Publications by authors named "Peter Loh"

55 Publications

Feasibility study of a 3D camera to reduce electrode repositioning errors during longitudinal ECG acquisition.

J Electrocardiol 2021 Mar 24;66:69-76. Epub 2021 Mar 24.

Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; ECG Excellence BV, Nieuwerbrug, the Netherlands. Electronic address:

Introduction: Longitudinal monitoring of sometimes subtle waveform changes of the 12‑lead electrocardiogram (ECG) is complicated by patient-specific and technical factors, such as the inaccuracy of electrode repositioning. This feasibility study uses a 3D camera to reduce electrode repositioning errors, reduce ECG waveform variability and enable detailed longitudinal ECG monitoring.

Methods: Per subject, three clinical ECGs were obtained during routine clinical follow-up. Additionally, two ECGs were recorded guided by two 3D cameras, which were used to capture the precordial electrode locations and direct electrode repositioning. ECG waveforms and parameters were quantitatively compared between 3D camera guided ECGs and clinical ECGs. Euclidian distances between original and repositioned precordial electrodes from 3D guided ECGs were measured.

Results: Twenty subjects (mean age 65.1 ± 8.2 years, 35% females) were included. The ECG waveform variation between routine ECGs was significantly higher compared to 3D guided ECGs, for both the QRS complex (correlation coefficient = 0.90 vs 0.98, p < 0.001) and the STT segment (correlation coefficient = 0.88 vs. 0.96, p < 0.001). QTc interval variation was reduced for 3D camera guided ECGs compared to routine clinical ECGs (5.6 ms vs. 9.6 ms, p = 0.030). The median distance between 3D guided repositioned electrodes was 10.0 [6.4-15.2] mm, and did differ between males and females (p = 0.076).

Conclusions: 3D guided repositioning of precordial electrodes resulted in, a low repositioning error, higher agreement between waveforms of consecutive ECGs and a reduction of QTc variation. These findings suggest that longitudinal monitoring of disease progression using 12‑lead ECG waveforms is feasible in clinical practice.
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http://dx.doi.org/10.1016/j.jelectrocard.2021.03.006DOI Listing
March 2021

Novel CineECG enables anatomical 3D localization and classification of bundle branch blocks.

Europace 2021 Mar;23(Supplement_1):i80-i87

Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht 3508 GA, Heidelberglaan 100, Utrecht, The Netherlands.

Aims: Ventricular conduction disorders can induce arrhythmias and impair cardiac function. Bundle branch blocks (BBBs) are diagnosed by 12-lead electrocardiogram (ECG), but discrimination between BBBs and normal tracings can be challenging. CineECG computes the temporo-spatial trajectory of activation waveforms in a 3D heart model from 12-lead ECGs. Recently, in Brugada patients, CineECG has localized the terminal components of ventricular depolarization to right ventricle outflow tract (RVOT), coincident with arrhythmogenic substrate localization detected by epicardial electro-anatomical maps. This abnormality was not found in normal or right BBB (RBBB) patients. This study aimed at exploring whether CineECG can improve the discrimination between left BBB (LBBB)/RBBB, and incomplete RBBB (iRBBB).

Methods And Results: We utilized 500 12-lead ECGs from the online Physionet-XL-PTB-Diagnostic ECG Database with a certified ECG diagnosis. The mean temporo-spatial isochrone trajectory was calculated and projected into the anatomical 3D heart model. We established five CineECG classes: 'Normal', 'iRBBB', 'RBBB', 'LBBB', and 'Undetermined', to which each tracing was allocated. We determined the accuracy of CineECG classification with the gold standard diagnosis. A total of 391 ECGs were analysed (9 ECGs were excluded for noise) and 240/266 were correctly classified as 'normal', 14/17 as 'iRBBB', 55/55 as 'RBBB', 51/51 as 'LBBB', and 31 as 'undetermined'. The terminal mean temporal spatial isochrone contained most information about the BBB localization.

Conclusion: CineECG provided the anatomical localization of different BBBs and accurately differentiated between normal, LBBB and RBBB, and iRBBB. CineECG may aid clinical diagnostic work-up, potentially contributing to the difficult discrimination between normal, iRBBB, and Brugada patients.
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http://dx.doi.org/10.1093/europace/euaa396DOI Listing
March 2021

Efficacy of multi-electrode linear irreversible electroporation.

Europace 2021 Mar;23(3):464-468

Department of Cardiology, Isala Hospital, Heart Centre, Dr Van Heesweg 2, 8025 AB Zwolle, The Netherlands.

Aims: We investigated the efficacy of linear multi-electrode irreversible electroporation (IRE) ablation in a porcine model.

Methods And Results: The study was performed in six pigs (weight 60-75 kg). After median sternotomy and opening of the pericardium, a pericardial cradle was formed and filled with blood. A linear seven polar 7-Fr electrode catheter with 2.5 mm electrodes and 2.5 mm inter-electrode spacing was placed in good contact with epicardial tissue. A single IRE application was delivered using 50 J at one site and 100 J at two other sites, in random sequence, using a standard monophasic defibrillator connected to all seven electrodes connected in parallel. The pericardium and thorax were closed and after 3 weeks survival animals were euthanized. A total of 82 histological sections from all 18 electroporation lesions were analysed. A total of seven 50 J and fourteen 100 J epicardial IRE applications were performed. Mean peak voltages at 50 and 100 J were 1079.2 V ± 81.1 and 1609.5 V ± 56.8, with a mean peak current of 15.4 A ± 2.3 and 20.2 A ± 1.7, respectively. Median depth of the 50 and 100 J lesions were 3.2 mm [interquartile range (IQR) 3.1-3.6] and 5.5 mm (IQR 4.6-6.6) (P < 0.001), respectively. Median lesion width of the 50 and 100 J lesions was 3.9 mm (IQR 3.7-4.8) and 5.4 mm (IQR 5.0-6.3), respectively (P < 0.001). Longitudinal sections showed continuous lesions for 100 J applications.

Conclusion: Epicardial multi-electrode linear application of IRE pulses is effective in creating continuous deep lesions.
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http://dx.doi.org/10.1093/europace/euaa280DOI Listing
March 2021

In vivo analysis of the origin and characteristics of gaseous microemboli during catheter-mediated irreversible electroporation.

