Arrhythmogenic Ventricular Remodeling by Next-Generation Bruton's Tyrosine Kinase Inhibitor Acalabrutinib.

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca2+ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca2+ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca2+ leak and Ca2+ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca2+ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.

Orientation of conduction velocity vectors on cardiac mapping surfaces.

AIMS: Electroanatomical maps using automated conduction velocity (CV) algorithms are now being calculated using two-dimensional (2D) mapping tools. We studied the accuracy of mapping surface 2D CV, compared to the three-dimensional (3D) vectors, and the influence of mapping resolution in non-scarred animal and human heart models. METHODS AND RESULTS: Two models were used: a healthy porcine Langendorff model with transmural needle electrodes and a computer stimulation model of the ventricles built from an MRI-segmented, excised human heart. Local activation times (LATs) within the 3D volume of the mesh were used to calculate true 3D CVs (direction and velocity) for different pixel resolutions ranging between 500 µm and 4 mm (3D CVs). CV was also calculated for endocardial surface-only LATs (2D CV). In the experimental model, surface (2D) CV was faster on the epicardium (0.509 m/s) compared to the endocardium (0.262 m/s). In stimulation models, 2D CV significantly exceeded 3D CVs across all mapping resolutions and increased as resolution decreased. Three-dimensional and 2D left ventricle CV at 500 µm resolution increased from 429.2 ± 189.3 to 527.7 ± 253.8 mm/s (P < 0.01), respectively, with modest correlation (R = 0.64). Decreasing the resolution to 4 mm significantly increased 2D CV and weakened the correlation (R = 0.46). The majority of CV vectors were not parallel (<30°) to the mapping surface providing a potential mechanistic explanation for erroneous LAT-based CV over-estimation. CONCLUSION: Ventricular CV is overestimated when using 2D LAT-based CV calculation of the mapping surface and significantly compounded by mapping resolution. Three-dimensional electric field-based approaches are needed in mapping true CV on mapping surfaces.

Decrement Evoked Potential (DEEP) Mapping of the Atria: Unmasking Atrial Fibrillation Substrate.

BACKGROUND: Atrial myopathy may underlie the progression of atrial fibrillation (AF) from a treatable disease to an irreversible condition with poor ablation outcomes. Electrophysiological methods to unmask areas prone to re-entry initiation could be key to defining latent atrial myopathy. METHODS: Consecutive patients referred for AF ablation were prospectively included at four institutions. Decrement evoked potential mapping (DEEP) was performed in eight left atrial sites and five right atrial sites, from two different pacing locations (endocardially from the left atrial appendage, epicardially from the proximal coronary sinus). The electrograms (EGMs) during S1 600 ms drive and after an extra stimulus (S2 at +30 ms above atrial refractoriness) were studied at each location and assessed for decremental properties. Follow-up was 12 months. RESULTS: Seventy-four patients were included and 85% had persistent AF. A total of 17,614 EGMs were individually analysed and measured. Nine percent of the EGMs showed DEEP properties (local delay of >10 ms after S2) with a mean decrement of 33±26 ms. DEEPs were more frequent in the left atrium than the right atrium (9.4% vs 8.0%; p<0.001) and more prevalent in persistent AF patients than paroxysmal AF patients (9.8% vs 4.6% p=0.001). Atrial DEEPs were more frequently unmasked in normal bipolar voltage areas and by epicardial pacing than endocardial pacing (9.6% vs 8.4%, respectively; p=0.004). Within the left atrium, the roof had the highest prevalence of DEEP EGMs. CONCLUSIONS: DEEP mapping of both atria is useful for highlighting areas with a tendency for unidirectional block and re-entry initiation. Those areas are more easily unmasked by epicardial pacing from the coronary sinus and more prevalent in persistent AF patients than in paroxysmal AF patients.

Effects of azumolene on arrhythmia substrate in a model of recurrent long-duration ventricular fibrillation.

