The jugular approach for leadless pacing: A novel and safe alternative.

AIMS: To evaluate safety of leadless pacemaker implantation through the internal jugular vein in a larger cohort with longer follow-up. Moreover, feasibility of non-apical pacing as well as relation between pacing site and QRS duration were assessed. METHODS: Eighty Two consecutive patients, who received a leadless pacemaker though the internal jugular vein, were included. Electrical parameters were measured at regular follow-up and any complications were registered. Paced QRS interval was compared for three pacing sites, RVOT, RV mid septum, and RV apical septum. RESULTS: In all patients, the leadless pacemaker was implanted successfully. In 69 patients, the device was implanted in a non-apical position. In 71% of cases, the device could be deployed at first attempt. The median fluoroscopy time was 4.4 min (range 0.9-51) The paced QRS interval was significantly narrower for non-apical pacing sites compared to apical pacing si 156  vs. 179 ms. p = .04, respectively. During mean follow-up of 16 months (range 0-43 months), electrical parameters remained stable. Two complications occurred, which could be resolved during the implant procedure. There were no access site related complications. CONCLUSION: The jugular approach for leadless pacemaker implantation is feasible and may avoid vascular complications. It facilitates non-apical positioning of leadless pacemakers leading to a narrower paced QRS interval. The jugular approach allows for immediate post procedural ambulation.

Multielectrode Contact Measurement Can Improve Long-Term Outcome of Pulmonary Vein Isolation Using Circular Single-Pulse Electroporation Ablation.

BACKGROUND: Irreversible electroporation (IRE) ablation is generally performed with multielectrode catheters. Electrode-tissue contact is an important predictor for the success of pulmonary vein (PV) isolation; however, contact force is difficult to measure with multielectrode ablation catheters. In a preclinical study, we assessed the feasibility of a multielectrode impedance system (MEIS) as a predictor of long-term success of PV isolation. In addition, we present the first-in-human clinical experience with MEIS. METHODS: In 10 pigs, one PV was ablated based on impedance (MEIS group), and the other PV was solely based on local electrogram information (EP group). IRE ablations were performed at 200 J. After 3 months, recurrence of conduction was assessed. Subsequently, in 30 patients undergoing PV isolation with IRE, MEIS was evaluated and MEIS contact values were compared to local electrograms. RESULTS: In the porcine study, 43 IRE applications were delivered in 19 PVs. Acutely, no reconnections were observed in either group. After 3 months, 0 versus 3 (P=0.21) PVs showed conduction recurrence in the MEIS and EP groups, respectively. Results from the clinical study showed a significant linear relation was found between mean MEIS value and bipolar dV/dt (r2=0.49, P<0.001), with a slope of 20.6 mV/s per Ohm. CONCLUSIONS: Data from the animal study suggest that MEIS values predict effective IRE applications. For the long-term success of electrical PV isolation with circular IRE applications, no significant difference in efficacy was found between ablation based on the measurement of electrode interface impedance and ablation using the classical EP approach for determining electrode-tissue contact. Experiences of the first clinical use of MEIS were promising and serve as an important basis for future research.

Characteristics and time course of acute and chronic myocardial lesion formation after electroporation ablation in the porcine model.

