The Experts below are selected from a list of 1914 Experts worldwide ranked by ideXlab platform
András Varró - One of the best experts on this subject based on the ideXlab platform.
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Characterisation of familial Idiopathic Ventricular Fibrillation linked to DPP6
European Heart Journal, 2013Co-Authors: Pieter G Postema, J Ten N Sande, Imke Christiaans, M Boekholdt, Connie R Bezzina, Marielle Alders, Stanley Nattel, András Varró, X Ling, A A M WildeAbstract:Purpose: Idiopathic Ventricular Fibrillation (IVF) is a rare but notoriously difficult to manage arrhythmia syndrome as there are no clinical identifiers to establish the risk for a premature cardiac arrest. However, we recently uncovered a link between familial IVF and a risk haplotype on the new arrhythmia gene DPP6 on chromosome 7q36 in several related IVF families. DPP6 is putatively involved in the Ito current in heart. In this study we characterise both the extended bench and bedside evaluations in IVF linked to DPP6. Methods: We studied 235 carriers and 267 non-carriers of the DPP6 risk haplotype. Clinical parameters and a combination of all cause mortality and cardiac arrest were evaluated. Additional expression studies in human cardiac tissue samples and adenovirus-mediated gene transfer studies in cultured canine Purkinje cells and cardiomyocytes were performed. Results: Successfully resuscitated patients did not have any sign of other inheritable arrhythmia syndromes. Recorded IVF was always initiated by monomorphic short-coupled extrasystoles from the right Ventricular apex/lower free wall. Ablation of extrasystole preceding Purkinje potentials and/or the administration quinidine led to suppression of subsequent arrhythmias. Carriers and non-carriers had normal and similar electrocardiographic and echocardiographic indices. Cardiac MRI showed a trend to slightly larger right Ventricular volumes in carriers, but these were still within normal limits and not clinically useful. Death and/or cardiac arrest occurred in 84 carriers and 10 non-carriers. Median survival of carriers was 68 years (p
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unique cardiac purkinje fiber transient outward current β subunit composition a potential molecular link to Idiopathic Ventricular Fibrillation
Circulation Research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:textabstractRationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current (Ito) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Itoand that its overexpression might specifically alter PF Itoproperties and repolarization. Objective: To assess the potential role of DPP6 in PF Ito. Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle Itohad similar density, but PF Itodiffered from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Itodensity and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K+-channel interacting β-subunit K+-channel interacting protein type-2, essential for normal expression of Itoin Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small Ito; Itoamplitude was greatly enhanced by coexpression with K+-channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K+-channel interacting protein type-2 failed to alter Itocompared with Kv4.3/K+-channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF Itocomposition) greatly enhanced Itocompared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that Itoenhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF Ito, with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
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unique cardiac purkinje fiber transient outward current β subunit compositionnovelty and significance a potential molecular link to Idiopathic Ventricular Fibrillation
Circulation Research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current ( I to ) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I to and that its overexpression might specifically alter PF I to properties and repolarization. Objective: To assess the potential role of DPP6 in PF I to . Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle I to had similar density, but PF I to differed from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I to density and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K + -channel interacting β-subunit K + -channel interacting protein type-2, essential for normal expression of I to in Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I to ; I to amplitude was greatly enhanced by coexpression with K + -channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K + -channel interacting protein type-2 failed to alter I to compared with Kv4.3/K + -channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I to composition) greatly enhanced I to compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I to enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF I to , with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
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Unique Cardiac Purkinje Fiber Transient Outward Current β-Subunit Composition: A Potential Molecular Link to Idiopathic Ventricular Fibrillation
Circulation research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current ( I to ) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I to and that its overexpression might specifically alter PF I to properties and repolarization. Objective: To assess the potential role of DPP6 in PF I to . Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle I to had similar density, but PF I to differed from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I to density and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K + -channel interacting β-subunit K + -channel interacting protein type-2, essential for normal expression of I to in Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I to ; I to amplitude was greatly enhanced by coexpression with K + -channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K + -channel interacting protein type-2 failed to alter I to compared with Kv4.3/K + -channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I to composition) greatly enhanced I to compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I to enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF I to , with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