BACKGROUND: Proarrhythmic risk of conventional anti-arrhythmic agents is linked to unintended modulation of membrane voltage dynamics. We have demonstrated that the anti-fibrillatory effect of azumolene is mediated via stabilization of the hyperphosphorylated ryanodine receptor (RyR2), leading to attenuation of diastolic calcium leak. However, the concomitant effects on membrane voltage dynamics have not been evaluated yet. METHODS: After baseline optical mapping, Langendorff-perfused rabbit hearts treated with azumolene, or vehicle, were subjected to global ischemia-reperfusion (I/R) followed by two episodes of long-duration ventricular fibrillation (LDVF). Simultaneous dual epicardial calcium transient (CaT) and voltage dynamics were studied optically. RESULTS: Pre-treatment with azumolene was associated with higher CaT amplitude alternans ratios (0.94 ± 0.02 vs. 0.78 ± 0.03 in control hearts, at 6 Hz; p = 0.005; and action potential amplitude alternans ratio (0.95 ± 0.02 vs. 0.78 ± 0.04 at 6.0 Hz; p = 0.02), and reduction of action potential duration (APD80) dispersion (9.0 ± 4.8 msec vs. 19.3 ± 6.6 msec at 6.0 Hz p = 0.02) and optical action potential upstroke rise time (26.3 ± 2.6 msec in control vs. 13.8 ± 0.6 msec at 6.0 Hz, p = 0.02) after LDVF. No change in action potential duration (APD) was noted with azumolene treatment. CONCLUSION: In a model of ischemic recurrent LDVF, treatment with azumolene led to reduction of cardiac alternans, i.e., calcium and voltage alternans. Unlike conventional anti-arrhythmic agents, reduction of action potential upstroke rise time and preservation of action potential duration following azumolene treatment may reduce the proarrhythmia risk.

Role of Purkinje-muscle junction in early ventricular fibrillation in a porcine model: Beyond the trigger concept.

BACKGROUND: The role of the Purkinje network in triggering ventricular fibrillation (VF) has been studied; however, its involvement after onset and in early maintenance of VF is controversial. AIM: We studied the role of the Purkinje-muscle junctions (PMJ) on epicardial-endocardial activation gradients during early VF. METHODS: In a healthy, porcine, beating-heart Langendorff model [control, n = 5; ablation, n = 5], simultaneous epicardial-endocardial dominant frequent mapping was used (224 unipolar electrograms) to calculate activation rate gradients during the onset and early phase of VF. Selective Purkinje ablation was performed using Lugol's solution, followed by VF re-induction and mapping and finally, histological evaluation. RESULTS: Epicardial activation rates were faster than endocardial rates for both onset and early VF. After PMJ ablation, activation rates decreased epicardially and endocardially for both onset and early VF [Epi: 9.7 ± 0.2 to 8.3 ± 0.2 Hz (p <.0001) and 10.9 ± 0.4 to 8.8 ± 0.3 Hz (p < .0001), respectively; Endo: 8.2 ± 0.3 Hz to 7.4 ± 0.2 Hz (p < .0001) and 7.0 ± 0.4 Hz to 6.6 ± 0.3 Hz (p = .0002), respectively]. In controls, epicardial-endocardial activation rate gradients during onset and early VF were 1.7 ± 0.3 Hz and 4.5 ± 0.4 Hz (p < .001), respectively. After endocardial ablation of PMJs, these gradients were reduced to 0.9 ± 0.3 Hz (onset VF, p < .001) and to 2.2 ± 0.3 Hz (early VF, p <.001). Endocardial-epicardial Purkinje fiber arborization and selective Purkinje fiber extinction after only endocardial ablation (not with epicardial ablation) was confirmed on histological analysis. CONCLUSIONS: Beyond the trigger paradigm, PMJs determine activation rate gradients during onset and during early maintenance of VF.

Exploring the cause of conduction delays in patients with repaired Tetralogy of Fallot.