INTRODUCTION: Electroporation ablation creates deep and wide myocardial lesions. No data are available on time course and characteristics of acute lesion formation. METHODS: For the acute phase of myocardial lesion development, seven pigs were investigated. Single 200 J applications were delivered at four different epicardial right ventricular sites using a linear suction device, yielding a total of 28 lesions. Timing of applications was designed to yield lesions at seven time points: 0, 10, 20, 30, 40, 50, and 60 min, with four lesions per time point. After killing, lesion characteristics were histologically investigated. For the chronic phase of myocardial lesion development, tissue samples were used from previously conducted studies where tissue was obtained at 3 weeks and 3 months after electroporation ablation. RESULTS: Acute myocardial lesions induce a necrosis pattern with contraction band necrosis and interstitial edema, immediately present after electroporation ablation. No further histological changes such as hemorrhage or influx of inflammatory cells occurred in the first hour. After 3 weeks, the lesions consisted of sharply demarcated loose connective tissue that further developed to more fibrotic scar tissue after 3 months without additional changes. Within the scar tissue, arteries and nerves were unaffected. CONCLUSION: Electroporation ablation immediately induces contraction band necrosis and edema without additional tissue changes in the first hour. After 3 weeks, a sharply demarked scar has been developed that remains stable during follow-up of 3 months. This is highly relevant for clinical application of electroporation ablation in terms of the electrophysiological endpoint and waiting period after ablation.

High-frequency irreversible electroporation for cardiac ablation using an asymmetrical waveform.

BACKGROUND: Irreversible electroporation (IRE) using direct current (DC) is an effective method for the ablation of cardiac tissue. A major drawback of the use of DC-IRE, however, are two problems: requirement of general anesthesia due to severe muscle contractions and the formation of bubbles containing gaseous products from electrolysis. The use of high-frequency alternating current (HF-IRE) is expected to solve both problems, because HF-IRE produces little to no muscle spasms and does not cause electrolysis. METHODS: In the present study, we introduce a novel asymmetric, high-frequency (aHF) waveform for HF-IRE and present the results of a first, small, animal study to test its efficacy. RESULTS: The data of the experiments suggest that the aHF waveform creates significantly deeper lesions than a symmetric HF waveform of the same energy and frequency (p = 0.003). CONCLUSION: We therefore conclude that the use of the aHF enhances the feasibility of the HF-IRE method.

Leadless pacing: Going for the jugular.

BACKGROUND: Leadless pacing is generally performed from a femoral approach. However, the femoral route is not always available. Until now, data regarding implantation using a jugular approach other than a single-case report were lacking. METHODS: The case records of all patients who underwent internal jugular venous (IJV) leadless pacemaker implantation (Micra, Medtronic, Dublin, Ireland) at our center were analyzed retrospectively. RESULTS: Nineteen patients underwent IJV leadless pacemaker implantation, nine females, mean age of 77.5 ±9.6  years; permanent atrial fibrillation in all patients with normal left ventricular ejection fraction. Implant indication was atrioventricular conduction disturbance in 10, pre-AV node ablation in seven, and replacement of a conventional VVI pacemaker in two (infection in one and lead malfunction in the other). The device was positioned at the superior septum in seven patients, apicoseptal in seven patients, and midseptal in five patients. In 12 patients, a sufficient device position was obtained at the first attempt, in three at the second, in one at the third, in one at the fourth, and in two at the sixth attempt. The mean pacing threshold was 0.56 ± 0.39V at 0.24-ms pulse width, sensed amplitude was 9.1 ± 3.2 mV, mean fluoroscopy duration was 3.1 ± 1.6 min. There were no vascular or other complications. At follow-up, electrical parameters remained stable in 18 of 19 patients. CONCLUSION: Although experience is minimal, we suggest that the IJV approach is safe and may be considered in patients where the femoral approach is contraindicated.

Novel method for electrode-tissue contact measurement with multi-electrode catheters.

