians working in high-volume centres reported a lower failure rate compared with others (16 vs. 34%; P = 0.03). If the coronary sinus lead could not be positioned in the target branch, 80% placed it in another vein, whereas 16% opted for a surgical approach or for conduction system pacing (CSP). Eighty percent accomplished CRT optimization in all patients, 17% only in nonresponders. Regarding anticoagulation, high agreement with EHRA guidelines emerged. CRT represents a valid therapeutic option in heart failure treatment. Nowadays, CRT implantations remain stable and are mainly performed in patients with class I indications. ECG remains the preferred tool for patient selection, whereas imaging is increasingly used to determine the left pacing target area. In most patients, the left ventricular lead can be successfully positioned in the target vein, but in some cases, the result can be unsatisfactory; however, the decision to explore alternative resynchronization approaches is rarely pursued.

The role of atrial pacing site in reducing filling pressures by accelerated pacing in virtual HFpEF patients

Abstract Background Patients with heart failure with preserved ejection fraction (HFpEF) and pacemakers have been shown to benefit from moderately accelerated pacing rates compared to the standard 60bpm. HFpEF patients often present with prolonged P-wave duration (PWD) and atrial fibrillation. Right atrial appendage pacing (RAAP) lengthens PWD, RA septal (RASP) has a neutral effect, while Bachmann’s bundle pacing (BBP) normalizes or shortens PWD compared to sinus rhythm. The mechanical and hemodynamic effects of atrial pacing site selection remain unknown. Aim To investigate the impact of RAAP, RASP and BBP on cardiac mechanics and hemodynamics in an established cohort of virtual HFpEF patients undergoing accelerated pacing. Method HFpEF with prolonged PWD was simulated using the validated CircAdapt computational model of the human cardiovascular system. First, left ventricular (LV) diastolic dysfunction was simulated by decreasing LV myocardial relaxation rate and compliance, such that mean left atrial (LA) pressure (mLAP) was 15mmHg. Second, PWD was prolonged by prescribing a gradual electrical activation delay from RA to LA of 140ms. We then simulated atrial pacing with three different lead positions (Fig.1, left) and gradually increased pacing rate with a constant 120-ms paced atrioventricular (AV) delay. The CircAdapt model computed regional LA strain and mLAP with RAAP, RASP, and BBP. Cardiac output (5L/min) and mean arterial pressure (92mmHg) were kept constant in all simulations. Results Simulated BBP demonstrated the most synchronous LA mechanical activation and function, characterized by uniform segmental LA strain patterns and highest LA reservoir strain (LASR) (Fig.1, middle, with colored arrows highlighting the mechanical dyssynchrony). Hemodynamically (Fig.1, right), BBP acutely decreased mLAP (-1.0mmHg) at the initial heart rate of 60bpm, while RAAP increased it (+0.3mmHg). As pacing rate accelerated, BBP reduces filling pressure (mLAP: -2.8mmHg), more than RASP (-1.8mmHg) or RAAP (-1.2mmHg) at 80bpm. At high pacing rates, RASP and RAAP adversely increase mLAP, due to the prolonged atrial contraction duration and shorter LV filling time. Conclusion Our simulations of different atrial pacing sites in virtual HFpEF patients suggest that BBP yields the most synchronous LA activation pattern and a more substantial reduction in filling pressures with accelerated atrial pacing compared to RASP. Reduction in mLAP with accelerated pacing was attenuated with RAAP. While our study concentrated on a specific paced AV interval, the favorable outcomes observed with BBP could be further improved by including different, rate-adaptive, AV protocols.Fig 1.

Atrioventricular optimization improves cardiac resynchronization response in patients with long interventricular electrical delays: A pooled analysis of the SMART-AV and SMART-CRT trials