AIMS: Cardiac dyssynchrony in patients with repaired Tetralogy of Fallot (rToF) has been attributed to right bundle branch block (RBBB), fibrosis and/or the patches that are inserted during repair surgery. We aimed to investigate the basis of abnormal activation in rToF patients by mapping the electrical activation sequence during sinus rhythm (SR) and right ventricular (RV) pacing. METHODS AND RESULTS: A total of 17 patients were studied [13 with rToF, 2 with left bundle branch block (LBBB), and 2 without RBBB or LBBB (non-BBB)] during medically indicated cardiac surgery. During SR and RV pacing, measurements were performed using 112-electrode RV endocardial balloons (rToF only) and biventricular epicardial sock arrays (four of the rToF and all non-rToF patients). During SR, functional lines of block occurred in five rToF patients, while RV pacing caused functional blocks in four rToF patients. The line of block persisted during both SR and RV pacing in only 2 out of 13 rToF patients. Compared to SR, RV pacing increased dispersion of septal activation, but not dispersion of endocardial and epicardial activation of the RV free wall. During pacing, RV and left ventricular activation dispersion in rToF patients were comparable to that of the non-rToF patients. CONCLUSION: The results of the present study indicate that the delayed activation in the right ventricle of rToF patients is predominantly due to block(s) in the Purkinje system and that conduction in RV tissue is fairly normal.

High density intramural mapping of post-infarct premature ventricular contractions and ventricular tachycardia.

BACKGROUND: Spontaneous ventricular premature contractions (PVCs) and ventricular tachycardia (VT) in the acute post infarct milieu is assumed to be due to automaticity. However, the mechanism has not been studied with intramural mapping. OBJECTIVE: To study the mechanism of spontaneous PVCs with high density intramural mapping in a canine model, and to test the hypothesis that post-infarct PVCs and VT are due to re-entry rather than automaticity. METHODS: In 15 anesthetized dogs, using 768 intramural unipolar electrograms, simultaneous recordings were made. After 20 min of stabilization, recordings were made during the first 10 min of ischemia, and activation maps of individual beats were constructed. Acute ischemia was produced by clamping the left anterior descending coronary artery proximal to the first diagonal branch. RESULTS: In all experiments ST-T alternans was present. Spontaneous ventricular beats occurred in five of 15 dogs where the earliest ectopic activity was manifested in the endocardium, well within the ischemic zone. From there, activity spread rapidly along the subendocardium, with endo-to epicardial spread along the non-ischemic myocardium. Epicardial breakthrough always occurred at the border of the ischemic myocardium. In three dogs, delayed potentials were observed, which were earliest at the ischemic epicardium and extended transmurally with increasing delay towards the endocardium, where they culminated in a premature beat. A similar sequence was observed in VT that followed. CONCLUSION: Graded responses that occur with each sinus beat intramurally, when able to propagate from epicardium to endocardium are the mechanism of PVCs and VT in post-infarct myocardium.

Death, discharge and arrhythmias among patients with COVID-19 and cardiac injury.

