Patrick F.H. Lai

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• Research Associate at UHN: Toronto General Hospital

Background We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib‐induced vulnerability to VA that can be modulated for cardioprotection remains unclear. Methods and Results The eff...

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton’s tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investiga...

Background: We previously described the mortality associated with cardiac injury in patients with coronavirus disease 2019 (COVID-19). The activation of immune and thrombotic biomarkers at admission, and their ability to predict cardiac injury and mortality patterns in COVID-19, remains unclear. Methods: This retrospective cohort study included 170...

The current antiarrhythmic paradigm is mainly centered around modulating membrane voltage. However, abnormal cytosolic calcium (Ca²⁺) signaling, which plays an important role in driving membrane voltage, has not been targeted for therapeutic purposes in arrhythmogenesis. There is clear evidence for bidirectional coupling between membrane voltage an...

To better understand sodium channel (SCN5A)-related cardiomyopathies, we generated ventricular cardiomyocytes from induced pluripotent stem cells obtained from a dilated cardiomyopathy patient harbouring the R222Q mutation, which is only expressed in adult SCN5A isoforms. Because the adult SCN5A isoform was poorly expressed, without functional diff...

Funding Acknowledgements Type of funding sources: None. Background In addition to variety of force time indices, electrophysiologist use peak to peak voltage (Vpp) and or S wave on unipolar electrogram to assess RF lesions they deliver. This strategy ignores cardiac conduction speed, direction, and wave curvature, all of which are affected by deli...

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by the Lefoulon Delalande Foundation OBJECTIVE Electroanatomical maps using automated conduction velocity (CV) algorithms are now being calculated using 2D mapping tools. The basis of substrate-based functional assessment is to detect slow...

Funding Acknowledgements Type of funding sources: None. Background In addition to wave propagation, tissue anisotropy is thought to determine repolarization (repol). This may explain PVC-induced vulnerability to re-entry, based on change of activation setting up arrhythmogenic repol gradients. However, differential repolarization effects produced...

Aims Electroanatomical maps using automated conduction velocity (CV) algorithms are now being calculated using two-dimensional (2D) mapping tools. We studied the accuracy of mapping surface 2D CV, compared to the three-dimensional (3D) vectors, and the influence of mapping resolution in non-scarred animal and human heart models. Methods and result...

Background Doxorubicin-induced cardiomyopathy (DICM) is one of the complications that can limit treatment for a significant number of cancer patients. In animal models, the administration of statins can prevent the development of DICM. Therefore, the use of statins with anthracyclines could potentially enable cancer patients to complete their chemo...

Background Post-defibrillation myocardial contractile dysfunction adversely affects the survival of patients after cardiac arrest. Attenuation of diastolic calcium (Ca²⁺) overload by stabilization of the cardiac ryanodine receptor (RyR2) is found to reduce refibrillation after long-duration ventricular fibrillation (LDVF). Objective In the present...

Background Conventional mapping of focal ventricular arrhythmias relies on unipolar electrogram characteristics and early local activation times. Deep intramural foci are common and associated with high recurrence rates following catheter-based radiofrequency ablation. We assessed the accuracy of unipolar morphological patterns and mapping surface...

Background Proarrhythmic risk of conventional anti-arrhythmic agents is linked to unintended modulation of membrane voltage dynamics. We have demonstrated that the anti-fibrillatory effect of azumolene is mediated via stabilization of the hyperphosphorylated ryanodine receptor (RyR2), leading to attenuation of diastolic calcium leak. However, the c...

Background: The role of the Purkinje network in triggering ventricular fibrillation (VF) has been studied, however, its involvement after onset and in early maintenance of VF is controversial. Aim: We studied the role of the Purkinje-muscle junctions (PMJ) on epicardial-endocardial activation gradients during early VF. Methods: In a healthy, p...

Background Doxorubicin (Dox) is a potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. Intracellular calcium dysregulation has been reported to be involved in doxorubicin-induced cardiomyopathy (DICM). The cardioprotective role of RyR stabilizer dantrolene (Dan) on the calcium dynamics of DICM has not yet been e...

Background: Ryanodine receptor 2 (RyR2) is important for cardiac calcium release from the sarcoplasmic reticulum. RyR2 activation triggers a spatio-temporally regulated calcium spark. Synchronous activation of RyR2 clusters creates a steeper slope and shorter systolic rise time in calcium transients. Doxorubicin (Dox) is a commonly used chemotherap...

Aim An adverse side-effect of Liraglutide (LG), a Glucagon-Like Peptide 1 (GLP1)-analog commonly used in treatments for diabetes, is positive chronotropy. The goal of this study is to investigate on the mechanism of this drug-induced chronotropy and explore potential means to mitigate this side-effect so as to maximize the therapeutic benefits from...

Background We developed a multi-axis lead (MaxLead) incorporating four electrodes arranged at the lead-tip organized in an equidistant tetrahedron. Here, we studied MaxLead performance in sensing, pacing and activation wavefront-direction analysis. Methods Sixteen explanted animal hearts (from 7 pigs, 7 sheep and 2 rabbits) were used. Pacing thres...