Europace 2021 Jan;23(1):139-146

Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Aims : Irreversible electroporation (IRE) ablation is a non-thermal ablation method based on the application of direct current between a multi-electrode catheter and skin electrode. The delivery of current through blood leads to electrolysis. Some studies suggest that gaseous (micro)emboli might be associated with myocardial damage and/or (a)symptomatic cerebral ischaemic events. The aim of this study was to compare the amount of gas generated during IRE ablation and during radiofrequency (RF) ablation.

Methods And Results: In six 60-75 kg pigs, an extracorporeal femoral shunt was outfitted with a bubble-counter to detect the size and total volume of gas bubbles. Anodal and cathodal 200 J IRE applications were delivered in the left atrium (LA) using a 14-electrode circular catheter. The 30 and 60 s 40 W RF point-by-point ablations were performed. Using transoesophageal echocardiography (TOE), gas formation was visualized. Average gas volumes were 0.6 ± 0.6 and 56.9 ± 19.1 μL (P < 0.01) for each anodal and cathodal IRE application, respectively. Also, qualitative TOE imaging showed significantly less LA bubble contrast with anodal than with cathodal applications. Radiofrequency ablations produced 1.7 ± 2.9 and 6.7 ± 7.4 μL of gas, for 30 and 60 s ablation time, respectively.

Conclusion : Anodal IRE applications result in significantly less gas formation than both cathodal IRE applications and RF applications. This finding is supported by TOE observations.
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http://dx.doi.org/10.1093/europace/euaa243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842095PMC
January 2021

Pulmonary Vein Isolation With Single Pulse Irreversible Electroporation: A First in Human Study in 10 Patients With Atrial Fibrillation.

Circ Arrhythm Electrophysiol 2020 10 8;13(10):e008192. Epub 2020 Sep 8.

Department of Cardiology, University Medical Centre Utrecht, the Netherlands (P.L., R.v.E., M.H.A.G., W.K., F.H.M.W., P.A.D.).

Background: Irreversible electroporation (IRE) is a promising new nonthermal ablation technology for pulmonary vein (PV) isolation in patients with atrial fibrillation. Experimental data suggest that IRE ablation produces large enough lesions without the risk of PV stenosis, artery, nerve, or esophageal damage. This study aimed to investigate the feasibility and safety of single pulse IRE PV isolation in patients with atrial fibrillation.

Methods: Ten patients with symptomatic paroxysmal or persistent atrial fibrillation underwent single pulse IRE PV isolation under general anesthesia. Three-dimensional reconstruction and electroanatomical voltage mapping (EnSite Precision, Abbott) of left atrium and PVs were performed using a conventional circular mapping catheter. PV isolation was performed by delivering nonarcing, nonbarotraumatic 6 ms, 200 J direct current IRE applications via a custom nondeflectable 14-polar circular IRE ablation catheter with a variable hoop diameter (16-27 mm). A deflectable sheath (Agilis, Abbott) was used to maneuver the ablation catheter. A minimum of 2 IRE applications with slightly different catheter positions were delivered per vein to achieve circular tissue contact, even if PV potentials were abolished after the first application. Bidirectional PV isolation was confirmed with the circular mapping catheter and a post ablation voltage map. After a 30-minute waiting period, adenosine testing (30 mg) was used to reveal dormant PV conduction.

Results: All 40 PVs could be successfully isolated with a mean of 2.4±0.4 IRE applications per PV. Mean delivered peak voltage and peak current were 2154±59 V and 33.9±1.6 A, respectively. No PV reconnections occurred during the waiting period and adenosine testing. No periprocedural complications were observed.

Conclusions: In the 10 patients of this first-in-human study, acute bidirectional electrical PV isolation could be achieved safely by single pulse IRE ablation.
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http://dx.doi.org/10.1161/CIRCEP.119.008192DOI Listing
October 2020

Follow-up after hemodynamically not tolerated ventricular tachycardia in patients with midrange reduced to normal ejection fraction: A retrospective single-centre case series.

Eur J Clin Invest 2021 Jan 7;51(1):e13359. Epub 2020 Aug 7.

Department of Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands.

Introduction: The benefit of implantable cardioverter-defibrillator (ICD) implantation in patients with hemodynamically not tolerated ventricular tachycardia (VT) and midrange reduced to normal ejection fraction (LVEF >35%) is currently unclear. The purpose of this study was to investigate follow-up after hemodynamically not tolerated VT in patients with LVEF >35%. In addition, we aimed to find possible predictive factors to identify who will benefit from ICD implantation.

Methods: In a retrospective single-centre case series, all patients with hemodynamically not tolerated VT and LVEF >35% that underwent electrophysiological study (EPS) and/or radiofrequency VT ablation were included.

Results: Forty-two patients (5 women, median age 68 years) with hemodynamically not tolerated VT and LVEF >35% underwent EPS. VT ablation was performed in thirty-one patients, which was considered successful in twenty-three patients. Nineteen patients had an ICD at discharge while 23 patients were discharged without an ICD. The severity of hemodynamic compromise, LVEF and ablation success played an important role in the decision-making for ICD implantation. Six patients (14.3%) had recurrence of VT, all hemodynamically tolerated.

Conclusions: In this small case series, patients with hemodynamically not tolerated VT and LVEF >35% had a relatively low recurrence rate and all recurrences were nonfatal. Based on our results, we hypothesize that the severity of hemodynamic compromise, LVEF and ablation success might modify the risk for VA recurrence. A prospective study to determine the prognostic value of these factors in patients with hemodynamically not tolerated VT and LVEF >35% is necessary.
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http://dx.doi.org/10.1111/eci.13359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757240PMC
January 2021

Quantitative Approach to Fragmented QRS in Arrhythmogenic Cardiomyopathy: From Disease towards Asymptomatic Carriers of Pathogenic Variants.

J Clin Med 2020 Feb 17;9(2). Epub 2020 Feb 17.

Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3508 GA Utrecht, The Netherlands.