BACKGROUND: Cardiac injury is common in severe coronavirus disease 2019 (COVID-19) and is associated with poor outcomes. We aimed to study predictors of in-hospital death, characteristics of arrhythmias and the effects of QT-prolonging therapy in patients with cardiac injury. METHODS: We conducted a retrospective cohort study involving patients with severe COVID-19 who were admitted to Tongji Hospital in Wuhan, China, between Jan. 29 and Mar. 8, 2020. Among patients who had cardiac injury, which we defined as an elevated level of cardiac troponin I (cTnI), we identified demographic and clinical characteristics associated with mortality and need for invasive ventilation. RESULTS: Among 1284 patients with severe COVID-19, 1159 had a cTnI level measured on admission to hospital, of whom 170 (14.7%) had results that showed cardiac injury. We found that mortality was markedly higher in patients with cardiac injury (71.2% v. 6.6%, p < 0.001). We determined that initial cTnI (per 10-fold increase, hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.06-1.66) and peak cTnI level during illness (per 10-fold increase, HR 1.70, 95% CI 1.38-2.10) were associated with poor survival. Peak cTnI was also associated with the need for invasive ventilation (odds ratio 3.02, 95% CI 1.92-4.98). We found arrhythmias in 44 of the 170 patients with cardiac injury (25.9%), including 6 patients with ventricular tachycardia or fibrillation, all of whom died. We determined that patients who received QT-prolonging drugs had longer QTc intervals than those who did not receive them (difference in medians, 45 ms, p = 0.01), but such treatment was not independently associated with mortality (HR 1.04, 95% CI 0.69-1.57). INTERPRETATION: We found that in patients with COVID-19 and cardiac injury, initial and peak cTnI levels were associated with poor survival, and peak cTnI was a predictor of need for invasive ventilation. Patients with COVID-19 warrant assessment for cardiac injury and monitoring, especially if therapy that can prolong repolarization is started. TRIAL REGISTRATION: Chinese Clinical Trial Registry, No. ChiCTR2000031301.

Trans-myocardial bipolar electrogram: A strategy for mapping and determining efficacy of bipolar ablation of deep foci.

Mapping and ablation of intramural ventricular tachycardia (VT) remain a challenge. We developed a trans-myocardial electrogram recording across distal tips of two separate ablation catheters placed on contralateral sides of the myocardium to record a trans-myocardial bipole and a novel pacing electrode configuration. This trans-myocardial bipole was applied during bipolar ablation in a patient with septal VT. Local activation in this trans-myocardial bipole was similar to the earliest activation recorded from detailed activation maps from both sides of the septum. Pacing from this trans-myocardial bipole resulted in a perfect morphology match. After bipolar ablation, the trans-myocardial bipolar voltage decreased by 82%, and pacing threshold increased by 800%. These findings correlated with VT noninducibility.

Minimalistic strategy for coronary sinus lead implant: A single tool capable of electrophysiological mapping, pressure measurement, and angiography.

BACKGROUND: Left ventricular (LV) lead implantation for cardiac resynchronization therapy (CRT) may be confounded by contrast load during attempted cannulation and lead dislodgement during guiding catheter splitting. An LV lead implant system with a steerable single catheter that completely avoids the use of guiding catheters when needed, acquires atrioventricular electrograms, measures intracardiac pressures, permits CS angiography, and has the ability to direct a coronary angioplasty wire that will lead the final delivery of LV lead into a CS tributary, may help limit contrast use and avoid lead dislodgement at CS guide sheath removal. METHODS AND RESULTS: In this article as a proof of concept, we describe the use of this minimalist technique as a first line approach in six patients who had standard indications for CRT. The LV lead was successfully implanted in a target vein in all patients without acute complications. Contrast was not used in half the group and the LV lead was successfully implanted without guiding catheter in four patients. The implantation technique evolved through the series and in the final patient, no guiding sheath or contrast was used. Postimplant lead positions on chest X-ray and lead parameters were stable in all patients at follow-up. CONCLUSION: In proof of concept paper, we describe a technique of LV lead implantation potentially without the use of contrast and standard CS guiding catheters. Once familiar, this approach may provide a less complicated strategy.

Information theory to tachycardia therapy: electrogram entropy predicts diastolic microstructure of reentrant ventricular tachycardia.

