Left ventricular activation-recovery interval variability predicts spontaneous ventricular tachyarrhythmia in patients with heart failure.

BACKGROUND: Enhanced beat-to-beat variability of repolarization is strongly linked to arrhythmogenesis and is largely due to variation in ventricular action potential duration (APD). Previous studies in humans have relied on QT interval measurements; however, a direct relationship between beat-to-beat variability of APD and arrhythmogenesis in humans has yet to be demonstrated. OBJECTIVE: This study aimed to explore the beat-to-beat repolarization dynamics in patients with heart failure at the level of ventricular APD. METHODS: Forty-three patients with heart failure and implanted cardiac resynchronization therapy - defibrillator devices were studied. Activation-recovery intervals as a surrogate for APD were recorded from the left ventricular epicardial lead while pacing from the right ventricular lead to maintain a constant cycle length. RESULTS: During a mean follow-up of 23.6±13.6 months, 11 patients sustained ventricular fibrillation/ventricular tachycardia (VT/VF) and received appropriate implantable cardioverter-defibrillator therapies (antitachycardia pacing or shock therapy). Activation-recovery interval variability (ARIV) was significantly greater in patients with subsequent VT/VF than in those without VT/VF (3.55±1.3 ms vs 2.77±1.09 ms; P=.047). Receiver operating characteristic curve analysis (area under the curve 0.71; P=.046) suggested high- and low-risk ARIV groups for VT/VF. Kaplan-Meier survival analysis demonstrated that the time until first appropriate therapy for VT/VF was significantly shorter in the high-risk ARIV group (P=.028). ARIV was a predictor for VT/VF in the multivariate Cox model (hazard ratio 1.623; 95% confidence interval 1.1-2.393; P=.015). CONCLUSION: Increased left ventricular ARIV is associated with an increased risk of VT/VF in patients with heart failure.

Unraveling the Underlying Arrhythmia Mechanism in Persistent Atrial Fibrillation: Results From the STARLIGHT Study.

BACKGROUND: The mechanisms that initiate and sustain persistent atrial fibrillation are not well characterized. Ablation results remain significantly worse than in paroxysmal atrial fibrillation in which the mechanism is better understood and subsequent targeted therapy has been developed. The aim of this study was to characterize and quantify patterns of activation during atrial fibrillation using contact mapping. METHODS: Patients with persistent atrial fibrillation (n=14; mean age, 61±8 years; ejection fraction, 59±10%) underwent simultaneous biatrial contact mapping with 64 electrode catheters. The atrial electrograms were transformed into phase, and subsequent spatiotemporal mapping was performed to identify phase singularities (PSs). RESULTS: PSs were located in both atria, but we observed more PSs in the left atrium compared with the right atrium (779±302, 552±235; P=0.015). Although some PSs of duration sufficient to complete >1 rotation were detected, the maximum PS duration was only 1150 ms, and the vast majority (97%) of PSs persisted for too short a period to complete a full rotation. Although in selected patients there was evidence of PS local clustering, overall, PSs were distributed globally throughout both chambers with no clear anatomic predisposition. In a subset of patients (n=7), analysis was repeated using an alternative established atrial PS mapping technique, which confirmed our initial findings. CONCLUSIONS: No sustained rotors or localized drivers were detected, and instead, the mechanism of arrhythmia maintenance was consistent with the multiple wavelet hypothesis, with passive activation of short-lived rotational activity. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01765075.

Personalized Models of Human Atrial Electrophysiology Derived From Endocardial Electrograms.

OBJECTIVE: Computational models represent a novel framework for understanding the mechanisms behind atrial fibrillation (AF) and offer a pathway for personalizing and optimizing treatment. The characterization of local electrophysiological properties across the atria during procedures remains a challenge. The aim of this work is to characterize the regional properties of the human atrium from multielectrode catheter measurements. METHODS: We propose a novel method that characterizes regional electrophysiology properties by fitting parameters of an ionic model to conduction velocity and effective refractory period restitution curves obtained by a s1-s2 pacing protocol applied through a multielectrode catheter. Using an in-silico dataset we demonstrate that the fitting method can constrain parameters with a mean error of 21.9 ± 16.1% and can replicate conduction velocity and effective refractory curves not used in the original fitting with a relative error of 4.4 ± 6.9%. RESULTS: We demonstrate this parameter estimation approach on five clinical datasets recorded from AF patients. Recordings and parametrization took approx. 5 and 6 min, respectively. Models fitted restitution curves with an error of ~ 5% and identify a unique parameter set. Tissue properties were predicted using a two-dimensional atrial tissue sheet model. Spiral wave stability in each case was predicted using tissue simulations, identifying distinct stable (2/5), meandering and breaking up (2/5), and unstable self-terminating (1/5) spiral tip patterns for different cases. CONCLUSION AND SIGNIFICANCE: We have developed and demonstrated a robust and rapid approach for personalizing local ionic models from a clinically tractable.