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familial Idiopathic Ventricular Fibrillation linked to chromosome 7q36 harboring dpp6
Journal of Arrhythmia, 2011Co-Authors: Pieter G Postema, Imke Christiaans, Tamara T. Koopmann, Connie R Bezzina, Marielle Alders, Stanley Nattel, András Varró, Ling Xiao, A A M WildeAbstract:Background: Until recently it was impossible to identify presymptomatic family members at risk for fatal events in familial Idiopathic Ventricular Fibrillation (IVF). We uncovered a large IVF-family and linked their arrhythmic events to a new arrhythmia gene on chromosome 7q36: DPP6. Methods and Results: We studied 169 carriers and 195 non-carriers. ECGs and echocardiography were normal. All-cause mortality or IVF/resuscitation occurred in 67 carriers and 7 non-carriers (no IVF/resuscitation). At 62 years of age, 50% of carriers had an event (p<0.001), the youngest 16 years old, males earlier than females (56 vs. 72 years, p<0.001). IVF was always elicited by monomorphic short-coupled extrasystoles from the right Ventricular apex/lower free wall and an origin in the Purkinje network was suspected. Expression-studies showed overexpression of DPP6 mRNA in carriers (p<0.01). Expression-studies in non-diseased explanted human hearts showed higher DPP6 mRNA expression in Purkinje fiber than in any other region (p<0.01). Conclusions: A new arrhythmia gene on chromosome 7q36, DPP6, is linked to familial IVF and shows a very malignant phenotype. Short-coupled extrasystoles from the right-Ventricular apex/free wall, presumably originating from the Purkinje network, trigger IVF. For the first time, only genetic predisposition can be used as a risk-marker for future events in IVF.
Pieter G Postema - One of the best experts on this subject based on the ideXlab platform.
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Idiopathic Ventricular Fibrillation and early repolarization.
Channelopathies in Heart Disease, 2018Co-Authors: Pieter G PostemaAbstract:In this chapter, an overview is provided on Idiopathic Ventricular Fibrillation (IVF) and early repolarization. Idiopathic Ventricular Fibrillation is a tragic and notoriously difficult disease entity to manage. The IVF patients in whom a cardiac arrest occurs are generally considered healthy and do not show any currently identifiable abnormalities that denote their increased risk for malignant and life-threatening arrhythmias. Importantly, IVF can be inheritable and tear through families. The number of patients who survive their first manifestation of the disease is low, and the recurrence rate of IVF is appreciable. Treatment in patients who survived their event is performed by implantation of a cardioverter defibrillator (ICD) and a decrease of the risk of IVF recurrence may be achieved by prescription of quinidine. During a VF storm, administration of isoproterenol can be essential, and possibly also sedation might be effective. Research into the origin and genetic underpinning of IVF is limited by its malignant character, yet has revealed genetic variants in the DPP6 gene and CALM1 gene that impact on cellular cardiac electrophysiology. In contrast, early repolarization is a description of electrocardiographic variants with elevation, slurring, or notching in the terminal QRS complex or early ST segment. Although considered a benign electrocardiographic characteristic for many decades, in the past decade associations have been made with a propensity to sudden cardiac arrest by VF. Importantly, early repolarization is of very common occurrence in many young and healthy individuals. The description of a rare malignant association has spurred scientific interest in this phenomenon. Fortunately, its benign prognosis is still valid for the vast majority of individuals who display an early repolarization pattern. The challenge for the future will be to delineate benign from malignant variants of early repolarization, the development of aids in risk stratification and a better understanding underlying pathophysiology on cellular and genetic level, to further guide clinicians and patients.
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detailed characterization of familial Idiopathic Ventricular Fibrillation linked to the dpp6 locus
Heart Rhythm, 2016Co-Authors: J Ten N Sande, M Boekholdt, Katja Zeppenfeld, Jeroen F Van Der Heijden, Paul G A Volders, Lucas V.a. Boersma, Eline A. Nannenberg, Natasja M.s. De Groot, Pieter G Postema, Imke ChristiaansAbstract:Background Familial Idiopathic Ventricular Fibrillation (IVF) is a severe disease entity and is notoriously difficult to manage because there are no clinical risk indicators for premature cardiac arrest. Previously, we identified a link between familial IVF and a risk haplotype on chromosome 7q36 (involving the arrhythmia gene DPP6 ). Objective The purpose of this study was to expand our knowledge of familial IVF and to discuss its (extended) clinical characteristics. Methods We studied 601 family members and probands: 286 DPP6 risk-haplotype positive (haplotype-positive) and 315 DPP6 risk-haplotype negative (haplotype-negative) individuals. Clinical parameters, a combination of all-cause mortality and (aborted) cardiac arrest and differences between haplotype-positives and haplotype-negatives, were evaluated. Results There were no differences in electrocardiographic indices between haplotype-positives and haplotype-negatives, or between haplotype-positives with or without events. Cardiac magnetic resonance documented slightly larger Ventricular volumes in haplotype-positives compared to controls ( P P P Conclusion Despite our extensive analysis, the complexity in identifying asymptomatic IVF family members at risk for future arrhythmias based on clinical parameters is once more demonstrated.