There is no known strategy to differentiate which multicomponent electrograms in sinus rhythm maintain reentrant ventricular tachycardia (VT). Low entropy in the voltage breakdown of a multicomponent electrogram can localize conditions suitable for reentry but has not been validated against the classic VT activation mapping. We examined whether low entropy in a late and diversely activated ventricular scar region characterizes and differentiates the diastolic path of VT and represents protected tissue channels devoid of side branches. Intraoperative bipolar electrogram (BiEGM) activation and entropy maps were obtained during sinus rhythm in 17 patients with ischemic cardiomyopathy and compared with diastolic activation paths of VT (total of 39 VTs). Mathematical modeling of a zigzag main channel with side branches was also used to further validate structural representation of low entropy in the ventricular scar. A median of one region per patient (range: 1-2 regions) was identified in sinus rhythm, in which BiEGM with the latest mean activation time and adjacent minimum entropy were assembled together in a high-activation dispersion region. These regions accurately recognized diastolic paths of 34 VTs, often to multiple inducible VTs within a single individual arrhythmogenic region. In mathematical modeling, side branching from the main channel had a strong influence on the BiEGM composition along the main channel. The BiEGM obtained from a long unbranched channel had the lowest entropy compared with those with multiple side branches. In conclusion, among a population of multicomponent sinus electrograms, those that demonstrate low entropy and are delayed colocalize to critical long-protected channels of VT. This information is pertinent for planning VT ablation in sinus rhythm. NEW & NOTEWORTHY Entropy is a measure to quantify breakdown in information. Electrograms from a protected tissue channel can only possess a few states in their voltage and thus less information. In contrast, current-load interactions from side branches in unprotected channels introduce a number of dissimilar voltage deflections and thus high information. We compare here a mapping approach based on entropy against a rigorous reference standard of activation mapping during VT and entropy was assessed in sinus rhythm.

Exit sites on the epicardium rarely subtend critical diastolic path of ischemic VT on the endocardium: Implications for noninvasive ablation.

BACKGROUND: Noninvasive electrocardiographic mapping of ventricular tachycardia (VT) and ablation using stereotactic radiotherapy was recently reported. This strategy does not directly evaluate the critical diastolic components and assumes that the epicardial exit site of VT subtends closely over the endocardial mid-diastolic isthmus. OBJECTIVE: To determine if the epicardial exit site of VT spatially corresponds to the critical diastolic components of ischemic scar-related VT. MATERIALS AND METHODS: Intraoperative simultaneous endocardial and epicardial mapping were performed during VT using a 112-bipole endocardial balloon and 112-bipole epicardial sock array. In eight patients, nine VTs having entire diastolic circuit mapped were included in the study. The diastolic path and VT-exit sites (epicardial and endocardial) were determined. RESULTS: The diastolic path was mapped in the endocardium for all nine VTs (median length, 50; interquartile range [IQR], 28 mm). The tachycardia cycle length ranged from 210-500 ms. The VT-exit site was early in the endocardium for six VTs and on the epicardium for three VTs. The mid-diastolic isthmus and endocardial exit site of the six endocardial VTs were spatially distant from their epicardial exit site by a median distance of 32 and 27 mm, respectively. For the three VTs with an early epicardial exit, the isthmus and endocardial exit sites were distant from the epicardial exit site by a median distance of 34 and 38 mm, respectively. CONCLUSION: The epicardial exit site and the mid-diastolic isthmus sites were spatially distant and discrepant. Surface electrocardiography (ECG)-derived strategy in identifying epicardial exit site to select noninvasive ablation targets is prone to identify epicardial exit sites and may not identify critical targets in ischemic scar VT.

Omnipolarity applied to equi-spaced electrode array for ventricular tachycardia substrate mapping.