Aims: With multi-electrode catheters, measuring contact force (CF) on each electrode is technically challenging. Present electrical methods, like the electrical coupling index (ECI) may yield false positive values in pulmonary veins. We developed a novel method that measures electrode-interface resistance (IR) by applying a very local electrical field between neighbouring catheter electrodes while measuring voltage between each catheter electrode and a skin patch. The aim of this study was to evaluate the new IR method to measure electrode-tissue contact. Methods and results: In vitro, effects of remote high-impedance structures were studied. In addition, both ECI and IR were directly compared with true electrode-tissue CF. In five pigs, the influence of high-impedance pulmonary tissue on ECI and IR was investigated while navigating the free floating catheter into the caval veins. Inside the left atrium (LA), IR was directly compared with CF. Finally, multi-electrode IR measurements in the LA and inferior pulmonary vein (IPV) were compared. In vitro, IR is much less affected by remote high-impedance structures than ECI (3% vs. 32%). Both IR and ECI strongly relate to electrode-tissue CF (r2 = 0.84). In vivo, and in contrast to ECI, IR was not affected by nearby pulmonary tissue. Inside the LA, a strong relation between IR and CF was found. This finding was confirmed by simultaneous multi-electrode measurements in LA and IPV. Conclusion: Data of the present study suggest that electrode-tissue contact affects the IR while being highly insensitive to remote structures. This method facilitates electrode-tissue contact measurements with circular multi-electrode ablation catheters.

Acute and Long-Term Effects of Full-Power Electroporation Ablation Directly on the Porcine Esophagus.

BACKGROUND: Esophageal ulceration and fistula are complications of pulmonary vein isolation using thermal energy sources. Irreversible electroporation is a novel, nonthermal ablation modality for pulmonary vein isolation. A single 200 J application can create deep myocardial lesions. Acute and chronic effects of this new energy source on the esophagus are unknown. METHODS AND RESULTS: In 8 pigs (±70 kg), the suprasternal esophagus was surgically exposed. A linear suction device with a single 35-mm long and 6-mm wide protruding linear electrode inside a plastic suction cup was used for ablation. Single, nonarcing, nonbarotraumatic, cathodal 100 and 200 J applications were delivered at 2 different sites on the anterior esophageal adventitia. No proton-pump inhibitors were administered during follow-up. Esophagoscopy was performed at days 2 and 7. After euthanasia at day 60, the esophagus was evaluated visually and histologically. All ablations were uneventful. Esophagoscopy at day 2 showed small white densities in the ablated areas, which appeared to be small intraepithelial vesicles. No epithelial erythema, erosions, or ulcerations were seen. At day 7, all densities had disappeared, and all esophaguses appeared completely normalized. After euthanasia, there were no macroscopically visible lesions on the adventitia or epithelium. Histologically, a small scar was observed at the outer part of the muscular layer, whereas the mucosa and submucosa were normal. CONCLUSIONS: Esophageal architecture remains unaffected 2 months after irreversible electroporation, purposely targeting the adventitia. Irreversible electroporation seems to be a safe modality for catheter ablation near the esophagus.

Low vulnerability of the right phrenic nerve to electroporation ablation.

BACKGROUND: Circular electroporation ablation is a novel ablation modality for electrical pulmonary vein isolation. With a single 200-J application, deep circular myocardial lesions can be created. However, the acute and chronic effects of this energy source on phrenic nerve (PN) function are unknown. OBJECTIVE: The purpose of this study was to analyze nerve vulnerability to electroporation ablation in a porcine model. METHODS: In 20 animals (60-75 kg), the course of the right PN was pace-mapped inside the superior caval vein (SCV). Thereafter, a single 200-J circular electroporation ablation was performed via a multipolar circular catheter in firm contact with the inner SCV wall. RESULTS: In 19 of 20 animals, the PN could be captured along an estimated 6-8 cm trajectory above the right atrial contour. Directly after the application, the PN could be captured above the ablation level in 17 of 19 animals and after maximally 30 minutes in all animals. Fifteen animals were restudied after 3-13 weeks, and PN functionality was unaffected in all. Histological analysis in 5 animals in which the application had been delivered in the muscular sleeve just above the right atrium showed a transmural circular lesion. However, no lesion was found in the other animals in which the application had been delivered in the fibrous section more cranial in the SCV. CONCLUSIONS: Electroporation ablation at an energy level that may create deep myocardial lesions may spare the targeted right PN. These animal data suggest that electroporation may be a safe ablation modality near the right PN.

