Publications by authors named "Benjamin Pang"

15 Publications

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An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of -Catecholaminergic Polymorphic Ventricular Tachycardia.

Circulation 2020 Sep 22;142(10):932-947. Epub 2020 Jul 22.

Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (K.N., J.W., A.S.T., A.C.S., J.M., J.D.R.).

Background: Genetic variants in calsequestrin-2 () cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of -CPVT was sought through an international multicenter collaboration.

Methods: Genotype-phenotype segregation in -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure.

Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic variant, were identified. Among homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to heterozygotes, homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers.

Conclusions: This international multicenter study of -CPVT redefines its heritability and confirms that pathogenic heterozygous variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484339PMC
September 2020

Cobalt/Lewis Acid Catalysis for Hydrocarbofunctionalization of Alkynes via Cooperative C-H Activation.

J Am Chem Soc 2020 07 7;142(29):12878-12889. Epub 2020 Jul 7.

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.

A catalytic system comprising a cobalt-diphosphine complex and a Lewis acid (LA) such as AlMe has been found to promote hydrocarbofunctionalization reactions of alkynes with Lewis basic and electron-deficient substrates such as formamides, pyridones, pyridines and related azines, imidazo[1,2-]pyridines, and azole derivatives through site-selective C-H activation. Compared with known Ni/LA catalytic systems for analogous transformations, the present catalytic systems not only feature convenient setup using inexpensive and bench-stable precatalyst and ligand such as Co(acac) and 1,3-bis(diphenylphosphino)propane (dppp) but also display distinct site-selectivity toward C-H activation of pyridone and pyridine derivatives. In particular, a completely C4-selective alkenylation of pyridine has been achieved for the first time. Meanwhile, the present catalytic system proved to promote exclusively C5-selective alkenylation of imidazo[1,2-]pyridine derivatives. Mechanistic studies including DFT calculations on the Co/Al-catalyzed addition of formamide to alkyne have suggested that the reaction involves cleavage of the carbamoyl C-H bond as the rate-limiting step, which proceeds through a ligand-to-ligand hydrogen transfer (LLHT) mechanism leading to an alkenyl(carbamoyl)cobalt intermediate.
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http://dx.doi.org/10.1021/jacs.0c06412DOI Listing
July 2020

Pregnancy in Catecholaminergic Polymorphic Ventricular Tachycardia.

JACC Clin Electrophysiol 2019 03 26;5(3):387-394. Epub 2018 Dec 26.

Heart Rhythm Services, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Objectives: This investigation was a retrospective study of catecholaminergic polymorphic ventricular tachycardia (CPVT) patients in Canada and the Netherlands to compare pregnancy, postpartum, and nonpregnant event rates.

Background: CPVT is characterized by life-threatening arrhythmias during exertion or emotional stress. The arrhythmic risk in CPVT patients during pregnancy is unknown.

Methods: Baseline demographics, genetics, treatment, and pregnancy complications were reviewed. Event rate calculations assumed a 40-week pregnancy and 24-week postpartum period.

Results: Ninety-six CPVT patients had 228 pregnancies (median 2 pregnancies per patient; range: 1 to 10; total: 175.4 pregnant patient-years). The median age of CPVT diagnosis was 40.7 years (range: 12 to 84 years), with a median follow-up of 2.9 years (range: 0 to 20 years; total 448.1 patient-years). Most patients had pregnancies before CPVT diagnosis (82%). Pregnancy and postpartum cardiac events included syncope (5%) and an aborted cardiac arrest (1%), which occurred in patients who were not taking beta-blockers. Other complications included miscarriages (13%) and intrauterine growth restriction (1 case). There were 6 cardiac events (6%) during the nonpregnant period. The pregnancy and postpartum event rates were 1.71 and 2.85 events per 100 patient-years, respectively, and the combined event rate during the pregnancy and postpartum period was 2.14 events per 100 patient-years. These rates were not different from the nonpregnant event rate (1.46 events per 100 patient-years).

Conclusions: The combined pregnancy and postpartum arrhythmic risk in CPVT patients was not elevated compared with the nonpregnant period. Most patients had pregnancies before diagnosis, and all patients with events were not taking beta-blockers at the time of the event.
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http://dx.doi.org/10.1016/j.jacep.2018.10.019DOI Listing
March 2019

Challenge and Impact of Quinidine Access in Sudden Death Syndromes: A National Experience.

JACC Clin Electrophysiol 2019 03 28;5(3):376-382. Epub 2018 Nov 28.

University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Objectives: This study sought to determine the nature of quinidine use and accessibility in a national network of inherited arrhythmia clinics.

Background: Quinidine is an antiarrhythmic medication that has been shown to be beneficial in select patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation. Because of the low prevalence of these conditions and restricted access to quinidine through a single regulatory process, quinidine use is rare in Canada.