Development, Preclinical Validation, and Clinical Translation of a Cardiac Magnetic Resonance - Electrophysiology System With Active Catheter Tracking for Ablation of Cardiac Arrhythmia.

OBJECTIVES: This study sought to develop an actively tracked cardiac magnetic resonance-guided electrophysiology (CMR-EP) system and perform first-in-human clinical ablation procedures. BACKGROUND: CMR-EP offers high-resolution anatomy, arrhythmia substrate, and ablation lesion visualization in the absence of ionizing radiation. Implementation of active tracking, where catheter position is continuously transmitted in a manner analogous to electroanatomic mapping (EAM), is crucial for CMR-EP to take the step from theoretical technology to practical clinical tool. METHODS: The setup integrated a clinical 1.5-T scanner, an EP recording and ablation system, and a real-time image guidance platform with components undergoing ex vivo validation. The full system was assessed using a preclinical study (5 pigs), including mapping and ablation with histological validation. For the clinical study, 10 human subjects with typical atrial flutter (age 62 ± 15 years) underwent MR-guided cavotricuspid isthmus (CTI) ablation. RESULTS: The components of the CMR-EP system were safe (magnetically induced torque, radiofrequency heating) and effective in the CMR environment (location precision). Targeted radiofrequency ablation was performed in all animals and 9 (90%) humans. Seven patients had CTI ablation completed using CMR guidance alone; 2 patients required completion under fluoroscopy, with 2 late flutter recurrences. Acute and chronic CMR imaging demonstrated efficacious lesion formation, verified with histology in animals. Anatomic shape of the CTI was an independent predictor of procedural success. CONCLUSIONS: CMR-EP using active catheter tracking is safe and feasible. The CMR-EP setup provides an effective workflow and has the potential to change the way in which ablation procedures may be performed.

Biophysical Modeling Predicts Ventricular Tachycardia Inducibility and Circuit Morphology: A Combined Clinical Validation and Computer Modeling Approach.

INTRODUCTION: Computational modeling of cardiac arrhythmogenesis and arrhythmia maintenance has made a significant contribution to the understanding of the underlying mechanisms of arrhythmia. We hypothesized that a cardiac model using personalized electro-anatomical parameters could define the underlying ventricular tachycardia (VT) substrate and predict reentrant VT circuits. We used a combined modeling and clinical approach in order to validate the concept. METHODS AND RESULTS: Non-contact electroanatomic mapping studies were performed in 7 patients (5 ischemics, 2 non-ischemics). Three ischemic cardiomyopathy patients underwent a clinical VT stimulation study. Anatomical information was obtained from cardiac magnetic resonance imaging (CMR) including high-resolution scar imaging. A simplified biophysical mono-domain action potential model personalized with the patients' anatomical and electrical information was used to perform in silico VT stimulation studies for comparison. The personalized in silico VT stimulations were able to predict VT inducibility as well as the macroscopic characteristics of the VT circuits in patients who had clinical VT stimulation studies. The patients with positive clinical VT stimulation studies had wider distribution of action potential duration restitution curve (APD-RC) slopes and APDs than the patient with a negative VT stimulation study. The exit points of reentrant VT circuits encompassed a higher percentage of the maximum APD-RC slope compared to the scar and non-scar areas, 32%, 4%, and 0.2%, respectively. CONCLUSIONS: VT stimulation studies can be simulated in silico using a personalized biophysical cardiac model. Myocardial spatial heterogeneity of APD restitution properties and conductivity may help predict the location of crucial entry/exit points of reentrant VT circuits.

An activation-repolarization time metric to predict localized regions of high susceptibility to reentry.