Background: Safety and efficacy parameters for bipolar RF ablation is not well defined. Objective: To study the safe range of power, the utility of trans-myocardial bipolar EGM amplitude and circuit impedance in ablation monitoring. Methods: Sixteen beating ex vivo Human and Swine hearts were studied in the Langendorff set up. Ninety-two bipol...

Background Empagliflozin (EMPA) reduces heart failure hospitalization and mortality. The benefit in terms of ventricular arrhythmia and contractility has not been explored. Objective To determine the direct effects of EMPA on ventricular arrhythmia and cardiac contractility in an ex-vivo model of global ischemia-reperfusion (I/R). Methods Langend...

Background Characterizing wave-front generation and impulse conduction in left bundle (LB) has implications for Left Bundle Branch Area Pacing (LBBAP). Objective To describe the pacing characteristics of LB and to study the role of pacing pulse width (PW) to overcome Left Bundle Branch Block (LBBB). Methods Twenty, fresh ovine heart slabs contain...

OBJECTIVES This study sought to investigate the acute effects of ibrutinib on left ventricular (LV) VA vulnerability, cytosolic calcium dynamics, and membrane electrophysiology in old and young spontaneous hypertensive rats (SHRs). METHODS Langendorff-perfused hearts of young (10 to 14 weeks) and old (10 to 14 months) SHRs were treated with ibrutin...

Aims Bipolar electrogram (BiEGM)-based substrate maps are heavily influenced by direction of a wavefront to the mapping bipole. In this study, we evaluate high-resolution, orientation-independent peak-to-peak voltage (Vpp) maps obtained with an equi-spaced electrode array and omnipolar EGMs (OTEGMs), measure its beat-to-beat consistency, and asses...

Introduction Following long‐duration ventricular fibrillation (LDVF), re‐initiation of ventricular fibrillation (VF) poses a major challenge during resuscitation. Ryanodine receptor‐2 (RyR2) becomes dysfunctional following ventricular fibrillation (VF). The relationship between LDVF, RyR2 modulation, and ventricular refibrillation, as well as the r...

Background: Low-voltage-guided substrate modification is an emerging strategy in atrial fibrillation (AF) ablation. A major limitation to contemporary bipolar electrogram (EGM) analysis in AF is the resultant lower peak-to-peak voltage (Vpp) from variations in wavefront direction relative to electrode orientation and from fractionation and collisi...

Background-—Characterization of myocardial health by bipolar electrograms are critical for ventricular tachycardia therapy. Dependence of bipolar electrograms on electrode orientation may reduce reliability of voltage assessment along the plane of arrhythmic myocardial substrate. Hence, we sought to evaluate voltage assessment from orientation-inde...

Background— The therapeutic potential of renal denervation (RDN) for arrhythmias has not been fully explored. Detailed mechanistic evaluation is in order. The objective of the present study was to determine the antiarrhythmic potential of RDN in a postinfarct animal model and to determine whether any benefits relate to RDN-induced reduction of symp...

Background: After defibrillation of initial ventricular fibrillation (VF), it is crucial to prevent refibrillation to ensure successful resuscitation outcomes. Inability of the late Na(+) current to inactivate leads to intracellular Ca(2+) dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of t...

Most existing studies of cardiac arrhythmia rely on surface measurements through optical or electrical mapping techniques. Current density imaging (CDI) is a method which enables us to study current pathways inside the tissue. However, this method entails implementation complexities for beating ex vivo hearts. Hence, this work presents an approach...

Current practices in studying cardiac arrhythmias primarily use electrical or optical surface recordings of a heart, spatially limited transmural recordings, and mathematical models. However, given that such arrhythmias occur on a 3D myocardial tissue, information obtained from such practices lack in dimension, completeness, and are sometimes prone...

Renal sympathetic denervation (RDN) was primarily developed to treat hypertension, and is potentially a new method for treating arrhythmias. Due to the lack of a standardized protocol to measure renal sympathetic nerve activity, RDN is administered in a blinded manner. This inability to assess efficacy at the time of delivery of treatment may be a...

Introduction: Changes in cardiac repolarization parameters such as QT interval and QT dispersion have been implicated in cardiac arrhythmogenesis following acute myocardial infarction (AMI). These parameters are susceptible to sympathetic modulation. We therefore hypothesized that renal sympathetic denervation (RDN) may produce potential anti-arrhy...

Ventricular fibrillation (VF) is an important cause of sudden cardiac arrest following myocardial infarction. Following resuscitation from VF, decreased cardiac contractile function is a common problem. During and following myocardial ischemia, decreased glucose oxidation, increased anaerobic glycolysis for cardiac energy production are harmful and...

Objectives This study sought to determine the characteristics of human LDVF, particularly as it contrasts with short-duration VF (SDVF), and evaluate the role of Purkinje fibers in its maintenance. Background The electrophysiological mechanisms of long-duration ventricular fibrillation (LDVF) have not been studied in the human heart. Methods VF w...