AIMS: Bipolar electrogram (BiEGM)-based substrate maps are heavily influenced by direction of a wavefront to the mapping bipole. In this study, we evaluate high-resolution, orientation-independent peak-to-peak voltage (Vpp) maps obtained with an equi-spaced electrode array and omnipolar EGMs (OTEGMs), measure its beat-to-beat consistency, and assess its ability to delineate diseased areas within the myocardium compared against traditional BiEGMs on two orientations: along (AL) and across (AC) array splines. METHODS AND RESULTS: The endocardium of the left ventricle of 10 pigs (three healthy and seven infarcted) were each mapped using an Advisor™ HD grid with a research EnSite Precision™ system. Cardiac magnetic resonance images with late gadolinium enhancement were registered with electroanatomical maps and were used for gross scar delineation. Over healthy areas, OTEGM Vpp values are larger than AL bipoles by 27% and AC bipoles by 26%, and over infarcted areas OTEGM Vpp values are 23% larger than AL bipoles and 27% larger than AC bipoles (P < 0.05). Omnipolar EGM voltage maps were 37% denser than BiEGM maps. In addition, OTEGM Vpp values are more consistent than bipolar Vpps showing less beat-by-beat variation than BiEGM by 39% and 47% over both infarcted and healthy areas, respectively (P < 0.01). Omnipolar EGM better delineate infarcted areas than traditional BiEGMs from both orientations. CONCLUSION: An equi-spaced electrode grid when combined with omnipolar methodology yielded the largest detectable bipolar-like voltage and is void of directional influences, providing reliable voltage assessment within infarcted and non-infarcted regions of the heart.

Groin Haemostasis With a Purse String Suture for Patients Following Catheter Ablation Procedures (GITAR Study).

BACKGROUND: The most frequent complications from percutaneous electrophysiology procedures relate to vascular access. We sought to perform the first randomised controlled trial for femoral venous haemostasis utilising a simple and novel purse string suture (PSS) technique. METHODS: We randomised 200 consecutive patients who were referred for electrophysiology procedures at two different hospitals to either 10minutes of manual pressure or a PSS over the femoral vein and determined the incidence of vascular access site complications. RESULTS: The mean age was 61.8±12.1years and 138 (69%) were male. Bleeding requiring addition pressure or a FemStop (Abbott Laboratories, Abbott Park, IL, USA) for complete haemostasis occurred in 17/99 (17%) patients in the PSS arm and 19/101 (19%) patients in the manual pressure arm (p=0.72). There were no cases of haematoma prolonging hospital stay, arterio-venous fistula, pseudoaneurysm or retroperitoneal bleeding. The mean duration to achieve haemostasis was 45seconds in the PSS arm and 10minutes 44seconds in the manual pressure arm (p<0.001). Pain/discomfort associated with haemostasis occurred in 15/99 (15%) patients in the PSS arm and in 29/101 (29%) patients receiving manual pressure (p=0.03). CONCLUSIONS: In this randomised trial we demonstrate that an easy to perform PSS is as effective at achieving haemostasis as 10minutes of manual pressure for catheter ablation procedures. The PSS is considerably faster to perform and is more comfortable for patients than manual pressure.

Essential role of ryanodine receptor 2 phosphorylation in the effect of azumolene on ventricular arrhythmia vulnerability in a rabbit heart model.

INTRODUCTION: Following long-duration ventricular fibrillation (LDVF), reinitiation of ventricular fibrillation (VF) poses a major challenge during resuscitation. Ryanodine receptor 2 (RyR2) becomes dysfunctional following VF. The relationship between LDVF, RyR2 modulation, and ventricular refibrillation, as well as the role of RyR2 phosphorylation, remains unknown. METHODS: Langendorff-perfused rabbit hearts were subjected to global ischemia and treated with azumolene (or vehicle alone in controls) upon reperfusion. After electrical induction of an initial LDVF episode, each heart was further stimulated electrically to assess reinducibility of VF. Myocardial calcium dynamics were assessed by optical mapping. RyR2 phosphorylation in left ventricular tissue extracts was analyzed by Western blot analysis. RESULTS: Fewer episodes of refibrillation (lasting ≥ 10 seconds) were induced in azumolene-treated hearts than in controls (P = 0.01); however, this reduction in refibrillation was abrogated in the presence of the protein kinase A inhibitor H89. Spontaneous calcium elevation was significantly lower in azumolene-treated hearts than in control hearts ( P = 0.002) and in hearts pretreated with H89 before azumolene ( P = 0.01). RyR2 phosphorylation at Ser2808 was higher in hearts subjected to LDVF than in non-VF hearts ( P = 0.029), while no significant difference was found at Ser2814. Pretreatment with H89 led to significantly less RyR2 phosphorylation at Ser2808 ( P = 0.04) after LDVF, while pretreatment with KN93 or azumolene alone showed no effects on RyR2 phosphorylation. CONCLUSION: Ventricular refibrillation following LDVF was reduced by azumolene, which also improves calcium dynamics. RyR2 phosphorylation at Ser2808 is a prerequisite for the beneficial effects of azumolene.