Fragmented QRS complexes (fQRS) are common in patients with arrhythmogenic cardiomyopathy (ACM). A new method of fQRS quantification may aid early disease detection in pathogenic variant carriers and assessment of prognosis in patients with early stage ACM. Patients with definite ACM ( = 221, 66%), carriers of a pathogenic ACM-associated variant without a definite ACM diagnosis ( = 57, 17%) and control subjects ( = 58, 17%) were included. Quantitative fQRS (Q-fQRS) was defined as the total amount of deflections in the QRS complex in all 12 electrocardiography (ECG) leads. Q-fQRS was scored by a single observer and reproducibility was determined by three independent observers. Q-fQRS count was feasible with acceptable intra- and inter-observer agreement. Q-fQRS count is significantly higher in patients with definite ACM (54 ± 15) and pathogenic variant carriers (55 ± 10) compared to controls (35 ± 5) ( < 0.001). In patients with ACM, Q-fQRS was not associated with sustained ventricular arrhythmia ( = 0.701) at baseline or during follow-up ( = 0.335). Both definite ACM patients and pathogenic variant carriers not fulfilling ACM diagnosis have a higher Q-fQRS than controls. This may indicate that increased Q-fQRS is an early sign of disease penetrance. In concealed and early stages of ACM the role of Q-fQRS for risk stratification is limited.
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http://dx.doi.org/10.3390/jcm9020545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073517PMC
February 2020

MRI-guided pulmonary vein isolation for atrial fibrillation: what is good enough? An early health technology assessment.

Open Heart 2019;6(2):e001014. Epub 2019 Nov 11.

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Next to anticoagulation, pulmonary vein isolation (PVI) is the most important interventional procedure in the treatment of atrial fibrillation (AF). Despite widespread clinical application of this therapy, patients often require multiple procedures to reach clinical success. In contrast to conventional imaging modalities, MRI allows direct visualisation of the ablation lesion. Therefore, the use of real-time MRI to guide cardiac electrophysiology procedures may increase clinical effectiveness. An essential aspect, from a decision-making point of view, is the effect on costs and the potential cost-effectiveness of new technologies. Generally, health technology assessment (HTA) studies are performed when innovations are close to clinical application. However, stage HTA can inform users, researchers and funders about the ultimate clinical and economic potential of a future innovation. Ultimately, this can guide funding allocation. In this study, we performed an early HTA evaluate MRI-guided PVIs.

Methods: We performed an economic evaluation using a decision tree with a time-horizon of 1 year. We calculated the (defined as the proportion of patients that is long-term free of AF after a single procedure) required for MRI-guided PVI to be cost-effective compared with conventional treatment.

Results: Depending on the (willingness to pay for one additional quality-of-life adjusted life year (QALY), interventional MRI (iMRI) guidance for PVI can be cost-effective if clinical effectiveness is 69.8% (at €80 000/QALY) and 77.1% (at €20 000/QALY), compared with 64% for fluoroscopy-guided procedures.

Conclusion: Using an early HTA, we established a clinical effectiveness threshold for interventional MRI-guided PVIs that can inform a clinical implementation strategy. If crucial technologies are developed, it seems plausible that iMRI-guided PVIs will be able to reach this threshold.
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http://dx.doi.org/10.1136/openhrt-2019-001014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861091PMC
February 2021

Incidence and predictors of implantable cardioverter-defibrillator therapy and its complications in idiopathic ventricular fibrillation patients.

Europace 2019 Oct;21(10):1519-1526

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Aims: Idiopathic ventricular fibrillation (IVF) is a rare cause of sudden cardiac arrest. Implantable cardioverter-defibrillator (ICD) implantation is currently the only treatment option. Limited data are available on the prevalence and complications of ICD therapy in these patients. We sought to investigate ICD therapy and its complications in patients with IVF.

Methods And Results: Patients were selected from a national registry of IVF patients. Patients in whom no underlying diagnosis was found during follow-up were eligible for inclusion. Recurrence of ventricular arrhythmia (VA) was derived from medical and ICD records, electrogram records of ICD therapies were used to differentiate between appropriate or inappropriate interventions. Independent predictors for appropriate ICD shock were calculated using cox regression. In 217 IVF patients, recurrence of sustained VAs occurred in 66 patients (30%) during a median follow-up period of 6.1 years. Ten patients died (4.6%). Thirty-eight patients (17.5%) experienced inappropriate ICD therapy, and 32 patients (14.7%) had device-related complications. Symptoms before cardiac arrest [hazard ratio (HR): 2.51, 95% confidence interval (CI): 1.48-4.24], signs of conduction disease (HR: 2.27, 95% CI: 1.15-4.47), and carrier of the DPP6 risk haplotype (HR: 3.24, 1.70-6.17) were identified as independent predictors of appropriate shock occurrence.

Conclusion: Implantable cardioverter-defibrillator therapy is an effective treatment in IVF, treating recurrences of potentially lethal VAs in approximately one-third of patients during long-term follow-up. However, device-related complications and inappropriate shocks were also frequent. We found significant predictors for appropriate ICD therapy. This may imply that these patients require additional management to prevent recurrent events.
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http://dx.doi.org/10.1093/europace/euz151DOI Listing
October 2019

Atrial Dysfunction in Arrhythmogenic Right Ventricular Cardiomyopathy.

Circ Cardiovasc Imaging 2018 09;11(9):e007344

Department of Radiology, University Medical Center Utrecht, The Netherlands (B.K.V.).

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy that is predominantly known to affect the ventricles. Evidence for atrial involvement remains limited. Therefore, we aimed to characterize atrial involvement in ARVC using functional cardiac magnetic resonance, define the extent of atrial size and function variation attributable to ventricular variables, and identify cardiac magnetic resonance-based predictors of atrial arrhythmias (AA) in ARVC.

Methods And Results: We analyzed cine cardiac magnetic resonance images of 66 definite ARVC patients without a history of AA or severe heart failure and 24 healthy controls. Using tissue tracking, we evaluated phasic biatrial volumes, ejection fractions (EFs), peak longitudinal strain, and strain rates (SRs). The primary outcome was the occurrence of AA during 6.8 years [3.0-10.8 years] of follow-up. Compared with controls, ARVC patients had higher biatrial volumes, reduced right atrial (RA) conduit function (passive EF [RAEF] and peak early-diastolic SR), reduced RA and left atrial (LA) reservoir function (peak systolic SR), and reduced RA and LA pump function (peak late-diastolic SR; P<0.05). Using multivariable analysis, predictors of increased risk of AA during follow-up were higher atrial volumes (RAV and LAV), decreased LA reservoir function (total LAEF and LA peak longitudinal strain), and decreased RA conduit function (passive RAEF and RA early-diastolic SR).