BackgroundThe utility of atrioventricular (AV) optimization (AVO) algorithms remains in question. A substudy of the SMART-AV trial found that patients with prolonged interventricular delays ≥70 ms were more likely to benefit from cardiac resynchronization therapy (CRT) with AVO. The SMART-CRT trial evaluated AVO on the basis of these results, but the study was underpowered. ObjectiveTo increase statistical power, data from SMART-AV patients meeting the inclusion criterion of interventricular delay ≥70 ms were pooled with data from SMART-CRT to reassess AVO. MethodsSMART-CRT and SMART-AV were prospective, randomized, multicenter clinical trials. Patients in both studies were randomized to be programmed with an AVO algorithm (SmartDelay) or fixed AV delay (120 ms). Paired echocardiograms obtained at baseline and 6 months were compared, with CRT response defined as ≥15% reduction in left ventricular end-systolic volume. ResultsA total of 451 complete patient data sets were pooled and analyzed. The baseline demographics between studies did not differ statistically in terms of age, sex, left ventricular ejection fraction, or left ventricular end-systolic volume. The AVO group had a greater proportion of CRT responders (SmartDelay, 73.9%; fixed, 63.1%; P = .014) and greater changes in measures of reverse remodeling. SmartDelay patients with a recommended sensed AV delay outside the nominal range (100–120 ms) had 2.3 greater odds of CRT response than fixed AV delay patients. ConclusionGreater CRT response and measures of reverse remodeling were observed in patients with SmartDelay enabled vs a fixed AV delay. This study supports the use of SmartDelay in patients with a CRT indication and interventricular delay ≥70 ms.

Changes in electrical delay is associated with the hemodynamic response to cardiac pacing

Changes in electrical delay is associated with the hemodynamic response to cardiac pacing

Broadband Beam-Scanning Phased Array Based on Microwave Photonics

A one-dimensional active broadband phased array based on microwave photonics that works in the Ku band is proposed to achieve a large instantaneous bandwidth. The phased array uses a feeding network based on microwave photonics to provide the true time delay and a wide operating bandwidth. The array is mainly composed of a broadband horn antenna, an RF transmitting/receiving module, an optical network module, and a temperature control module. The form of a horn was selected for the antenna unit, and it was fed through a waveguide to obtain a wide operating bandwidth. An optical fiber delay line that could realize the true time delay at different frequencies was adopted for the time-delay module of the optical network. To obtain a large time delay and small quantization error, a hybrid time-delay diagram utilizing electrical and optical time delays was used in the design. In addition, a temperature control module was added to the antenna system to enhance the stability of the photonic time-delay module. For verification, a prototype of the presented antenna system was designed, fabricated, and measured. The experimental results showed that the optical phased array antenna was able to scan ±20° from 12 GHz to 17 GHz, and the beam pointing did not appear to be offset over the wide operating bandwidth.

Influence of molecular orientation on the photodissociation process of LiH molecules

AbstractRegulation of photodissociation dynamics of oriented LiH molecules in different dissociation channels is proposed based on time dependent quantum wave packet theory. The enhancement of molecular orientation on the photodissociation of LiH is obvious with our theoretical scheme. The results show that the molecular orientation in the ground state has a great effect on the angular distributions of wave packets. By using the proper laser pulses and controlling the polarization direction of the laser pulses, the enhancement of the photodissociation could be realized. After the molecular orientation, an optimal dissociation channel is observed with an improved dissociation probability. Compared with the results without molecular orientation, the maximal dissociation probability is increased by 8.1% in the indirect dissociation channel and 30.7% in the direct dissociation channel. The enhancement effect is more obvious in the direct dissociation channel, which provides a possible method to manipulate the dissociation of LiH molecules experimentally. Additionally, the photodissociation process of LiH also relies on the electric intensity and delay time of two pump pulses.

Research on SiC Speed Controller for High‐Voltage Distributed Electric Propulsion System