The effect of left ventricular pacing on transmural activation delay in myopathic human hearts.

Aims: Left ventricular (LV) epicardial pacing (LVEpiP) in human myopathic hearts does not decrease global epicardial activation delay compared with right ventricular (RV) endocardial pacing (RVEndoP); however, the effect on transmural activation delay has not been evaluated. To characterize the transmural electrical activation delay in human myopathic hearts during RVEndoP and LVEpiP compared with global epicardial activation delay. Methods and results: Explanted hearts from seven patients (5 male, 46 ± 10 years) undergoing cardiac transplantation were Langendorff-perfused and mapped using an epicardial sock electrode array (112 electrodes) and 25 transmural plunge needles (four electrodes, 2 mm spacing), for a total of 100 unipolar transmural electrodes. Electrograms were recorded during LVEpiP and RVEndoP, and epicardial (sock) and transmural (needle) activation times, along with patterns of activation, were compared. There was no difference between the global epicardial activation times (LVEpiP 147 ± 8 ms vs. RVEndoP 156 ± 17 ms, P = 0.46). The mean LV transmural activation time during LVEpiP was significantly shorter than that during RVEndoP (125 ± 44 vs. 172 ± 43 ms, P < 0.001). During LVEpiP, of the transmural layers endo-, mid-myocardium and epicardium, LV endocardial layer was often the earliest compared with other transmural layers. Conclusion: In myopathic human hearts, LVEpiP did not decrease global epicardial activation delays compared with RVEndoP. LV epicardial pacing led to early activation of the LV endocardium, revealing the importance of the LV endocardium even when pacing from the LV epicardium.

Heart rate in patients with reduced ejection fraction: relationship between single time point measurement and mean heart rate on prolonged implantable cardioverter defibrillator monitoring.

BACKGROUND: Heart rate (HR) is a prognostic marker that is increasingly used as a therapeutic target in patients with cardiovascular disease. The association between resting and mean HR remains unclear. We therefore set out to determine the relationship between resting HR on the electrocardiogram (ECG) obtained at a single time point, and mean HR on implantable cardioverter defibrillator (ICD) interrogation amongst patients with a reduced left ventricular ejection fraction (LVEF). METHODS: Prospective ICD data were obtained from 54 patients with LVEF < 40%. Mean HR determined using the ICD HR histograms was compared with resting HR measured on the ECG performed in the clinic. RESULTS: Average resting and ICD mean HRs were 67.9 ± 10.1 and 67.8 ± 9.6 bpm respectively. There was good correlation in the overall cohort (r = 0.79), in those with resting ECG HRs ≤ 70 bpm (r = 0.62), and amongst the 27 patients on intermediate-to-high dose beta-blockers (r = 0.91). However, Bland-Altman analysis demonstrated wide limits of agreement in the overall cohort (- 12.5, 12.7 bpm), at resting HRs ≤ 70 bpm (- 12.7, 9.8 bpm), and on intermediate-to-high dose beta-blockers (- 8.9, 7.4 bpm). Moreover, resting HR did not predict the 10-bpm interval where the most time was spent. CONCLUSIONS: While resting HR correlated with mean HR in patients with reduced LVEF, and in important subgroups, the limits of agreement were unacceptably wide raising concern over the use of single time point resting HR as a therapeutic target.