Conclusions: Compared with controls, patients with ARVC were found to have enlarged atria with decreased function on functional cardiac magnetic resonance examination. RA and LA parameters predict incident AA after adjusting for clinical and ventricular characteristics which suggests atrial involvement in ARVC.
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http://dx.doi.org/10.1161/CIRCIMAGING.117.007344DOI Listing
September 2018

Incidence of Pulmonary Vein Stenosis After Radiofrequency Catheter Ablation of Atrial Fibrillation.

JACC Clin Electrophysiol 2017 06 26;3(6):589-598. Epub 2017 Apr 26.

Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Objectives: This study aimed to determine incidence of pulmonary vein stenosis (PVS) and evaluate PVS-related symptoms.

Background: The real-life incidence of PVS after radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) is unknown.

Methods: All patients who underwent RFCA of AF from 2005 to 2016 with routine pre- and post-ablation screening by magnetic resonance imaging or computed tomography were included. Primary ablation strategy was PV antrum isolation alone in all patients. PVS, defined as a significant reduction in the superoinferior or anteroposterior PV diameter, was classified as mild (30% to 50%), moderate (50% to 70%), or severe (>70%).

Results: Sufficient quality imaging of the PV anatomy before ablation and during follow-up (mean 6 ± 4 months) was performed in 976 patients (76.4% men, 59.1% paroxysmal AF). Of these patients, 306 (31.4%) showed mild stenosis, 42 (4.3%) revealed moderate stenosis, and 7 (0.7%) had a severe stenosis in at least 1 PV. Incidence of PVS fluctuated over the past decade. All severe PVS cases were likely caused by ablations being performed inside the PVs. Only 1 (0.1%) patient reported PVS-related symptoms of severe dyspnea during follow-up. Computed tomography revealed a subtotal occlusion of the left inferior PV and a severe stenosis of the left superior PV, requiring stenting.

Conclusions: Although mild PVS was frequently observed after RFCA in this large cohort, incidence of severe PVS was <1% and incidence of symptomatic PVS necessitating intervention was negligible. Based on these findings, it seems appropriate to only screen for PVS in patients with suggestive symptoms.
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http://dx.doi.org/10.1016/j.jacep.2017.02.003DOI Listing
June 2017

Evaluation of Structural Progression in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.

JAMA Cardiol 2017 03;2(3):293-302

Division of Cardiology, Department of Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.

Importance: Considerable research has described the arrhythmic course of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, objective data characterizing structural progression, such as ventricular enlargement and cardiac dysfunction, in ARVD/C are relatively scarce.

Objectives: To define the extent of structural progression, identify determinants of structural progression, and determine the association between structural progression and electrocardiographic (ECG) changes in patients with ARVD/C.

Design, Setting, And Participants: In this cohort study, first- and last-available echocardiograms of 85 patients with ARVD/C fulfilling 2010 Task Force diagnostic criteria (TFC) from a transatlantic ARVD/C registry were retrospectively compared to assess structural disease progression. Right ventricular (RV) size and systolic function between baseline and last follow-up were compared. The RV size was determined by RV outflow tract dimension, and RV and left ventricular (LV) systolic function were determined by RV fractional area change (RV-FAC) and LV ejection fraction (LVEF), respectively. Multivariable logistic regression was used to study associations between baseline characteristics and the occurrence of structural progression.

Main Outcomes And Measures: The main outcome was the change in variables indicating structural progression. Secondary outcomes were the correlation with electrical progression and identification of the association between baseline characteristics and occurence structural progression.

Results: Among the 85 patients with ARVD/C, mean (SD) age at baseline was 42.8 (14.4) years and 47 (55%) were men. After a mean (SD) follow-up of 6.4 (2.5) years, RV outflow tract dimension increased from 35 mm (interquartile range [IQR], 31 to 39) to 37 mm (IQR, 33 to 41) (P < .001), RV-FAC decreased from 39% (IQR, 33% to 44%) to 34% (IQR, 24% to 42%) (P < .001) (rate -3.3% per 5 years; IQR, -8.9% to 1.2%), indicating large interpatient variability. The LVEF decreased from 55% (IQR, 52% to 60%) to 54% (IQR, 49% to 57%) (P = .001) (rate, -0.2% per 5 years; IQR, -6.5% to 1.7%). Forty examinations were reanalyzed to establish the measurement error. Patients exceeding the measurement error by ±2 SDs were identified with significant progressive disease for RV, with a decrease in RV-FAC greater than 10% (n = 21) and, for LV, a decrease in LVEF greater than 7% (n = 23). Progression of RV disease was associated with depolarization criteria at baseline (odds ratio [OR], 9.0; 95% CI, 1.1-74.2; P = .04), whereas progression of LV disease was associated with phospholamban (PLN) mutation (OR, 8.8; 95% CI, 2.1-37.2; P = .003). There was no association between progressive RV/LV structural disease and newly developed ECG TFC.

Conclusions And Relevance: Structural dysfunction in ARVD/C is progressive with substantial interpatient variability. Significant structural RV progression was associated with prior depolarization abnormalities, whereas LV progression is modified by genetic background. Structural progression was not associated with development of new ECG TFC. The results of this study pave the way for designing and launching trials aimed at reducing structural progression in patients with ARVD/C.
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http://dx.doi.org/10.1001/jamacardio.2016.5034DOI Listing
March 2017

Next-generation sequencing of a large gene panel in patients initially diagnosed with idiopathic ventricular fibrillation.

Heart Rhythm 2017 07 11;14(7):1035-1040. Epub 2017 Jan 11.

Department of Cardiology, University Medical Centre, Utrecht, The Netherlands; Department of Internal Medicine and Cardiology, Bergman Clinics, Bilthoven, The Netherlands.

Background: Idiopathic ventricular fibrillation (IVF) is a rare primary cardiac arrhythmia syndrome that is diagnosed in a resuscitated cardiac arrest victim, with documented ventricular fibrillation, in whom no underlying cause is identified after comprehensive clinical evaluation. In some patients, causative genetic mutations are detected that facilitate patient treatment and follow-up. The feasibility of next-generation sequencing (NGS) has increased with its greater availability and decreasing costs.