The shift towards green aviation necessitates the adoption of all‐electric aircraft, marking an essential trend in the aviation industry. Distributed propulsion systems enhance aircraft flexibility and reliability, synchronously reducing performance demands and costs of single propulsion units compared to centralized propulsion system. The high reliability and lightweight characteristics of brushless DC motors have made them increasingly popular in distributed propulsion systems. Despite its advantage which helps to build efficient aircraft aerodynamic layout, there are more cables in the distributed propulsion system, which accounts for most of the weight of the aircraft. To address this, all‐electric aircraft utilizes high‐voltage power supply to reduce the current, so it uses SiC MOSFETs as power devices to improve its efficiency and heat dissipation. The speed controller in all‐electric aircraft determines the efficiency and reliability of the propulsion unit. However, the traditional high‐voltage speed controller poses challenges for aircraft maintenance because of high cost. Therefore, this paper emphasizes the significance of designing a low‐cost, high‐performance speed controller for all‐electric aircraft. Challenges such as circuit interference, battery voltage fluctuation, and sampling noise affecting the high‐voltage controller during operation are solved, respectively. First, to address the likelihood of mutual interference in the bridge arm, a self‐bootstrapping voltage reduction drive mode is designed to turn off SiC MOSFET and enhance circuit anti‐interference. Second, to solve the challenge of wide battery voltage fluctuation range and inconsistent controller output, an adaptive pulse width modulation (PWM) regulation mode for battery voltage is proposed, ensuring stable controller output. Finally, to counteract the impact of the comparator threshold on zero‐crossing sampling, an electrical angle delay method based on delay compensation is designed to improve the efficiency of the brushless DC motor during operation. Experimental results show that the three solutions proposed in this paper are helpful to improve the anti‐interference, stability, and efficiency of the controller in the high‐voltage distributed electric propulsion system and contribute to reduce the cost and weight in the propulsion unit.

Electrical or structural delay?

Electrical or structural delay?

The predictive role of left ventricular cathode topography relative to CMR-determined latest mechanical activation and scar segments on response to cardiac resynchronisation therapy

Abstract Background Cardiac resynchronisation therapy (CRT) is still burdened by considerable rates of non-response. Herein left ventricular cathode (LVC) positioning has the greatest room for optimisation. Nonetheless, a purely CMR-based approach exploring LVC topography relative to both mechanical delay and tissue viability is yet to be investigated. Purpose To retrospectively analyse the effect on reverse remodelling of CMR-determined LVC topography relative to latest mechanical activation (LMA) and scar segments in a CRT population. Methods This is a retrospective single-centre analysis of 104 CRT-D/P consecutive patients with CMR performed within 6 months before implantation. Electrical delay (Q-LV time) was mapped on all suitable veins with LV lead positioning and cathode programming set in the region of latest electrical activation. Through CART-Tech® software analysis of CMR images, 36-segment 3D anatomical models of radial strain and scar were superimposed on their corresponding fluoroscopy images (Figure 1). Patients were then stratified based on LVC concordance (within), semi-concordance (adjacent) or non-concordance (at least one segment away) with LMA and scar segments (defined as segments with &amp;gt;50% scar transmurality). Follow-up echocardiography was performed at least 6 months after implantation and the degree of reverse remodelling expressed as percentage reduction in end-systolic volume (ESV). Results Of the 104 patients, 36 were excluded due to suboptimal CMR quality (8), switch to conduction system pacing (5), loss to follow-up (18) or death within 6 months of implantation (5), leaving a total of 68 (63 CRT-D and 5 CRT-P). LVC concordance with LMA was associated with a statistically significant improvement in reverse remodelling (Figure 2, A), while the contrary occurred with regards to scar (Figure 2, B). A greater impact of distance from scar compared to LMA proximity was observed, thus a combined analysis of LVC topography relative to both was developed accordingly. Patients were stratified into 4 categories of LVC optimality: optimal (LVC-LMA concordance + LVC-scar non-concordance), semi-optimal (LVC-LMA semi-concordance + LVC-scar non-concordance), suboptimal (LVC-LMA non-concordance + LVC-scar non-concordance), and unfavourable (LVC-scar semi-concordance or concordance regardless of LVC-LMA). The unfavourable group had higher rates of atrial fibrillation, non-LBBB QRS morphology and higher scar burden, while no significant differences were observed in the other 3 groups. This classification appears to predict the degree of reverse remodelling, ESV reduction being more pronounced the more optimal the group (Figure 2, C). Conclusions CMR-determined LVC topography relative to LMA and scar segments predicts left ventricular reverse remodelling in Q-LV-guided CRT implants. Optimisation of CRT response may thus benefit from a CMR-based approach assessing mechanical delay and tissue viability to guide LVC positioning.Figure 1Figure 2

Abstract 13542: Electrical Delay, LA Electromechanical Delay, and LA Volume Contribute to Increased LA Stiffness in Relatively Elderly Patients With Pulmonary Vein Isolation for Atrial Fibrillation