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Characterisation of familial Idiopathic Ventricular Fibrillation linked to DPP6
European Heart Journal, 2013Co-Authors: Pieter G Postema, J Ten N Sande, Imke Christiaans, M Boekholdt, Connie R Bezzina, Marielle Alders, Stanley Nattel, András Varró, X Ling, A A M WildeAbstract:Purpose: Idiopathic Ventricular Fibrillation (IVF) is a rare but notoriously difficult to manage arrhythmia syndrome as there are no clinical identifiers to establish the risk for a premature cardiac arrest. However, we recently uncovered a link between familial IVF and a risk haplotype on the new arrhythmia gene DPP6 on chromosome 7q36 in several related IVF families. DPP6 is putatively involved in the Ito current in heart. In this study we characterise both the extended bench and bedside evaluations in IVF linked to DPP6. Methods: We studied 235 carriers and 267 non-carriers of the DPP6 risk haplotype. Clinical parameters and a combination of all cause mortality and cardiac arrest were evaluated. Additional expression studies in human cardiac tissue samples and adenovirus-mediated gene transfer studies in cultured canine Purkinje cells and cardiomyocytes were performed. Results: Successfully resuscitated patients did not have any sign of other inheritable arrhythmia syndromes. Recorded IVF was always initiated by monomorphic short-coupled extrasystoles from the right Ventricular apex/lower free wall. Ablation of extrasystole preceding Purkinje potentials and/or the administration quinidine led to suppression of subsequent arrhythmias. Carriers and non-carriers had normal and similar electrocardiographic and echocardiographic indices. Cardiac MRI showed a trend to slightly larger right Ventricular volumes in carriers, but these were still within normal limits and not clinically useful. Death and/or cardiac arrest occurred in 84 carriers and 10 non-carriers. Median survival of carriers was 68 years (p
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unique cardiac purkinje fiber transient outward current β subunit composition a potential molecular link to Idiopathic Ventricular Fibrillation
Circulation Research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:textabstractRationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current (Ito) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Itoand that its overexpression might specifically alter PF Itoproperties and repolarization. Objective: To assess the potential role of DPP6 in PF Ito. Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle Itohad similar density, but PF Itodiffered from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Itodensity and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K+-channel interacting β-subunit K+-channel interacting protein type-2, essential for normal expression of Itoin Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small Ito; Itoamplitude was greatly enhanced by coexpression with K+-channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K+-channel interacting protein type-2 failed to alter Itocompared with Kv4.3/K+-channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF Itocomposition) greatly enhanced Itocompared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that Itoenhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF Ito, with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
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unique cardiac purkinje fiber transient outward current β subunit compositionnovelty and significance a potential molecular link to Idiopathic Ventricular Fibrillation
Circulation Research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current ( I to ) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I to and that its overexpression might specifically alter PF I to properties and repolarization. Objective: To assess the potential role of DPP6 in PF I to . Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle I to had similar density, but PF I to differed from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I to density and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K + -channel interacting β-subunit K + -channel interacting protein type-2, essential for normal expression of I to in Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I to ; I to amplitude was greatly enhanced by coexpression with K + -channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K + -channel interacting protein type-2 failed to alter I to compared with Kv4.3/K + -channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I to composition) greatly enhanced I to compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I to enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF I to , with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
Ling Xiao - One of the best experts on this subject based on the ideXlab platform.