Objective: The aim of this study was to assess the diagnostic yield of NGS in patients with IVF.

Methods: A total of 33 patients initially diagnosed with IVF were included (mean age 53 ± 15 years; 14(42%) men). In all included patients, NGS of 33 genes and the DPP6 haplotype revealed no pathogenic mutations. Genetic screening comprised NGS of a panel of 179 additional genes. Variants with a minor allele frequency of <0.05% were assessed for pathogenicity by using existing mutation databases and in silico predictive algorithms.

Results: In 1 of 33 patients, a likely pathogenic mutation was detected. The added yield of genetic testing with NGS of 179 additional genes is 3% in patients with IVF. In 15% of patients, 1 or multiple variants of uncertain clinical significance were detected.

Conclusion: The added yield of genetic screening of extended NGS panels in patients initially diagnosed with IVF is minimal. Routine analysis of large diagnostic NGS panels is therefore not recommended.
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http://dx.doi.org/10.1016/j.hrthm.2017.01.010DOI Listing
July 2017

Right Ventricular Imaging and Computer Simulation for Electromechanical Substrate Characterization in Arrhythmogenic Right Ventricular Cardiomyopathy.

J Am Coll Cardiol 2016 11;68(20):2185-2197

Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands; IHU Liryc, Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Université, Bordeaux, France. Electronic address:

Background: Previous studies suggested that electrical abnormalities precede overt structural disease in arrhythmogenic right ventricular cardiomyopathy (ARVC). Abnormal RV deformation has been reported in early ARVC without structural abnormalities. The pathophysiological mechanisms underlying these abnormalities remain unknown.

Objectives: The authors used imaging and computer simulation to differentiate electrical from mechanical tissue substrates among ARVC clinical stages.

Methods: ARVC desmosomal mutation carriers (n = 84) were evaluated by electrocardiography (ECG), Holter monitoring, late-enhancement cardiac magnetic resonance imaging, and echocardiographic RV deformation imaging. Subjects were categorized based on the presence of 2010 International Task Force criteria: 1) subclinical stage (n = 21); 2) electrical stage (n = 15); and 3) structural stage (n = 48). Late enhancement was not present in any subclinical or electrical stage subjects.

Results: Three distinctive characteristic RV longitudinal deformation patterns were identified: type I: normal deformation (n = 12); type II: delayed onset of shortening, reduced systolic peak strain, and mild post-systolic shortening (n = 35); and type III: systolic stretching with large post-systolic shortening (n = 37). A majority (69%) of structural staged mutation carriers were type III, whereas a large proportion of both electrical and subclinical stage subjects (67% and 48%, respectively) were type II. Computer simulations demonstrated that the type II pattern can be explained by a combination of reduced contractility and mildly increased passive myocardial stiffness. This evolved into type III by aggravating both mechanical substrates. Electrical activation delay alone explained none of the patterns.

Conclusions: Different ARVC stages were characterized by distinct RV deformation patterns, all of which could be reproduced by simulating different degrees of mechanical substrates. Subclinical and electrical staged ARVC subjects already showed signs of local mechanical abnormalities. Our novel approach could lead to earlier disease detection and, thereby, influence current definitions of electrical and subclinical ARVC stages.
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http://dx.doi.org/10.1016/j.jacc.2016.08.061DOI Listing
November 2016

Long-Term Outcome of Patients Initially Diagnosed With Idiopathic Ventricular Fibrillation: A Descriptive Study.

Circ Arrhythm Electrophysiol 2016 10;9(10)

From the Departments of Cardiology (M.V., J.F.v.d.H., P.A.D., P.L., R.J.H.) and Clinical Genetics (J.J.v.d.S.), University Medical Centre, Utrecht, The Netherlands; Department of Internal Medicine and Cardiology, Bergman Clinics, Bilthoven, The Netherlands (M.V., R.J.H.); and Department of Clinical and Experimental Cardiology, Heart Centre, AMC, Amsterdam, The Netherlands (A.A.W.).

Background: Idiopathic ventricular fibrillation (IVF) is a rare cause of sudden cardiac arrest. Limited data are available on the long-term outcome of IVF patients.

Methods And Results: In this retrospective cohort study, 107 consecutive patients with an initial diagnosis of IVF were analyzed (age at index event 40.4 years, 60% male). Missing diagnostic data were acquired during follow-up, including genetic testing, to exclude underlying disease. A specific diagnosis was revealed in 22 of 107 patients (21%) during a median follow-up of 10.2 years. Mortality rate was 9% in IVF patients (8/85). Appropriate implantable cardioverter-defibrillator therapy was delivered in 23 patients (29%) of 78 IVF patients with an implantable cardioverter-defibrillator, with a median of 3 appropriate shocks per patient.

Conclusions: One fifth of the patients initially diagnosed with IVF reveal a specific diagnosis during long-term follow-up. Additional diagnostic testing, including genetic testing, contributes to the detection of specific diseases. The recurrence rate of ventricular arrhythmias in IVF patients is high. Our data show the importance of thorough follow-up and reassessment of diagnosis in IVF patients.
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http://dx.doi.org/10.1161/CIRCEP.116.004258DOI Listing
October 2016

Time matters: adenosine testing immediately after pulmonary vein isolation does not substitute a waiting period.

Europace 2017 Jul;19(7):1140-1145

Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Aims: Adenosine testing can reveal dormant pulmonary vein (PV) conduction after PV antrum isolation (PVAI). However, the optimal timing for adenosine administration is unknown. We hypothesized that adenosine testing immediately after PVAI reliably reveals PV reconnection and thereby eliminates the need for an observation period.

Methods And Results: Fifty patients underwent PVAI. Immediately after isolation of a PV pair, adenosine was administered. Both PV pairs were separately tested. If adenosine restored PV conduction, PVs were re-isolated. During a ≥30 min observation period after immediate adenosine-guided isolation, spontaneous reconnection was assessed and reconnected PVs were re-isolated. After the observation period, adenosine testing was repeated. Immediate adenosine testing revealed dormant conduction in 10.4% of the left PVs and 16.3% of the right PVs. All PVs were successfully re-isolated. During a mean observation period of 36 ± 10 min, spontaneous reconnection occurred in 8.2% of the left and 16.3% of the right PVs. None of these PVs had shown reconnection during immediate testing. Late adenosine testing revealed dormant conduction in 12.5% of the left and 16.3% of the right PVs. In patients without reconnection during immediate adenosine testing, 14.6% of the left PVs and 30.6% of the right PVs showed either spontaneous reconnection or restored PV conduction during late adenosine testing.