Methods: Subjects prescribed quinidine were identified through the Hearts in Rhythm Organization that connects the network of inherited arrhythmia clinics across Canada. Cases were retrospectively reviewed for patient characteristics, indications for quinidine use, rate of recurrent ventricular arrhythmia, and issues with quinidine accessibility.

Results: In a population of 36 million, 46 patients are currently prescribed quinidine (0.0000013%, age 48.1 ± 16.1 years, 25 are male). Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation constituted a diagnosis in 13 subjects (28%), 6 (13%), and 21 (46%), respectively. Overall, 37 subjects (81%) had cardiac arrest as an index event. After initial presentation, subjects experienced 7.47 ± 12.3 implantable cardioverter-defibrillator shocks prior to quinidine use over 34.3 ± 45.9 months, versus 0.86 ± 1.69 implantable cardioverter-defibrillator shocks in 43.8 ± 41.8 months while on quinidine (risk ratio: 8.7, p < 0.001). Twenty-two patients access quinidine through routes external to Health Canada's Special Access Program.

Conclusions: Quinidine use is rare in Canada, but it is associated with a reduction in recurrent ventricular arrhythmias in patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation, with minimal toxicity necessitating discontinuation. Drug interruption is associated with frequent breakthrough events. Access to quinidine is important to deliver this potentially lifesaving therapy.
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http://dx.doi.org/10.1016/j.jacep.2018.10.007DOI Listing
March 2019

Beware of the coronary arteries with implantable cardiac electronic devices.

Herzschrittmacherther Elektrophysiol 2017 Sep;28(3):317-319

Department of Cardiology, Royal Melbourne Hospital, Parkville, Victoria, Australia.

The transvenous implantation of cardiac devices may sometimes cause serious complications involving the coronary arteries. The left anterior descending artery may be injured during nonapical right ventricular implantation while a right atrial lead may injure the right or circumflex coronary artery. Injury of a left internal mammary graft to a coronary artery may cause myocardial infarction.
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http://dx.doi.org/10.1007/s00399-017-0518-yDOI Listing
September 2017

Loss-of-Function Variants: True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation?

Circ Arrhythm Electrophysiol 2017 Aug;10(8)

For author affiliations, please see the Appendix.

Background: Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the -encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype.

Methods And Results: Individuals with reported pathogenic mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the variant was not the underlying culprit. The collective frequency of variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4%, in comparison with a 0.0005% estimated clinical prevalence for LQT6.

Conclusions: On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.
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http://dx.doi.org/10.1161/CIRCEP.117.005282DOI Listing
August 2017

Crossing the slow pathway bridge: A better method for decreasing long-term recurrences after cryoablation of atrioventricular nodal reentrant tachycardia?

Heart Rhythm 2017 11 29;14(11):1655-1656. Epub 2017 Jul 29.

University of Ottawa Heart Institute, Ottawa, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2017.07.031DOI Listing
November 2017

Retrospective Cohort Study Examining Reduced Intensity and Duration of Anticoagulant and Antiplatelet Therapy Following Left Atrial Appendage Occlusion with the WATCHMAN Device.

Heart Lung Circ 2017 May 15;26(5):477-485. Epub 2016 Nov 15.

Monash Cardiovascular Research Centre, Monash University, Melbourne, Vic, Australia; Monash Health, Melbourne, Vic, Australia.

Background: Anticoagulant and antiplatelet therapy are recommended following WATCHMAN implantation (45 days and 6 months) to reduce the risk of embolic events. These patients are often also at high risk of recurrent bleeding complications. We aimed to assess the safety of reduced duration of treatment with anticoagulant and antiplatelet therapy in the early post implant period.

Methods: This was a retrospective cohort study assessing the duration of antiplatelet and anticoagulant therapy in 47 consecutive patients following WATCHMAN implant. The primary outcome was rate of major bleeding, stroke and systemic embolic complications. The secondary endpoints were rate of device thrombus and peri-device leak >4mm as assessed by transoesophogeal echocardiography.

Results: Forty-seven patients were followed up for a mean of 2.4+/-1.7 years (111.4 total patient-years). The rate of stroke was 1.8/100 patient-years (two events) and the rate of major bleeding complication was 8.9/100 patient-years. Three patients had peri-device leak >4mm and no patients had device thrombus visualised. 70.2% of patients had discontinued anticoagulation at 45 days, 89.4% had discontinued dual antiplatelet therapy at 90 days. Seven patients were not on any form of anticoagulant or antiplatelet at five months. Comparison of probability of survival free from stroke by time of cessation of anticoagulant and antiplatelet therapy demonstrated no significant differences (p-value for log rank test 0.238 and 0.820).