Magnetic Resonance Imaging (MRI) techniques such as Current Density Imaging (CDI) and Diffusion Tensor Imaging (DTI) provide a complementing set of imaging data that can describe both the functional and structural states of biological tissues. This paper presents a Joint Independent Component Analysis (jICA) based fusion approach which can be utili...

Spatial distribution of injected current in a subject could be calculated and visualized through current density imaging (CDI). Calculated CDI paths however have a limited degree of accuracy due to both avoidable methodological errors and inevitable limitations dictated by MR imaging constraints. The source and impact of these limitations are scrut...

Resistant ventricular fibrillation, re-fibrillation and diminished myocardial contractility are important factors leading to poor survival following cardiac arrest. We hypothesized dantrolene improves survival following VF by rectifying calcium dysregulation caused by VF. VF was induced in 26 Yorkshire pigs for 4 min. CPR was then commenced for 3 m...

Background: Ventricular refibrillation frequently occurs after successful defibrillation of Ventricular Fibrillation (VF) and negatively affects outcomes. Diastolic elevation in cytosolic calcium and dysfunction in calcium handling is proposed to underlie post-shock arrhythmias. Ryanodine Receptor 2 (RyR2) is the major calcium handling protein in c...

Low frequency current density imaging (LFCDI) is a magnetic resonance imaging (MRI) technique which enables calculation of current pathways within the medium of study. The induced current produces a magnetic flux which presents itself in phase images obtained through MRI scanning. A class of LFCDI challenges arises from the subject rotation require...

Introduction: Transplantation of mesenchymal stem cells (MSCs) has shown therapeutic potential for cardiovascular diseases, but the electrophysiological implications are not understood. The purpose of this study was to evaluate the impact of MSC transplantation on adverse electrophysiological remodeling in the heart following myocardial infarction...

Background: Ventricular fibrillation (VF) is an important cause of cardiac arrest. After initial successful resuscitation, decreased cardiac contractility during reperfusion is a common problem that is poorly understood. In normal hearts the major energy source for cardiac contractility is oxidation of fatty acids (FA), while only a lesser amount o...

The aim of this study was to evaluate the impacts of mesenchymal stem cell (MSC) transplantation on electrophysiological remodelling following myocardial infarction (MI). Methods: Three weeks after coronary ligation, 3×10 ⁶ MSCs, or culture medium alone, were directly injected into infarcted Lewis rat hearts. Hearts were excised one to two weeks la...

Ventricular fibrillation (VF) leads to global ischemia. The modulation of ischemia-dependent pathways may alter the electrophysiological evolution of VF. We addressed the hypotheses that there is regional disease-related expression of K(ATP) channels in human cardiomyopathic hearts and that K(ATP) channel blockade promotes spontaneous VF terminatio...

Sepsis refers to the clinical syndrome of severe systemic inflammation precipitated by infection. Despite appropriate antimicrobial therapy, sepsis-related morbidity and mortality remain intractable problems in critically ill patients. Moreover, there is no specific treatment strategy for the syndrome of sepsis-induced multiple organ dysfunction. W...

The endothelial cell (EC)-selective receptor tyrosine kinase, Tie2, and its ligands angiopoietin Ang-1 and Ang-2, are essential for blood vessel maintenance and repair. Ang-1 is an agonist of Tie2 receptor activation, whereas Ang-2 is a context-dependent antagonist/agonist. Therefore, we investigated the role of the EC-selective phosphatase, human...

The acute respiratory distress syndrome is a significant cause of morbidity and mortality in critically ill patients. Angiopoietin-1 (Ang-1), a ligand for the endothelial Tie2 receptor, is an endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. We hypothesized...

Endothelin-1 (ET-1) is increasingly recognized as a proinflammatory mediator in various diseases, such as atherosclerosis and acute respiratory distress syndrome (ARDS). Angiopoietin-1 (Ang-1), a ligand of the endothelial receptor Tie2, inhibits endothelial apoptosis, reduces vascular leakage, and suppresses the induction of inflammatory markers, i...

See related article, pages 1115–1123 Transforming Growth Factor-β (TGF-β) is the prototype of a superfamily of multifunctional proteins which includes activins and bone morphogenetic proteins (BMPs). TGF-β is involved in the regulation of diverse cellular processes such as cell proliferation, differentiation, apoptosis and migration, as well as m...

We have previously shown that downregulation of endothelial nitric oxide synthase (eNOS) expression by tumour necrosis factor-alpha (TNF alpha) resulted entirely from the marked destabilization of the eNOS mRNA. As the 3'-untranslated region (3'UTR) in many eukaryotic mRNA has been well documented to bind regulatory trans-factors in the control of...

In order to evaluate the importance of cAMP and cAMP-dependent protein kinase (cAMPdPK) in the regulation of chloride efflux via the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, Caco-2, human colonic carcinoma cells were transfected with an expression vector encoding a mutant form of regulatory subunit of cAMPdPK und...