BACKGROUND: Initiation of reentrant ventricular tachycardia (VT) involves complex interactions between front and tail of the activation wave. Recent experimental work has identified the time interval between S2 repolarization proximal to a line of functional block and S2 activation at the adjacent distal side as a critical determinant of reentry. OBJECTIVES: We hypothesized that (1) an algorithm could be developed to generate a spatial map of this interval ("reentry vulnerability index" [RVI]), (2) this would accurately identify a site of reentry without the need to actually induce the arrhythmia, and (3) it would be possible to generate an RVI map in patients during routine clinical procedures. METHODS: An algorithm was developed that calculated RVI between all pairs of electrodes within a given radius. RESULTS: The algorithm successfully identified the region with increased susceptibility to reentry in an established Langendorff pig heart model and the site of reentry and rotor formation in an optically mapped sheep ventricular preparation and computational simulations. The feasibility of RVI mapping was evaluated during a clinical procedure by coregistering with cardiac anatomy and physiology of a patient undergoing VT ablation. CONCLUSION: We developed an algorithm to calculate a reentry vulnerability index from intervals between local repolarization and activation. The algorithm accurately identified the region of reentry in 2 animal models of functional reentry. The clinical application was demonstrated in a patient with VT and identified the area of reentry without the need of inducing the arrhythmia.

Persistent atrial fibrillation presenting in sinus rhythm: pulmonary vein isolation versus pulmonary vein isolation plus electrogram-guided ablation.

BACKGROUND: The classification of atrial fibrillation as paroxysmal or persistent (PsAF) is clinically useful, but does not accurately reflect the underlying pathophysiology and is therefore a suboptimal guide to selection of ablation strategy. AIM: To determine if additional substrate ablation is beneficial for a subset of patients with PsAF, in whom long periods of sinus rhythm (SR) can be maintained. METHODS: We included patients presenting with PsAF in whom continuous periods of SR>3months were documented. All patients were in SR on the day of the procedure. Electrical pulmonary vein isolation (PVI) was performed in all patients. Additional electrogram (EGM)-guided ablation was left to the discretion of the operator. Patient characteristics and follow-up were analysed with respect to presence or absence of additional EGM-guided ablation. RESULTS: Sixty-five patients (mean age 60.1±8.9years; 81.5% men) met the inclusion criteria. EGM-guided ablation was performed in 32 (49%) patients. Patients with and without EGM-guided ablation had similar baseline characteristics. Absence of EGM-guided ablation was one of the independent predictors for arrhythmia recurrences after the index procedure (hazard ratio 0.24; confidence interval 0.12-0.47). After a median follow-up of 18±10months, the number of procedures required was significantly higher in the 'PVI-only' group (2.24±0.75 vs. 1.84±0.81; P=0.04) to achieve a similar success rate (84% vs. 81%; P=0.833). CONCLUSION: The addition of EGM-guided ablation requires fewer procedures to achieve similar clinical efficacy in mid-term follow-up compared with a PVI-only strategy in patients with PsAF presenting for ablation in SR.

Real-time x-ray fluoroscopy-based catheter detection and tracking for cardiac electrophysiology interventions.