Background: Atrial dysfunction occurs after pulmonary vein isolation (PVI) for atrial fibrillation (AF), and some reports suggest that electrical conduction delay (ECD) via the Bachmann bundle could be a contributing factor. However, the relationship between ECD in the atria and LA function after PVI remains unclear. The LA reservoir strain (LARS) by speckle-tracking echocardiography (STE) is used to assess LA booster function, with a decrease indicating increased LA stiffness. Purpose: We aim to investigate ECD, LA electromechanical delay (LAEMD), and LA function in patients after PVI for AF. Methods: This single-center retrospective study included 74 patients (Mean age at 70.4 ± 9.1 years, 44 males, left ventricular ejection fraction (LVEF): 62.9 ± 6.8 %, LA volume index: LAVI 39.0 ± 10.8 ml/m 2 ) who were in sinus rhythm at the echocardiographic examination. ECD on the ECG was defined as the presence of biphasic P waves, which were classified into those not observed (group A; n=42), those observed only in III lead (group B; n=23), and those observed in all lower wall leads (II, III, aVF) (group C; n=9). LAEMD was defined as the time interval between the top of the R wave on the ECG and the start of the late diastolic wave (a') on the tissue doppler imaging, and the lateral (a' lateral) and septum (a' septum) time differences (a’ sep-lat time) were calculated. To evaluate the LA function, two-dimensional STE was analyzed. Results: Mean observation period was 19.2 months after PVI. Groups B and C showed significant differences in a' sep-lat time compared to group A. LARS was markedly reduced in all groups (average: 19.0 ± 6.3). LARS and LAVI showed a significant difference between groups A and C. Multivariate analysis of factors leading to LARS showed correlations with a', E/e'. Conclusion: These results suggest that in relatively elderly post-PVI AF patients with preserved LVEF, the ECD and LAEMD as well as LAVI may affect LA function long after PVI and contribute to increased LA stiffness.

Abstract 18337: Myocardial Work - A Novel Approach to Investigate the Effects of Right Ventricular Apical Pacing on Left Ventricular Regional Work and Function

Background: Right ventricular pacing (RVp) is the most common method of delivering bradycardia pacing, but it is associated with left ventricular (LV) systolic dysfunction (LVSD) in 40% of patients. Animal models have shown that RVp-induced electrical conduction delay leads to dyssynchronous LV activation, resulting in uneven myocardial work (MW) distribution. This work redistribution is believed to trigger adaptive structural remodelling, aiming to achieve a more uniform LV load distribution. Cardiac resynchronisation therapy (CRT) responders demonstrate normalised MW distribution and baseline constructive MW measurements may predict CRT response. However, there is limited evidence on MW in patients with pacemakers. Hypothesis: Long-term RVp in atrioventricular block (AVB) patients with pacemakers may influence MW. Method and Results: One hundred and eighteen patients (mean age 75±10 years; 69% male) with AVB receiving pacemaker therapy were included. Echocardiographic assessment and MW calculations were performed pre- and post-implant. LVSD was defined as LVEF &lt;50%. Among patients, 33 (28%) had LVSD at follow-up (mean time 26±19 months). RVp significantly influenced LVEF (F (1, 18) = 1193, p &lt;0.001), while MW changes were evaluated using repeated measures ANOVA. Constructive work showed a significant interaction effect at the septal wall (F (1, 21) = 8.57, p = 0.008), with no changes observed at the lateral wall (F (1, 51) = 0.93, p = 0.35). However, wasted work exhibited significant interaction effects at both the septal and lateral walls (F (1, 21) = 16.30, p &lt;0.001 vs. F (1, 51) = 7.10, p = 0.014, respectively) (Figure 1). Conclusion: Constructive and wasted work measures at septal and lateral walls are associated with LVSD in patients receiving a pacemaker for AVB. MW may add additional predictive value in identifying people at risk of developing RVp-associated LVSD who may benefit from more complex device therapy such as conduction system pacing, or CRT.