Safety and feasibility of closed chest epicardial catheter ablation using electroporation.

BACKGROUND: Permanent coronary artery damage is a hazardous complication of epicardial radiofrequency ablation. Irreversible electroporation (IRE) is a promising nonthermal ablation modality able to create deep myocardial lesions. We investigated the effects of epicardial IRE on luminal coronary artery diameter and lesion depth. METHODS AND RESULTS: In 5 pigs (60-75 kg), the pericardium was exposed using surgical subxiphoidal epicardial access. A custom deflectable octopolar 12-mm circular catheter with 2-mm ring electrodes was introduced in the pericardium via a steerable sheath. After coronary angiography (CAG), the proximal, mid, and distal left anterior descending, and circumflex coronary arteries were targeted with a single, cathodal 200 J application. CAG was repeated after IRE and after 3 months follow-up. Using quantitative CAG, the minimal luminal diameter at the lesion site was compared with the average of the diameters just proximal and distal to that lesion. Intimal hyperplasia and lesion size were measured histologically. CAG directly postablation demonstrated short-lasting luminal narrowing with normalization in the targeted area, suggestive of coronary spasm. After 3 months, all CAGs were identical to preablation CAGs: mean reference luminal diameter was 2.2±0.3 mm, mean luminal diameter at the lesion site was 2.1±0.3 mm (P=0.35). Average intimal hyperplasia in all arteries was 2±4%. Median lesion depth was 6.4±2.6 mm. CONCLUSIONS: Luminal coronary artery diameter remained unaffected 3 months after epicardial IRE, purposely targeting the coronary arteries. IRE can create deep lesions and is a safe modality for catheter ablation on or near coronary arteries.

Myocardial lesion size after epicardial electroporation catheter ablation after subxiphoid puncture.

BACKGROUND: Irreversible electroporation is a promising nonthermal ablation modality able to create deep myocardial lesions. We investigated lesion size after epicardial electroporation catheter ablation with various energy levels after subxiphoid pericardial puncture. METHODS AND RESULTS: In six 6-month-old pigs (60-75 kg), a custom deflectable octopolar 12-mm circular catheter with 2-mm ring electrodes was introduced via a deflectable sheath after pericardial access by subxiphoid puncture. Nonarcing, nonbarotraumatic, cathodal 50, 100, and 200 J electroporation applications were delivered randomly on the basal, mid and lateral left ventricle. After 3-month survival, myocardial lesion size and degree of intimal hyperplasia of the coronary arteries were analyzed histologically. Five animals survived the follow-up without complications and 1 animal died of shock after the subxiphoid puncture. At autopsy, whitish circular scars with indentation of the epicardium could be identified. Average lesion depths of the 50-, 100-, and 200-J lesions were 5.0±2.1, 7.0±2.0, and 11.9±1.5 mm, respectively. Average lesion widths of the 50-, 100-, and 200-J lesions were 16.6±1.1, 16.2±4.3, and 19.8±1.8 mm, respectively. In the 100- and 200-J cross sections, transmural left ventricular lesions and significant tissue shrinkage were observed. No intimal hyperplasia of the coronary arteries was observed. CONCLUSIONS: Epicardial electroporation ablation after subxiphoid pericardial puncture can create deep, wide, and transmural ventricular myocardial lesions. There is a significant relationship between the amounts of electroporation energy delivered epicardially and lesion size in the absence of major adverse events.

Pulmonary vein stenosis after catheter ablation: electroporation versus radiofrequency.