Conclusion: Following WATCHMAN implant shortened periods of anticoagulants and antiplatelets may be considered, particularly in the context of high bleeding risk.
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http://dx.doi.org/10.1016/j.hlc.2016.09.009DOI Listing
May 2017

Injury to the coronary arteries and related structures by implantation of cardiac implantable electronic devices.

Europace 2015 Apr 6;17(4):524-9. Epub 2015 Jan 6.

Department of Cardiology, Royal Melbourne Hospital, Grattan Street, Parkville 3050, Victoria, Australia Department of Medicine, University of Melbourne, Victoria, Australia

Damage to the coronary arteries and related structures from pacemaker and implantable cardioverter-defibrillator lead implantation is a rarely reported complication that can lead to myocardial infarction and pericardial tamponade that may occur acutely or even years later. We summarize the reported cases of injury to coronary arteries and related structures and review the causes of troponin elevation in the setting of cardiac implantable electronic device implantation.
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http://dx.doi.org/10.1093/europace/euu345DOI Listing
April 2015

Pacing and implantable cardioverter defibrillator lead perforation as assessed by multiplanar reformatted ECG-gated cardiac computed tomography and clinical correlates.

Pacing Clin Electrophysiol 2014 May;37(5):537-45

Introduction: We aimed to assess the utility of cardiac computed tomography (CT) in the evaluation of right atrial (RA) and right ventricular (RV) pacemaker and implantable cardiac defibrillator lead perforation.

Methods: Images from a 320-slice electrocardiogram-gated cardiac CT scanner were retrospectively independently analyzed by two reviewers for lead position, pericardial effusion, and perforation.Perforation results were correlated with pacing sensing, impedance, and threshold measurements.

Results: A total of 52 patients had RV leads and 35 had RA leads. Five of 17 RV apical, one of 35 RV nonapical, and none of the 35 RA leads perforated through the myocardium on CT imaging criteria. Two "clinically" perforated leads (that had protruded 5 mm and 15 mm from the outer edge of the myocardium)had pericardial effusions and changes in pacing parameters, and required RV lead repositioning. In contrast,there were four apparent "radiologic" perforations (that had protruded only an average 1.5±0.5 mm from the outer edge of the myocardium) that did not require repositioning. These had the radiologic appearance of perforation on cardiac CT; however, they were not associated with pericardial effusions or significant changes in RV pacing lead sensing, impedance, and threshold measurements.

Conclusions: Cardiac CT scanning with multiplanar reformatting is useful for documenting lead position and assessing for possible cardiac perforation. The clinical significance and natural history of leads with only the appearance of perforation on cardiac CT is uncertain.
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http://dx.doi.org/10.1111/pace.12307DOI Listing
May 2014

Capturing the His-Purkinje system is not possible from conventional right ventricular apical and nonapical pacing sites.

Pacing Clin Electrophysiol 2014 Jun 2;37(6):724-30. Epub 2014 Jan 2.

Department of Cardiology, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, University of Melbourne, Victoria, Australia.

Introduction: Direct His bundle capture may negate ventricular electrical dyssynchrony induced by right ventricular (RV) apical pacing. We sought to evaluate if direct His bundle pacing is possible with conventional pacemaker lead implantation at various sites in the RV.

Methods: Consecutive patients underwent RV pacing using standard implantable active fixation pacing leads in a random order in the RV outflow tract, middle RV, and RV apex at stimulation threshold and at increasing voltages of 2.5, 5, 7.5, and 10 volts (V). At each location, QRS width and morphology on 12-lead electrocardiograph (ECG) were compared in sinus and paced rhythm at the different voltages.

Results: Twelve patients underwent a total of 2,160 paced QRS measurements. Progressive increases in stimulation voltage did not change QRS morphology or duration regardless of site of pacing (RV outflow tract, middle RV, and RV apex) in any of the 12 ECG leads. In addition, apart from the stimulation threshold between the RV outflow tract and RV apex, there was no statistically significant difference in QRS duration between the three pacing sites.

Conclusion: In patients with a baseline normal QRS duration, none of the three conventional RV pacing sites were able to produce QRS narrowing and capture the His-Purkinje system. Furthermore, based on paced QRS duration as an indirect surrogate of electrical LV dyssynchrony, there was no clear advantage of one pacing site over another.
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http://dx.doi.org/10.1111/pace.12331DOI Listing
June 2014

Proximity of pacemaker and implantable cardioverter-defibrillator leads to coronary arteries as assessed by cardiac computed tomography.

Pacing Clin Electrophysiol 2014 Jun 20;37(6):717-23. Epub 2013 Dec 20.

Department of Cardiology, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, University of Melbourne, Victoria, Australia.

Introduction: There have been rare case reports of damage to adjacent coronary arteries by screw-in pacemaker and implantable cardioverter-defibrillator (ICD) leads. Our aim was to assess the proximity of pacemaker and ICD leads to the major coronary anatomy using cardiac computed tomography (CT).