Implications of ventricular arrhythmia after cardiac resynchronization therapy

Conflicting data are available on whether ventricular arrhythmia (VA) or shock therapy increases mortality. Although cardiac resynchronization therapy (CRT) reduces the risk of VA, little is known about the prognostic value of VA among patients with CRT devices. The purpose of this study was to evaluate the implications of VA as a prognostic marker for CRT. We investigated 330 CRT patients within 1 year after CRT device implantation. The primary endpoint was the composite endpoint of all-cause death or hospitalization for heart failure. Forty-three patients had VA events. These patients had a significantly higher risk of the primary endpoint, even among CRT responders (P = .009). Fast VA compared to slow VA was associated with an increased risk of the primary endpoint (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.06-4.34; P = .035). Shock therapy was not associated with a primary endpoint (shock therapy vs antitachycardia pacing: HR 1.49; 95% CI 0.73-3.03; P = .269). The patients with VA had a lower prevalence of response to CRT (23 [53%] vs 202 [70%]; P = .031) and longer left ventricular paced conduction time (174 ± 23 ms vs 143 ± 36 ms; P = .003) than the patients without VA. VA occurrence within 1 year was related to paced electrical delay and poor response to CRT. VA could be associated with poor prognosis among CRT patients.

Characterisation of responder profiles for cardiac resynchronisation therapy based on explainable machine-learning and virtual patient approaches

Abstract Funding Acknowledgements Type of funding sources: None. Context Cardiac resynchronisation therapy (CRT) is an implant-based therapy applied to patients with a specific heart failure (HF) profile. The characterisation and identification of CRT candidates is challenging since the application of current guidelines still induces a non-responder rate of about 30%. Recently, the assessment of left ventricular mechanics by speckle tracking echocardiography has been shown to provide useful information for patient’s selection. However, the interpretation of stain curves remains difficult due to the great heterogeneities in dyssynchrony patterns. The objective of this study is to propose a characterisation of HF patient profiles considering their responses to CRT, based on unsupervised machine-learning and virtual patient approaches. Methods The prospective database includes 250 patients. Before implantation of CRT, transthoracic echocardiography were performed in order to extract regional myocardial longitudinal strain curves. At 6-month follow-up, response to CRT were defined as 15 % decrease in LV end-systolic volume. Feature extraction was performed from clinical, electrocardiographic, and echocardiographic data, leading to a set of 70 features per patient. The set of all features was clustered by applying the K-Means method. Virtual patients were defined from patient-specific computational models for patients associated with the barycenter of each cluster. The proposed model includes the cardiac electrical system, right and left atria, multi-segment representation of the right and left ventricles, systemic and pulmonary circulations. Contractility, stiffness and electrical activation delays are identified from each virtual patient and each LV cardiac segment. Results Five clusters were identified from clinical, original and classical echocardiographic features with response rates ranging from 50% to 93%. Virtual patients were defined for the 5 patients associated with each cluster barycenter visualised by a principal component analysis. Patient-specific simulated strain curves were provided for the 16 LV segments of these 5 patients. A close match was observed between experimental and simulated curves pattern. The mean RMSE on the five patients is 3.97% ± 1.74. Cluster 1 and 2, which are the two groups with below-average rate, are associated with low contractility of myocardial segments. The other clusters with normal or elevated response rates present higher contractility and delayed electrical activation of the lateral wall. Conclusions A new pipeline, combining personalised cardiovascular modelling and unsupervised machine-learning algorithms, was proposed to provide a phenotyping of HF patient profiles in the context of CRT. This novel approach appears a promising tool to improve understanding of LV mechanics, patient characterisation and selection before CRT.

Transcranial Focal Electric Stimulation Avoids P-Glycoprotein Over-Expression during Electrical Amygdala Kindling and Delays Epileptogenesis in Rats.