Conclusion: Adenosine testing immediately after PVAI does not reliably exclude later spontaneous or adenosine-induced PV reconnection. Adenosine testing should be performed after an appropriate observation period to reduce risk of PV reconnection.
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http://dx.doi.org/10.1093/europace/euw173DOI Listing
July 2017

Double-contrast, single-phase computed tomography angiography for ruling out left atrial appendage thrombus prior to atrial fibrillation ablation.

Int J Cardiovasc Imaging 2017 Jan 6;33(1):121-128. Epub 2016 Sep 6.

Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.

Prior to atrial fibrillation (AF) ablation, computed tomography angiography (CTA) is increasingly used for left atrial appendage (LAA) thrombus detection. LAA filling defects on CTA may represent thrombus or incomplete contrast mixing with blood. A pre-bolus of contrast material with delay before the CTA contrast bolus can help distinguish between thrombus and incomplete contrast mixing. We present results from a double-contrast, single-phase CTA protocol used in our daily clinical practice. In patients who underwent AF ablation between 2011 and 2015, double-contrast, single-phase CTA was performed prior to ablation. Two contrast boluses (30 and 70 ml) with 25-s interbolus delay were administered followed by prospectively triggered cardiac CTA. Only patients with left atrial (LA) or LAA filling defects underwent transesophageal echocardiography (TEE) to rule out thrombus. Prior to ablation, 605 CTA-scans were performed (median radiation dose: 3.1 mSv). In 579 CTA-scans (95.7 %), the LA and LAA completely filled with contrast. In 26 CTA-scans (4.3 %) the LAA showed a filling defect whereby thrombus could not be excluded. In 2 of those 26 patients (7.7 % and 0.3 % of the total population), TEE verified LAA thrombus. Low-risk LAA filling defects on CTA (n = 7/26) with an inhomogeneous aspect, Houndsfield Unit values >100, and an indefinite border were all caused by incomplete contrast mixing. No thromboembolic complications occurred perioperatively or during 6 months follow-up. Prior to AF ablation, incidence of LAA filling defects on double-contrast, single-phase CTA is low. TEE remains warranted in all but low-risk filling defects to rule out thrombus.
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http://dx.doi.org/10.1007/s10554-016-0973-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247541PMC
January 2017

Influence of Genotype on Structural Atrial Abnormalities and Atrial Fibrillation or Flutter in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.

J Cardiovasc Electrophysiol 2016 12 6;27(12):1420-1428. Epub 2016 Oct 6.

Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Introduction: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is associated with desmosomal mutations. Although desmosomal disruption affects both ventricles and atria, little is known about atrial involvement in ARVD/C.

Objective: To describe the extent and clinical significance of structural atrial involvement and atrial arrhythmias (AA) in ARVD/C stratified by genotype.

Methods: We included 71 patients who met ARVD/C Task Force Criteria and underwent cardiac magnetic resonance (CMR) imaging and molecular genetic analysis. Indexed atrial end-diastolic volume and area-length-ejection-fraction (ALEF) were evaluated on CMR and compared to controls with idiopathic right ventricular outflow tract tachycardia (n = 40). The primary outcome was occurrence of AA (atrial fibrillation or atrial flutter) during follow-up, recorded by 12-lead ECG, Holter monitoring or implantable cardioverter defibrillator (ICD) interrogation.

Results: Patients harbored a desmosomal plakophilin-2 (PKP2) (n = 37) or nondesmosomal phospholamban (PLN) (n = 14) mutation. In 20 subjects, no pathogenic mutation was identified. Compared to controls, right atrial (RA) volumes were reduced in PKP2 (P = 0.002) and comparable in PLN (P = 0.441) mutation carriers. In patients with no mutation identified, RA (P = 0.011) and left atrial (P = 0.034) volumes were increased. Bi-atrial ALEF showed no significant difference between the groups. AA were experienced by 27% of patients and occurred equally among PKP2 (30%) and no mutation identified patients (30%), but less among PLN mutation carriers (14%).

Conclusion: Genotype influences atrial volume and occurrence of AA in ARVD/C. While the incidence of AA is similar in PKP2 mutation carriers and patients with no mutation identified, PKP2 mutation carriers have significantly smaller atria. This suggests a different arrhythmogenic mechanism.
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http://dx.doi.org/10.1111/jce.13094DOI Listing
December 2016

A patient with early repolarization syndrome and concurrent Brugada syndrome: Demonstration of a different pathophysiology?

Int J Cardiol 2016 Nov 5;223:58-60. Epub 2016 Aug 5.

Department of Cardiology, University Medical Centre, Utrecht, the Netherlands; Department of Internal Medicine and Cardiology, Bergman Clinics, Bilthoven, the Netherlands.

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http://dx.doi.org/10.1016/j.ijcard.2016.08.072DOI Listing
November 2016

Idiopathic Ventricular Fibrillation: The Struggle for Definition, Diagnosis, and Follow-Up.

Circ Arrhythm Electrophysiol 2016 May;9(5)

From the Department of Cardiology, University Medical Center, Utrecht, The Netherlands (M.V., J.F.v.d.H., P.A.D., P.L., R.J.H.); Department of Internal Medicine and Cardiology, Bergman Clinics, Bilthoven, The Netherlands (M.V., R.J.H.); and Department of Clinical and Experimental Cardiology, Heart Centre, AMC, Amsterdam, The Netherlands (A.A.W.).

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http://dx.doi.org/10.1161/CIRCEP.115.003817DOI Listing
May 2016

Five-year efficacy of pulmonary vein antrum isolation as a primary ablation strategy for atrial fibrillation: a single-centre cohort study.

Europace 2016 Sep 2;18(9):1335-42. Epub 2016 Feb 2.

Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands

Aims: Pulmonary vein antrum isolation (PVAI) is the cornerstone of atrial fibrillation (AF) ablation. There is an ongoing discussion on whether and when to add substrate modification to PVAI. This study evaluates (1) long-term efficacy of PVAI as a primary ablation strategy in all patients independently from AF type and (2) predictors of arrhythmia recurrence.

Methods And Results: A total of 509 consecutive patients (mean age 57 years, 38.9% non-paroxysmal AF) with AF underwent PVAI. In redo procedures, ablation was restricted to re-pulmonary vein (PV) isolation in case of PV reconnection. If the PVs were found to be isolated, substrate modification was performed. In total, 774 procedures were performed. Mean follow-up duration after the first and last ablation was, respectively, 66 ± 23 and 55 ± 25 months. A single PVAI was sufficient in restoring and maintaining long-term sinus rhythm in 41.3% (n = 210) of patients. Multiple procedures (mean 1.5) with re-PV isolation increased long-term success to 58.3% (n = 297). Additional substrate modification (n = 70) increased success to 62.5% (n = 318). After the last ablation, 87.5% of patients experienced success or significant clinical improvement on or off antiarrhythmic drugs. The incidence of left-sided atrial flutter or atrial tachycardia was 5% after PVAI and increased to 32% after additional substrate modification. Independent predictors for arrhythmia recurrence after the last ablation were non-paroxysmal AF, female sex, body mass index, hypertension, and AF duration.

Conclusion: Five-year freedom of atrial tachyarrhythmia could be achieved by PVAI as primary ablation strategy in 58.3% of patients. Additional substrate modification only moderately increased overall success.
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http://dx.doi.org/10.1093/europace/euv439DOI Listing
September 2016

Prolonged Electromechanical Interval Unmasks Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in the Subclinical Stage.

J Cardiovasc Electrophysiol 2016 Mar 14;27(3):303-14. Epub 2016 Jan 14.

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Introduction: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by high incidence of ventricular arrhythmias. Overt ARVD/C is preceded by a subclinical stage with lack of detectable ECG and structural abnormalities. Activation delay is present before structural abnormalities and is a hallmark of arrhythmogenesis. Deformation imaging may unmask activation delay in the subclinical stage.

Methods: Three groups were compared: (1) mutation-positive definite ARVD/C-patients fulfilling 2010 Task Force criteria (TFC) (n = 44); (2) asymptomatic mutation carriers not fulfilling TFC and without history of ventricular arrhythmias (n = 31); and (3) controls (n = 30). All underwent ECG and echocardiographic deformation imaging. As a surrogate for local activation delay the electromechanical interval (EMI) was measured, defined as time between onset-QRS and onset of shortening. Arrhythmic outcome (PVC-count, VT) of asymptomatic mutation carriers was correlated with EMI and ECG TFC.

Results: In definite ARVD/C-patients, EMI was prolonged in all lateral RV segments. In asymptomatic mutation carriers, prolonged EMI was detected in the subtricuspid area in 14/31. Terminal activation duration ≥55 milliseconds (definition: supporting information) was the only ECG abnormality in this group (8/31). After a mean follow-up of 4.2 ± 3.1 years 10/31 asymptomatic mutation carriers experienced arrhythmic outcome. Prolonged subtricuspid EMI was the only parameter significantly associated with arrhythmogenesis during follow-up.

Conclusion: In ARVD/C-patients, EMI prolongation was present throughout the RV. In asymptomatic mutation carriers, prolonged EMI in the subtricuspid area is often detected without any additional abnormalities. These preliminary results indicate that prolonged EMI is a new parameter unmasking activation delay in the subclinical stage and may contribute to risk stratification.
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http://dx.doi.org/10.1111/jce.12882DOI Listing
March 2016

Fever-induced atrial flutter associated with SCN5A mutation--a first report on successful catheter ablation in a very young child.

Int J Cardiol 2014 Feb 7;171(2):e31-4. Epub 2013 Dec 7.

University Medical Center Utrecht, Department of Cardiology, Utrecht, The Netherlands.

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http://dx.doi.org/10.1016/j.ijcard.2013.11.121DOI Listing
February 2014

Impact of pulmonary vein antrum isolation on left atrial size and function in patients with atrial fibrillation.

J Interv Card Electrophysiol 2014 Apr 7;39(3):201-9. Epub 2013 Dec 7.

Department of Cardiology, E03.511, University Medical Center, PO Box 85500, 3508 GA, Utrecht, The Netherlands.

Purpose: The success of PVAI in eliminating AF has been proven; however, its impact on the LA remains uncertain. This study aimed to determine the impact of pulmonary vein antrum isolation (PVAI) on left atrial (LA) size and function in patients with atrial fibrillation (AF).

Methods: Consecutive patients with AF were included (n = 206). Magnetic resonance imaging (MRI) was performed before and after PVAI in all patients. A subgroup (n = 52) underwent delayed enhancement MRI. Maximal LA volume (LAVmax) and minimal LA volume (LAVmin) were assessed by Simpson's rule. LA function was determined by calculating LA ejection fraction (LA EF). LA fibrosis was manually encircled and summed in the region of interest.

Results: Single procedure success rate was 64 %. LAVmax decreased post-ablation in all patients (125.1 to 111.9 ml, p < 0.001). LAVmin only decreased in patients with a successful outcome post-ablation (65.6 to 58.8 ml, p < 0.001). As a result, LA EF only showed a marked reduction in patients with AF recurrences (42.7 % to 37.9 %, p < 0.001). Post-ablation LA fibrosis could be visualized in 77 % of patients who underwent delayed enhancement MRI (mean amount 1.4 cm(3)). LA fibrosis showed no correlation with the decrease in LAVmax or LA EF.

Conclusions: PVAI resulted in a reduction of LAVmax in all patients, indicating an effect of ablation induced fibrosis. LAVmin only decreased in patients with a successful outcome, indicating an effect of reverse atrial remodeling. As a result, LA function post-ablation was preserved in patients with a successful outcome and decreased in patients with AF recurrence.
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http://dx.doi.org/10.1007/s10840-013-9860-0DOI Listing
April 2014

Cardiac resynchronization therapy beyond nominal settings: who needs individual programming of the atrioventricular and interventricular delay?

Europace 2012 Dec 28;14(12):1746-53. Epub 2012 Jun 28.