PURPOSE: X-ray fluoroscopically guided cardiac electrophysiology (EP) procedures are commonly carried out to treat patients with arrhythmias. X-ray images have poor soft tissue contrast and, for this reason, overlay of a three-dimensional (3D) roadmap derived from preprocedural volumetric images can be used to add anatomical information. It is useful to know the position of the catheter electrodes relative to the cardiac anatomy, for example, to record ablation therapy locations during atrial fibrillation therapy. Also, the electrode positions of the coronary sinus (CS) catheter or lasso catheter can be used for road map motion correction. METHODS: In this paper, the authors present a novel unified computational framework for image-based catheter detection and tracking without any user interaction. The proposed framework includes fast blob detection, shape-constrained searching and model-based detection. In addition, catheter tracking methods were designed based on the customized catheter models input from the detection method. Three real-time detection and tracking methods are derived from the computational framework to detect or track the three most common types of catheters in EP procedures: the ablation catheter, the CS catheter, and the lasso catheter. Since the proposed methods use the same blob detection method to extract key information from x-ray images, the ablation, CS, and lasso catheters can be detected and tracked simultaneously in real-time. RESULTS: The catheter detection methods were tested on 105 different clinical fluoroscopy sequences taken from 31 clinical procedures. Two-dimensional (2D) detection errors of 0.50 ± 0.29, 0.92 ± 0.61, and 0.63 ± 0.45 mm as well as success rates of 99.4%, 97.2%, and 88.9% were achieved for the CS catheter, ablation catheter, and lasso catheter, respectively. With the tracking method, accuracies were increased to 0.45 ± 0.28, 0.64 ± 0.37, and 0.53 ± 0.38 mm and success rates increased to 100%, 99.2%, and 96.5% for the CS, ablation, and lasso catheters, respectively. Subjective clinical evaluation by three experienced electrophysiologists showed that the detection and tracking results were clinically acceptable. CONCLUSIONS: The proposed detection and tracking methods are automatic and can detect and track CS, ablation, and lasso catheters simultaneously and in real-time. The accuracy of the proposed methods is sub-mm and the methods are robust toward low-dose x-ray fluoroscopic images, which are mainly used during EP procedures to maintain low radiation dose.

Left ventricular epicardial electrograms show divergent changes in action potential duration in responders and nonresponders to cardiac resynchronization therapy.

BACKGROUND: A consistent feature of electrophysiological remodeling in heart failure is ventricular action potential duration (APD) prolongation. However, the effect of reverse remodeling on APD during cardiac resynchronization therapy (CRT) has not been determined in these patients. We hypothesized (1) that CRT may alter APD and (2) that the effect of CRT on APD may be different in patients who exhibit a good hemodynamic response to CRT compared with those with a poor response. METHODS AND RESULTS: Left ventricular (LV) activation recovery intervals, as a surrogate for APD, were measured from the LV epicardium in 13 patients at day 0, 6 weeks, and 6 months after CRT implant. Responders to CRT were defined as those demonstrating a ≥15% reduction in LV end-systolic volume at 6 months. The responder group had a significant reduction in LV activation recovery interval (mean, -13±12 ms; median, -16 ms; interquartile range, -2 to -19 ms) during right ventricular pacing at 6 months (P<0.05). Conversely, the nonresponders showed a significant increase in activation recovery interval (mean, +22 ms±16; median, 17 ms; interquartile range, 8 to 35 ms; P<0.05). One patient in each group was on amiodarone. CONCLUSIONS: In patients with heart failure, LV epicardial APD (activation recovery interval) altered during CRT. The effect on APD was opposite in patients showing a good hemodynamic response compared with nonresponders. The findings may provide an explanation for the persistent high incidence of arrhythmias in some patients with CRT and the additional mortality benefit observed in responders of CRT.

Benefits of endocardial and multisite pacing are dependent on the type of left ventricular electric activation pattern and presence of ischemic heart disease: insights from electroanatomic mapping.

BACKGROUND: There is considerable heterogeneity in the myocardial substrate of patients undergoing cardiac resynchronization therapy (CRT), in particular in the etiology of heart failure and in the location of conduction block within the heart. This may account for variability in response to CRT. New approaches, including endocardial and multisite left ventricular (LV) stimulation, may improve CRT response. We sought to evaluate these approaches using noncontact mapping to understand the underlying mechanisms. METHODS AND RESULTS: Ten patients (8 men and 2 women; mean [SD] age 63 [12] years; LV ejection fraction 246%; QRS duration 161 [24] ms) fulfilling conventional CRT criteria underwent an electrophysiological study, with assessment of acute hemodynamic response to conventional CRT as well as LV endocardial and multisite pacing. LV activation pattern was assessed using noncontact mapping. LV endocardial pacing gave a superior acute hemodynamic response compared with conventional CRT (26% versus 37% increase in LV dP/dt(max), respectively; P<0.0005). There was a trend toward further incremental benefit from multisite LV stimulation, although this did not reach statistical significance (P=0.08). The majority (71%) of patients with nonischemic heart failure etiology or functional block responded to conventional CRT, whereas those with myocardial scar or absence of functional block often required endocardial or multisite pacing to achieve CRT response. CONCLUSIONS: Endocardial or multisite pacing may be required in certain subsets of patients undergoing CRT. Patients with ischemic cardiomyopathy and those with narrower QRS, in particular, may stand to benefit.