Recent evidence suggests that P-glycoprotein (P-gp) overexpression mediates hyperexcitability and is associated with epileptogenesis. Transcranial focal electrical stimulation (TFS) delays epileptogenesis and inhibits P-gp overexpression after a generalized seizure. Here, first we measured P-gp expression during epileptogenesis and second, we assessed if TFS antiepileptogenic effect was related with P-gp overexpression avoidance. Male Wistar rats were implanted in right basolateral amygdala and stimulated daily for electrical amygdala kindling (EAK), P-gp expression was assessed during epileptogenesis in relevant brain areas. Stage I group showed 85% increase in P-gp in ipsilateral hippocampus (p < 0.001). Stage III group presented 58% and 57% increase in P-gp in both hippocampi (p < 0.05). Kindled group had 92% and 90% increase in P-gp in both hippocampi (p < 0.01), and 93% and 143% increase in both neocortices (p < 0.01). For the second experiment, TFS was administrated daily after each EAK stimulation for 20 days and P-gp concentration was assessed. No changes were found in the TFS group (p > 0.05). Kindled group showed 132% and 138% increase in P-gp in both hippocampi (p < 0.001) and 51% and 92% increase in both cortices (p < 0.001). Kindled + TFS group presented no changes (p > 0.05). Our experiments revealed that progression of EAK is associated with increased P-gp expression. These changes are structure-specific and dependent on seizure severity. EAK-induced P-gp overexpression would be associated with neuronal hyperexcitability and thus, epileptogenesis. P-gp could be a novel therapeutical target to avoid epileptogenesis. In accordance with this, TFS inhibited P-gp overexpression and interfered with EAK. An important limitation of the present study is that P-gp neuronal expression was not evaluated under the different experimental conditions. Future studies should be carried out to determine P-gp neuronal overexpression in hyperexcitable networks during epileptogenesis. The TFS-induced lessening of P-gp overexpression could be a novel therapeutical strategy to avoid epileptogenesis in high-risk patients.

The last shall be the first: the role of combined QLV- and CMR-determined electromechanical concordance in predicting optimal left ventricular stimulation site in cardiac resynchronisation therapy

Abstract Funding Acknowledgements Type of funding sources: None. Background/introduction Optimisation of cardiac resynchronisation therapy (CRT) response still represents a significant challenge to cardiac electrophysiology. In this regard, perhaps the area of greatest uncertainty revolves around optimal left ventricular lead (LVL) position and in particular whether this should be directed at areas of latest electrical or mechanical activation given the equivocal evidence on their precise relationship in heart failure (HF) patients. Furthermore, while echocardiography has demonstrated that LVL aimed at regions of greatest mechanical delay maximises CRT response, cardiac magnetic resonance (CMR) with its greater spatial resolution and tissue definition is yet to demonstrate a role in doing so. Purpose To retrospectively evaluate concordance between latest electrical and CMR-determined mechanical activation in a CRT population and its relationship with reverse remodeling. Methods This is a retrospective single center analysis of 104 CRT patients. All patients had CMR and echocardiography performed before implantation. During implantation, coronary sinus angiogram was performed and electrical delay (QLV time with RV-LV time greater than 80 ms) was mapped on all veins suitable for lead implantation and LVL was positioned in the region of latest electrical activation programming LVL cathode accordingly. LVL cathode position was thus assumed to represent the region of latest electrical delay. A post-hoc analysis was then conducted by means of CART-Tech® software providing radial strain and scar maps on a 36-segment anatomical model. Patients were then stratified based on concordance between LVL cathode position (using 3D heart models superimposed on 2D angiography images) and most mechanically delayed segments (either the three most delayed segments or adjacent ones) or non concordance (one or more segments between LVL cathode and three most mechanically delayed segments). Data from patient follow-up was collected with echocardiography at least 3 months after implant date. CRT response was expressed as reduction in end-systolic volume (ESV) greater than 15%. Results A preliminary analysis of the first 30 patients of our cohort was conducted. Electromechanical concordance and non-concordance were present in 24 and 6 patients, respectively. Baseline patient characteristics including demographics, comorbidities, HF aetiology, ECG and echocardiography features were comparable between groups except for scar burden, which was higher in the non-concordance group. Response to CRT was 80% in the concordant vs. 20% in the non-concordant group. Conclusions While a confounding effect of scar burden cannot be excluded, these preliminary data suggest that electromechanical concordance in LVL cathode placement may represent a predictor of optimal CRT response. The full scope of this study will be fully appreciated in the coming month on completion of analysis of the entire patient cohort.