BACKGROUND: Radiofrequency ablation inside pulmonary vein (PV) ostia can cause PV stenosis. A novel alternative method of ablation is irreversible electroporation, but the long-term response of PVs to electroporation ablation is unknown. METHODS AND RESULTS: In ten 6-month-old pigs (60-75 kg), the response of PVs to circular electroporation and radiofrequency ablation was compared. Ten consecutive, nonarcing, electroporation applications of 200 J were delivered 5 to 10 mm inside 1 of the 2 main PVs, using a custom-deflectable, 18-mm circular decapolar catheter. Inside the other PV, circular radiofrequency ablation was performed using 30 W radiofrequency applications via an irrigated 4-mm ablation catheter. PV angiograms were made before ablation, immediately after ablation, and after 3-month survival. PV diameters and heart size were measured. With electroporation ablation, PV ostial diameter decreased 11±10% directly after ablation, but had increased 19±11% after 3 months. With radiofrequency ablation, PV ostial diameter decreased 23±15% directly after ablation and remained 7±17% smaller after 3 months compared with preablation diameter despite a 21±7% increase in heart size during aging from 6 to 9 months. CONCLUSIONS: In this porcine model, multiple circumferential 200-J electroporation applications inside the PV ostia do not affect PV diameter at 3-month follow-up. Radiofrequency ablation inside PV ostia causes considerable PV stenosis directly after ablation, which persists after 3 months.

Epicardial linear electroporation ablation and lesion size.

BACKGROUND: Electroporation can be used as a nonthermal method to ablate myocardial tissue. However, like with all electrical ablation methods, determination of the energy supplied into the myocardium enhances the clinically required controllability over lesion creation. OBJECTIVE: To investigate the relationship between the magnitude of epicardial electroporation ablation and the lesion size using an electrically isolating linear suction device. METHODS: In 5 pigs (60-75 kg), the pericardium was opened after medial sternotomy. A custom linear suction device with a single 35 × 6-mm electrode inside a 42-mm-long and 7-mm-wide plastic suction cup was used for electroporation ablation. Single cathodal applications of 30, 100, or 300 J were delivered randomly at 3 different epicardial left ventricular sites. Coronary angiography was performed before ablation, immediately after ablation, and after 3 months survival. Lesion size was measured histologically after euthanization. RESULTS: The mean depth of 30, 100, and 300 J lesions was 3.2 ± 0.7, 6.3 ± 1.8, and 8.0 ± 1.5 mm, respectively (P = .0003). The mean width of 30, 100, and 300 J lesions was 10.1 ± 0.8, 15.1 ± 1.5, and 17.1 ± 1.3 mm, respectively (P<.0001). Significant tissue shrinkage was observed at the higher energy levels. No luminal arterial narrowing was observed after 3 months: 2.3 ± 0.3 mm vs 2.3 ± 0.4 mm (P = .85). CONCLUSION: The relationship between the amount of electroporation energy delivered through a linear suction device with a single linear electrode and the mean myocardial lesion size is significant in the absence of major adverse events or permanent damage to the coronary arteries.

Minimal coronary artery damage by myocardial electroporation ablation.

AIMS: Radiofrequency catheter ablation is a successful treatment for cardiac arrhythmias, but may lead to major complications such as permanent coronary damage. Irreversible electroporation (IRE) is a new non-thermal ablation modality, but its effect on coronary arteries is still unknown. METHODS AND RESULTS: In a porcine model, epicardial IRE lesions were created at the base of the left ventricle in four hearts (group A) and directly on the left anterior descending artery (LAD) in five hearts (group B). After 3 weeks, coronary arteries inside IRE lesions and in apparently undamaged myocardium next to the lesions were (immuno-)histologically studied. Two untreated hearts served as controls. Coronary damage was defined as intimal hyperplasia. Left anterior descending artery angiograms were obtained before ablation, directly after ablation, and before termination in group B. In group A, 103 arterial branches were studied. Of these, 5 of 56 arterial branches inside lesions and 1 of 47 outside lesions showed intimal hyperplasia, but all had <50% area stenosis. Targeted LADs (group B) did not reveal intimal hyperplasia and angiograms showed no signs of stenosis. Expression of connective tissue growth factor was observed in the scar tissue, but not in the fibrotic tissue directly around the arteries, confirming that the arteries are indeed spared from tissue damage and remodelling. CONCLUSION: Coronary arteries remain free of clinically relevant damage 3 weeks after epicardial IRE ablation, even amid very large myocardial lesions. This suggests that IRE ablation can be applied safely near or even on coronary arteries. With IRE ablation, arterial blood flow does not appear to affect lesion formation.