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Aims: This study aimed to determine the additional acute haemodynamic effect of atrioventricular (AV) and interventricular (VV) delay optimization compared with current nominal cardiac resynchronization therapy (CRT) device settings, and to explore whether clinical characteristics correlate to the effect of optimization.

Methods And Results: Fifty CRT patients were prospectively enrolled. The optimal AV and VV delays were guided by relative improvement in maximum rate of left ventricular (LV) pressure rise (%dP/dt(max)). A significant improvement in %dP/dt(max) was obtained by optimization in 23-33% (sensed AV delay), 32-57% (paced AV delay), and 45% of patients (VV delay). Adjustment of the device nominal VV delay from 0 to 40 ms LV pre-activation would diminish the proportion of patients with additional effect of individual optimization from 45 to 15%. Heart failure aetiology [ischaemic 2 ± 2 vs. non-ischaemic 1 ± 1 percentage points (PP) %dP/dt(max), P= 0.013], gender (men 2 ± 2 vs. women 1 ± 1 PP %dP/dt(max), P= 0.012) and intrinsic PR interval (R= 0.49, P= 0.002) correlated to the degree of effect of AV delay optimization. Women yielded more effect of VV delay optimization (4 ± 3 vs. 2 ± 1 PP %dP/dt(max), P= 0.026).

Conclusion: Compared with the best of the currently available device nominal AV and VV delays, 23-45% of CRT patients can yield additional acute haemodynamic effect by individual optimization of the delays. A new nominal VV delay of 40 ms LV pre-activation is recommended. Male gender, ischaemic aetiology, and longer PR interval are associated with a larger effect of individual optimization.
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http://dx.doi.org/10.1093/europace/eus170DOI Listing
December 2012

The ECG in cardiac resynchronization therapy: influence of left and right ventricular preactivation and relation to acute response.

J Cardiovasc Electrophysiol 2012 Nov 26;23(11):1237-45. Epub 2012 Jun 26.

University Medical Center Utrecht, Department of Cardiology, Utrecht, The Netherlands.

Introduction: The aims of this study were to compare ECG signs of biventricular electrical resynchronization during cardiac resynchronization therapy (CRT) with various interventricular (VV) delays and to correlate these and other ECG characteristics with the acute hemodynamic benefit of CRT.

Methods And Results: Thirty-four patients with heart failure and a left bundle branch block (LBBB) pattern were prospectively enrolled. A 12-lead surface ECG and the relative improvement in left ventricular (LV) dP/dt(max) (the maximum rate of pressure rise) were recorded at baseline and during CRT with VV delays varying from 80 ms LV preactivation to 40 ms right ventricular (RV) preactivation. Rightward QRS-axis shift occurred in 71-80% among all VV delays. Activation reversal to dominant negative in leads I/aVL was progressively observed at increasing LV preactivation (53-65%) and less (18-22%) during RV preactivation. Activation reversal to dominant positive in leads V1/V2 was observed in 21-27% during LV preactivation and in 6-15% during RV preactivation. Higher acute response to CRT was independently predicted by a complete LBBB at baseline (regression coefficient B = 7.7 [0.3-15.0], P = 0.042), later timing of LV depolarization within the QRS at baseline (Q-LVsense: B = 0.2 [0.1-0.3], P = 0.002), and biventricular electrical resynchronization during CRT as evidenced by activation reversal in leads I/aVL (B = 9.9 [3.2-16.6], P = 0.005).

Conclusion: ECG signs of biventricular electrical resynchronization are present over a wide range of LV preactivated VV delays but to a lesser extent during RV preactivation. The presence of complete LBBB and longer Q-LVsense at baseline and signs of biventricular electrical resynchronization during CRT predict higher acute hemodynamic response.
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http://dx.doi.org/10.1111/j.1540-8167.2012.02388.xDOI Listing
November 2012

Minimal coronary artery damage by myocardial electroporation ablation.

Europace 2013 Jan 31;15(1):144-9. Epub 2012 May 31.

Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1093/europace/eus171DOI Listing
January 2013

Myocardial lesion depth with circular electroporation ablation.

Circ Arrhythm Electrophysiol 2012 Jun 6;5(3):581-6. Epub 2012 Apr 6.

Division of Heart and Lungs, the Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.

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.
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http://dx.doi.org/10.1161/CIRCEP.111.970079DOI Listing
June 2012

Reduced connexin40 protein expression in the right atrial appendage of patients bearing the minor connexin40 allele (-44 G --> A).

Europace 2012 Aug 15;14(8):1199-205. Epub 2012 Mar 15.

Division of Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Aims: The occurrence of connexin40 (Cx40) minor polymorphism (-44 G → A) was increased in patients with idiopathic atrial fibrillation (AF), although its effect on atrial Cx40 protein expression is unknown. We aimed to evaluate whether alterations in Cx40 are directly linked to the development of AF, we studied the effect of this polymorphism on Cx40 expression and distribution in patients without any history of AF and in patients who developed post-operative AF.

Methods And Results: Hundred and eight patients (mean age 67 ± 9 years), without a history of AF or conditions that predispose to AF, were included. During heart surgery, 10 cc blood was collected for DNA genotyping and the right atrial appendage was partly excised. Ten patients (9%) were homozygous for the minor allele (AA, Group 1), 30 (28%) were heterozygous (AG, Group 2), and 68 (63%) were non-carriers (GG, Group 3). Ten age- and sex-matched tissue samples per group were analysed for Cx40 expression by: (i) real-time quantitative polymerase chain reaction (Q-PCR), (ii) western blotting, and (iii) immunohistochemistry on cryosections. Real-time quantitative polymerase chain reaction showed no significant differences of Cx40 mRNA among the groups. Western blot analysis, however, revealed a reduction in Cx40 protein in Groups 1 (-36.4%) and 2 (-39.5%) as compared with Group 3. Immunohistochemistry confirmed this reduction but indicated an unaltered subcellular distribution of the remaining Cx40. Incidence of post-operative AF (28%) was age-dependent but unrelated to the presence of the polymorphism or fibrosis.

Conclusion: Presence of the Cx40 minor allele (-44 G → A) results in a uniform down-regulation of right atrial appendage Cx40 protein which was not significantly related to development of post-operative AF.
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http://dx.doi.org/10.1093/europace/eus047DOI Listing
August 2012