Prevalence and prognostic value of ventricular conduction delay in heart failure with preserved ejection fraction

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation; Health Foundation Limburg Background The pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF) is heterogeneous and incompletely understood. Identifying phenotypes of HFpEF is a promising approach to determine the underlying pathophysiological mechanisms and to improve treatment. Patients with electrical ventricular conduction delay (VCD) may represent a separate phenotype. Objectives To identify a VCD phenotype in HFpEF through assessment of QRS duration and vectorcardiographic QRS area. Moreover, to determine how differences in these VCD indices relate to adverse outcomes. Methods Consecutive patients underwent a comprehensive diagnostic work-up at baseline and were diagnosed with HFpEF. Baseline QRS duration was obtained clinically from a standard 12-leads electrocardiography (ECG). QRS area was derived from vectorcardiography analyses of the baseline ECG. Presence of VCD was categorically defined as QRS duration ≥120ms or QRS area ≥69µVs. Adverse outcome comprised a composite of HF hospitalization and cardiovascular mortality. Patients with cardiac devices before and up until one year after baseline were excluded in prognostic analyses. Results From a total of 346 HFpEF patients included in this study, 71.3% had a QRS duration &amp;lt;100ms compared to 20.1% with QRS duration 100-119ms and 8.6% with QRS duration ≥120ms. Only 3.8% of all patients had a QRS area ≥69µVs, indicating delayed left ventricular lateral wall activation. A history of coronary artery disease was more prevalent in patients with higher QRS duration or larger QRS area. Sex differences were mainly found in those with a QRS duration ≥100ms, which was present in 54.8% of all males and 17.5% of all females. After a median of 2 years follow-up, 16.4% of the patients had an adverse outcome. Longer QRS duration but not larger QRS area was associated with more adverse outcomes on a categorical scale (Figure). In multivariable Cox-regression analyses adjusted for sex and age, QRS duration was an independent predictor of adverse outcomes (hazard ratio per 1ms increase = 1.017, 95% confidence interval 1.004-1.030, P = 0.012) (Table). Conclusion HFpEF patients have a low prevalence of a VCD phenotype, 8.6% have a QRS duration ≥120ms and 3.8% a QRS area ≥69µVs. However, QRS duration &amp;gt;100ms was an independent predictor for adverse outcomes. Thus, future efforts are warranted to understand the biologic and mechanical mechanisms underlying the association of QRS duration and adverse outcomes, and to determine its clinical implications.

Effects of Atrioventricular Optimization on Left Ventricular Reverse Remodeling With Cardiac Resynchronization Therapy: Results of the SMART-CRT Trial.

The role of atrioventricular optimization (AVO) to improve cardiac resynchronization therapy outcomes remains controversial. Previous post hoc analyses of a multicenter trial showed that measures of electrical dyssynchrony (right ventricular-left ventricular [LV] or QLV durations) are associated with patients who benefit from AVO. This was a global, multicenter, prospective, randomized trial of de novo cardiac resynchronization therapy implant patients with an right ventricular-LV duration ≥70 ms to determine whether AVO results in greater reverse remodeling. Patients were randomized 1:1 for either an AVO algorithm (SmartDelay) that determines atrioventricular delay and pacing chamber, biventricular or LV only, or a fixed atrioventricular delay of 120 ms with biventricular pacing. Paired echocardiograms performed at baseline and 6 months were evaluated. The primary end point was echocardiographic cardiac resynchronization therapy response, defined dichotomously as a >15% reduction in LV end-systolic volume. A total of 310 patients (n=120 women) were randomized and had completed 6 months of follow-up. The echocardiographic cardiac resynchronization therapy response rate did not statistically differ between the groups (SmartDelay, 74.8%; fixed, 67.7%; P=0.17). Analyses of prespecified secondary end points demonstrated significant improvements in the absolute (median: SmartDelay, -41.0 mL; fixed, -33.0 mL; P=0.01) and relative change in LV end-systolic volume (SmartDelay, -38.3%; fixed, -27.8%; P=0.03) for patients with SmartDelay optimization. Similar results were observed for the relative improvement in LV ejection fraction (SmartDelay, 46.7%; fixed, 32.1%; P=0.050); absolute improvement in LV ejection fraction trended to be higher with SmartDelay (P=0.06). Analysis of reverse remodeling parameters demonstrated that AVO via SmartDelay, relative to the nonoptimized fixed atrioventricular delay comparator group, improved absolute and relative changes in LV function in patients with longer right ventricular-LV duration. URL: https://www. gov; Unique identifier: NCT03089281.