Myocardial lesion depth with circular electroporation ablation.

BACKGROUND: Recently, we demonstrated the feasibility and safety of circular electroporation ablation in porcine pulmonary vein ostia, but the relationship between the magnitude of the application and lesion dimensions is still unknown. METHODS AND RESULTS: An in vivo porcine study was performed on left ventricular epicardium submerged under 10 mm of blood, using devices that mimic a 20-mm-diameter 7F circular ablation catheter. Model D contained 10 separate electrodes, whereas model M consisted of 1 circular electrode. Ablations were performed at 50, 100, and 200 J with model D and at 100 J with model M. Lesion dimensions were measured after 3-week survival. All applications resulted in smooth voltage waveforms demonstrating the absence of vapor globe formation, arcing, and a pressure wave. Applications up to 100 J with model D resulted in separate lesions under the electrodes. At 200 J, continuous deep circular lesions were created despite the use of separate electrodes. There was a significant relationship between applied current and median lesion depth, with a slope of 0.17 mm/A. At 100 J, there was no difference in lesion depth or width between models D and M. The electrodes and ablation site directly after ablation showed no signs of thermal damage. CONCLUSIONS: In an epicardial porcine model with blood around the application site, continuous circular lesions, deep enough for electric pulmonary vein isolation, were created with a single circular 200-J application. Lesions were continuous despite the use of separate electrodes. Lesion depth increased with the magnitude of the application.

Complex fractionated electrograms in the right atrial free wall and the superior/posterior wall of the left atrium are affected by activity of the autonomic nervous system.

BACKGROUND: Complex fractionated atrial electrograms (CFAEs) are supposed to be related to structural and electrical remodeling. Animal studies suggest a role of the autonomic nervous system (ANS). However, this has never been studied in humans. OBJECTIVE: The goal of this study was to investigate the influence of ANS on CFAEs in patients with idiopathic atrial fibrillation (AF). METHODS: Thirty-six patients (28 men, 55 ± 9 years) were included before undergoing catheter ablation. In the 24 hours preceding the procedure, 20 patients were in AF (group 1) and 16 were in sinus rhythm (SR, group 2). With 2 decapolar catheters, 1 in the right atrium (RA) and 1 in the left atrium (LA), 20 unipolar electrograms were simultaneously recorded during a 100-second AF-period (in group 2 after induction of AF). After atropine and metoprolol administration, a second 100-second AF-period was recorded 30 minutes later. Five patients of group 2 served as controls and did not receive atropine and metoprolol prior to the second recording. CFAEs were assessed and the prevalence of CFAEs was expressed as percentage of the recording time. RESULTS: The prevalence of CFAEs was greater in group 1 than in group 2 in both RA and LA (P = 0.026, P < 0.001, respectively). Atropine and metoprolol significantly reduced CFAEs in group 1 (P < 0.001) and prevented the time-dependent increase of CFAEs in group 2. CONCLUSION: The prevalence of CFAEs is greater in long-lasting AF episodes. Atropine and metoprolol administration reduces CFAEs in both atria. Thus, CFAEs are at least partly influenced by the ANS.

Feasibility of electroporation for the creation of pulmonary vein ostial lesions.