Relationship between endocardial activation sequences defined by high-density mapping to early septal contraction (septal flash) in patients with left bundle branch block undergoing cardiac resynchronization therapy.

AIMS: Early inward motion and thickening/thinning of the ventricular septum associated with left bundle branch block is known as the septal flash (SF). Correction of SF corresponds to response to cardiac resynchronization therapy (CRT). We hypothesized that SF was associated with a specific left ventricular (LV) activation pattern predicting a favourable response to CRT. We sought to characterize the spatio-temporal relationship between electrical and mechanical events by directly comparing non-contact mapping (NCM), acute haemodynamics, and echocardiography. METHODS AND RESULTS: Thirteen patients (63 ± 10 years, 10 men) with severe heart failure (ejection fraction 22.8 ± 5.8%) awaiting CRT underwent echocardiography and NCM pre-implant. Presence and extent of SF defined visually and with M-mode was fused with NCM bull's eye plots of endocardial activation patterns. LV-dP/dt(max) was measured during different pacing modes. Five patients had a large SF, four small SF, and four no SF. Large SF patients had areas of conduction block in non-infarcted regions, whereas those with small or no SF did not. Patients with large SF had greater acute response to LV and biventricular (BIV) pacing vs. those with small/no SF (% increase dP/dt 28 ± 14 vs. 11 ± 19% for LV pacing and 42 ± 28 vs. 22 ± 21% for BIV pacing) (P < 0.05). This translated into a more favourable chronic response to CRT. The lines of conduction block disappeared with LV/BIV pacing while remaining with right ventricle pacing. CONCLUSION: A strong association exists between electrical activation and mechanical deformation of the septum. Correction of both mechanical synchrony and the functional conduction block by CRT may explain the favourable response in patients with SF.

Clinical evaluation of respiratory motion compensation for anatomical roadmap guided cardiac electrophysiology procedures.

X-ray fluoroscopically guided cardiac electrophysiological procedures are routinely carried out for diagnosis and treatment of cardiac arrhythmias. X-ray images have poor soft tissue contrast and, for this reason, overlay of static 3-D roadmaps derived from preprocedural volumetric data can be used to add anatomical information. However, the registration between the 3-D roadmap and the 2-D X-ray image can be compromised by patient respiratory motion. Three methods were designed and evaluated to correct for respiratory motion using features in the 2-D X-ray images. The first method is based on tracking either the diaphragm or the heart border using the image intensity in a region of interest. The second method detects the tracheal bifurcation using the generalized Hough transform and a 3-D model derived from 3-D preoperative volumetric data. The third method is based on tracking the coronary sinus (CS) catheter. This method uses blob detection to find all possible catheter electrodes in the X-ray image. A cost function is applied to select one CS catheter from all catheter-like objects. All three methods were applied to X-ray images from 18 patients undergoing radiofrequency ablation for the treatment of atrial fibrillation. The 2-D target registration errors (TRE) at the pulmonary veins were calculated to validate the methods. A TRE of 1.6 mm ± 0.8 mm was achieved for the diaphragm tracking; 1.7 mm ± 0.9 mm for heart border tracking, 1.9 mm ± 1.0 mm for trachea tracking, and 1.8 mm ± 0.9 mm for CS catheter tracking. We present a comprehensive comparison between the techniques in terms of robustness, as computed by tracking errors, and accuracy, as computed by TRE using two independent approaches.

Real-time respiratory motion correction for cardiac electrophysiology procedures using image-based coronary sinus catheter tracking.

X-ray fluoroscopically guided cardiac electrophysiological procedures are routinely carried out for diagnosis and treatment of cardiac arrhythmias. X-ray images have poor soft tissue contrast and, for this reason, overlay of static 3D roadmaps derived from pre-procedural volumetric data can be used to add anatomical information. However, the registration between the 3D roadmap and the 2D X-ray data can be compromised by patient respiratory motion. We propose a novel method to correct for respiratory motion using real-time image-based coronary sinus (CS) catheter tracking. The first step of the proposed technique is to use a blob detection method to detect all possible catheter electrodes in the Xray data. We then compute a cost function to select one CS catheter from all catheter-like objects. For correcting respiratory motion, we apply a low pass filter to the 2D motion of the CS catheter and update the 3D roadmap using this filtered motion. We tested our CS catheter tracking method on 1048 fluoroscopy frames from 15 patients and achieved a success rate of 99.3% and an average 2D tracking error of 0.4 mm +/- 0.2 mm. We also validated our respiratory motion correction strategy by computing the 2D target registration error (TRE) at the pulmonary veins and achieved a TRE of 1.6 mm +/- 0.9 mm.