Methods: Cardiac CT images were retrospectively analyzed to assess the spatial relationship of device lead tips to the major coronary anatomy.

Results: Fifty-two right ventricular (RV) leads (17 apical, 35 nonapical) and 35 right atrial (RA) leads were assessed. Leads on the RV antero-septal junction (20 of 52) were close (median 4.7 mm) to, and orientated toward, the left anterior descending (LAD) coronary artery. RA leads in the anterior (26 of 35) and lateral (seven of 35) walls of the RA appendage were not close to (16.9 ± 7.7 mm and 18.9 ± 12.4 mm, respectively) and directed away from the right coronary artery. However, an RA lead adjacent to the superior border of the tricuspid valve was 4.3 mm from the right coronary artery and an RA lead on the medial wall of the RA appendage was 1.6 mm away from the aorta. An RV pacemaker lead in the lateral wall of the RV inlet was 3.4 mm from the right coronary artery.

Conclusions: In our cohort, a majority of RV leads were on the antero-septal junction and close to the overlying LAD coronary artery. RA leads adjacent to the tricuspid valve or on the medial RA appendage were in close proximity to the right coronary artery and aorta, respectively.
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http://dx.doi.org/10.1111/pace.12330DOI Listing
June 2014

Validation of conventional fluoroscopic and ECG criteria for right ventricular pacemaker lead position using cardiac computed tomography.

Pacing Clin Electrophysiol 2014 Apr 11;37(4):495-504. Epub 2013 Nov 11.

Department of Cardiology, Royal Melbourne Hospital, Parkville, Victoria, Australia; The Department of Medicine, University of Melbourne, Victoria, Australia.

Introduction: It is hypothesized that pacing the right ventricular (RV) septum is associated with less deleterious outcomes than RV apical pacing. Our aim was to validate fluoroscopic and electrocardiography (ECG) criteria for describing pacemaker and implantable cardioverter defibrillator RV "septal" lead position against the proposed gold standard: cardiac computed tomography (CT).

Methods: Using the conventional fluoroscopic criteria, we intended to place RV nonapical leads on the interventricular septum. Lead positions were later retrospectively analyzed with CT and correlated with ECGs and fluoroscopic projections: posterior-anterior, 40° left anterior oblique (LAO), 40° right anterior oblique (RAO), and left lateral.

Results: Only 21% (nine of 35) of presumed "septal" RV nonapical leads using the conventional fluoroscopic criteria were on the true septum. A schema developed to define septal position in the RAO fluoroscopic view had high agreement with CT images. ECG criteria had only fair to moderate agreement with CT. The paced QRS duration was significantly longer (P < 0.001) with RV apical pacing (176 ± 10.7 ms), compared to RV nonapical pacing (144.5 ± 14.3 ms).

Conclusion: Using the conventional fluoroscopic criteria, only a minority of RV leads were implanted on the true RV septum. Instead, aiming for the middle of the cardiac silhouette in the RAO fluoroscopic view, confirming rightward orientation in the LAO view, and having a paced QRS duration <140 ms may allow the implanting cardiologist a simple, more accurate method to achieve true RV septal lead positioning.
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http://dx.doi.org/10.1111/pace.12301DOI Listing
April 2014

Where are the leads? Pacemaker implantation in dextrocardia.

Europace 2013 Apr 29;15(4):569. Epub 2012 Nov 29.

Department of Cardiology, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.

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http://dx.doi.org/10.1093/europace/eus387DOI Listing
April 2013

Applicability of two commercially available kits for forensic identification of saliva stains.

J Forensic Sci 2008 Sep 14;53(5):1117-22. Epub 2008 Jul 14.

Forensic Science Division, Hong Kong Government Laboratory, Homantin Government Offices, Kowloon, Hong Kong SAR, China.

The RSID-saliva test and the SALIgAE-saliva test are two recently developed forensic saliva detection kits. In this study, we compared the sensitivity and the specificity of the two test kits with the Phadebas amylase test by analyzing amylases from various sources including human, animals, plants, and micro-organism. The data demonstrate that the RSID-saliva test and the SALIgAE-saliva test offer higher sensitivity and specificity for the detection of saliva than the Phadebas amylase test. The detection limits of the RSID-saliva test, the SALIgAE-saliva test, and the Phadebas amylase test equate to 10, 4, and 1000 nL, respectively for human saliva. The RSID-saliva test and the SALIgAE-saliva test were further evaluated by analyzing semen, vaginal secretion, breast milk, blood, urine, sweat, and feces. The results of the two tests are in good agreement. The two tests reacted with urine, breast milk, and feces, but not with semen, vaginal secretion, blood, and sweat.
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http://dx.doi.org/10.1111/j.1556-4029.2008.00814.xDOI Listing
September 2008