INTRODUCTION: There is an obvious need for a better energy source for pulmonary vein (PV) antrum isolation. OBJECTIVE: We investigated the feasibility and safety of electroporation for the creation of PV ostial lesions. METHODS: After transseptal puncture, a custom 7F decapolar 20 mm circular ablation catheter was placed in the PV ostia of 10 pigs. Ablation was performed with a nonarcing, 200 J application delivered between the catheter and an indifferent patch electrode on the lower back. A single pulse was applied for each catheter position, with a maximum of 4 per ostium. Local PV electrogram amplitude and stimulation threshold were measured at multiple locations in both ostia before and directly after ablation, and after 3 weeks survival, using a regular 4 mm mapping catheter. All PV ostia were sectioned, stained, and histologically investigated. RESULTS: The 3-week survival period was uneventful. PV ostial electrogram amplitude decreased and stimulation threshold increased significantly in most ostia. PV angiograms did not show any stenosis during this short follow-up. Histologically, up to 3.5-mm-deep lesions were found. CONCLUSION: Data suggest that electroporation can safely be used to create lesions in a sensitive environment like PV ostia.

Can optimization of pacing settings compensate for a non-optimal left ventricular pacing site?

AIMS: Optimal left ventricular (LV) lead position improves the response to cardiac resynchronization therapy (CRT). However, in some patients it is not possible to position the LV lead at an optimal pacing site. The aim of this study was to determine whether optimization of the pacing settings atrioventricular delay (AVD) and interventricular delay (VVD) can compensate for a non-optimal LV pacing site. METHODS AND RESULTS: In 16 patients with heart failure [New York Heart Association class III (13) or IV (3), median QRS duration of 172 ms and median LV ejection fraction of 20%] the acute haemodynamic effect of biventricular pacing was assessed at > or =2 pacing sites by the increase in maximum rate of LV pressure rise (%dP/dt(max)). At each site the AVD and VVD were optimized. Biventricular pacing with nominal settings at a non-optimal LV pacing site improved dP/dt(max) by 12.8% (-0.5 to 23.2%). This could be further improved by 6.5 percentage points (1.2-13.9) by optimization of pacing settings (P = 0.001) and by 9.9 percentage points (3.7-13.3, P = 0.004) by optimization of pacing site. Optimization of the LV pacing site and pacing settings together improved %dP/dt(max) by 16.2 per cent points (10.0-21.8, P < 0.001). CONCLUSION: Optimization of the AVD and VVD can partly compensate for a non-optimal LV pacing site. However, a combination of an optimal LV pacing site and optimized pacing settings gives the best acute haemodynamic response.

Practical and conceptual limitations of tissue Doppler imaging to predict reverse remodelling in cardiac resynchronisation therapy.

BACKGROUND: Recent, conflicting results about the use of tissue Doppler imaging derived (TDI-) asynchrony indices to predict reverse remodelling after cardiac resynchronisation therapy (CRT) have raised questions about their physiological meaning and methodological limitations. METHODS: In 41 patients, baseline TDI-derived septal to lateral delays of peak velocities (TDI-SL), standard deviation of peak velocities over 12 segments (Ts-SD), and peak 2D longitudinal strain (strain-SL) were compared with volumetric response (reduction in end-systolic volume of > or =15%) after at least 6 months of CRT. Timing of peak TDI velocities was compared to timing of 2DS velocities and strain-SL. Influence of sample position, transverse motion, and interobserver inconsistency of the chosen peak velocities was assessed. Diagnostic accuracy of TDI-based delays was compared to accuracy of visual and 2D strain-based assessment. RESULTS: After 7.0+/-3.2 months of CRT, 24 patients were classified as responders. TDI-SL and Ts-SD were similar between responders and nonresponders at baseline, did not predict response, and were unaffected by CRT. Visual asynchrony scoring and strain-SL were better predictors of response than TDI-SL and Ts-SD. TDI measurements were highly susceptible to sample location and transverse motion components and poorly correlated with the timing of longitudinal contraction. There was a considerably poor agreement between observers with regard to scoring of TDI-SL and Ts-SD. CONCLUSION: TDI-based measurements of asynchrony do not appear robust predictors of volume response to CRT.