Successful transseptal puncture for radiofrequency ablation of left atrial tachycardia after closure of secundum atrial septal defect with Amplatzer septal occluder.

We report on a 37-year-old woman presenting with atrial arrhythmias after catheter closure of a secundum atrial septal defect with an Amplatzer septal occluder device. Electrophysiological studies suggested that the arrhythmia originated from the left atrium, from an area near the device. Transseptal puncture was successfully performed under transoesophageal guidance and the arrhythmia was successfully ablated. This case showed that transseptal puncture can be safely performed in the presence of an Amplatzer septal occluder device under transoesophageal echocardiography guidance and we speculate that the device may have created the substrate for the arrhythmia.

Occurrence of atrial fibrillation after flutter ablation: the significance of intra-atrial conduction and atrial vulnerability.

Atrial vulnerability and intra-atrial conduction delay are important substrates for paroxysmal atrial fibrillation (AFib); however, their significance is unknown in patients undergoing atrial flutter ablation. Antegrade (high right atrium to coronary sinus: HRA-CS) and retrograde (CS-HRA) intra-atrial conduction times and AFib inducibility were assessed in 61 patients undergoing ablation for type I atrial flutter. Twenty-three patients had structural heart disease and 18 AFib before the procedure. After 16 +/- 12 months of follow-up 17 patients experienced AFib, 5 of which progressed into chronic AFib. During the study, AFib was easily inducible in 14 patients, 7 of which developed AFib (P =.03). Patients with post- ablation AFib were older (59 +/- 11 vs. 44 +/- 15 years, P =.001), had longer intra-atrial conduction times before (98 +/- 17 ms vs. 68 +/- 20 ms, P <.001) and after ablation (91 +/- 19 ms vs. 73 +/- 21 ms, P =.01) than those without AFib. Discriminant analysis revealed that only age, previous AFib and inta-atrial conduction delay (>90 ms) were independent predictors of postablation AFib. Patients without a history of AFib and with normal intra-atrial conduction had a 3% risk of AFib, while patients with both factors had a 90% risk of AFib after ablation. Intra-atrial conduction delay is an important electrophysiological factor predicting atrial fibrillation after successful flutter ablation.

Effect of adrenergic stimulation on action potential duration restitution in humans.

BACKGROUND: Enhanced sympathetic activity facilitates complex ventricular arrhythmias and fibrillation. The restitution properties of action potential duration (APD) are important determinants of electrical stability in the myocardium. Steepening of the slope of APD restitution has been shown to promote wave break and ventricular fibrillation. The effect of adrenergic stimulation on APD restitution in humans is unknown. METHODS AND RESULTS: Monophasic action potentials were recorded from the right ventricular septum in 18 patients. Standard APD restitution curves were constructed at 3 basic drive cycle lengths (CLs) of 600, 500, and 400 ms under resting conditions and during infusion of isoprenaline (15 patients) or adrenaline (3 patients). The maximum slope of the restitution curves was measured by piecewise linear regression segments of sequential 40-ms ranges of diastolic intervals in steps of 10 ms. Under control conditions, the maximum slope was steeper at longer basic CLs; eg, mean values for the maximum slope were 1.053+/-0.092 at CL 600 ms and 0.711+/-0.049 at CL 400 ms (+/-SEM). Isoprenaline increased the steepness of the maximum slope of APD restitution, eg, from a maximum slope of 0.923+/-0.058 to a maximum slope of 1.202+/-0.121 at CL 500 ms. The effect of isoprenaline was greater at the shorter basic CLs. A similar overall effect was observed with adrenaline. CONCLUSIONS: The adrenergic agonists isoprenaline and adrenaline increased the steepness of the slope of the APD restitution curve in humans over a wide range of diastolic intervals. These results may relate to the known effects of adrenergic stimulation in facilitating ventricular fibrillation.