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unique cardiac purkinje fiber transient outward current β subunit compositionnovelty and significance a potential molecular link to Idiopathic Ventricular Fibrillation
Circulation Research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current ( I to ) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I to and that its overexpression might specifically alter PF I to properties and repolarization. Objective: To assess the potential role of DPP6 in PF I to . Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle I to had similar density, but PF I to differed from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I to density and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K + -channel interacting β-subunit K + -channel interacting protein type-2, essential for normal expression of I to in Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I to ; I to amplitude was greatly enhanced by coexpression with K + -channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K + -channel interacting protein type-2 failed to alter I to compared with Kv4.3/K + -channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I to composition) greatly enhanced I to compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I to enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF I to , with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
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unique cardiac purkinje fiber transient outward current β subunit composition a potential molecular link to Idiopathic Ventricular Fibrillation
Circulation Research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:textabstractRationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current (Ito) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Itoand that its overexpression might specifically alter PF Itoproperties and repolarization. Objective: To assess the potential role of DPP6 in PF Ito. Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle Itohad similar density, but PF Itodiffered from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Itodensity and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K+-channel interacting β-subunit K+-channel interacting protein type-2, essential for normal expression of Itoin Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small Ito; Itoamplitude was greatly enhanced by coexpression with K+-channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K+-channel interacting protein type-2 failed to alter Itocompared with Kv4.3/K+-channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF Itocomposition) greatly enhanced Itocompared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that Itoenhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF Ito, with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
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Unique Cardiac Purkinje Fiber Transient Outward Current β-Subunit Composition: A Potential Molecular Link to Idiopathic Ventricular Fibrillation
Circulation research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current ( I to ) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I to and that its overexpression might specifically alter PF I to properties and repolarization. Objective: To assess the potential role of DPP6 in PF I to . Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle I to had similar density, but PF I to differed from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I to density and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K + -channel interacting β-subunit K + -channel interacting protein type-2, essential for normal expression of I to in Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I to ; I to amplitude was greatly enhanced by coexpression with K + -channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K + -channel interacting protein type-2 failed to alter I to compared with Kv4.3/K + -channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I to composition) greatly enhanced I to compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I to enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF I to , with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
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familial Idiopathic Ventricular Fibrillation linked to chromosome 7q36 harboring dpp6
Journal of Arrhythmia, 2011Co-Authors: Pieter G Postema, Imke Christiaans, Tamara T. Koopmann, Connie R Bezzina, Marielle Alders, Stanley Nattel, András Varró, Ling Xiao, A A M WildeAbstract:Background: Until recently it was impossible to identify presymptomatic family members at risk for fatal events in familial Idiopathic Ventricular Fibrillation (IVF). We uncovered a large IVF-family and linked their arrhythmic events to a new arrhythmia gene on chromosome 7q36: DPP6. Methods and Results: We studied 169 carriers and 195 non-carriers. ECGs and echocardiography were normal. All-cause mortality or IVF/resuscitation occurred in 67 carriers and 7 non-carriers (no IVF/resuscitation). At 62 years of age, 50% of carriers had an event (p<0.001), the youngest 16 years old, males earlier than females (56 vs. 72 years, p<0.001). IVF was always elicited by monomorphic short-coupled extrasystoles from the right Ventricular apex/lower free wall and an origin in the Purkinje network was suspected. Expression-studies showed overexpression of DPP6 mRNA in carriers (p<0.01). Expression-studies in non-diseased explanted human hearts showed higher DPP6 mRNA expression in Purkinje fiber than in any other region (p<0.01). Conclusions: A new arrhythmia gene on chromosome 7q36, DPP6, is linked to familial IVF and shows a very malignant phenotype. Short-coupled extrasystoles from the right-Ventricular apex/free wall, presumably originating from the Purkinje network, trigger IVF. For the first time, only genetic predisposition can be used as a risk-marker for future events in IVF.
Tamara T. Koopmann - One of the best experts on this subject based on the ideXlab platform.
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unique cardiac purkinje fiber transient outward current β subunit composition a potential molecular link to Idiopathic Ventricular Fibrillation
Circulation Research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:textabstractRationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current (Ito) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Itoand that its overexpression might specifically alter PF Itoproperties and repolarization. Objective: To assess the potential role of DPP6 in PF Ito. Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle Itohad similar density, but PF Itodiffered from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Itodensity and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K+-channel interacting β-subunit K+-channel interacting protein type-2, essential for normal expression of Itoin Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small Ito; Itoamplitude was greatly enhanced by coexpression with K+-channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K+-channel interacting protein type-2 failed to alter Itocompared with Kv4.3/K+-channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF Itocomposition) greatly enhanced Itocompared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that Itoenhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF Ito, with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
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unique cardiac purkinje fiber transient outward current β subunit compositionnovelty and significance a potential molecular link to Idiopathic Ventricular Fibrillation
Circulation Research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current ( I to ) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I to and that its overexpression might specifically alter PF I to properties and repolarization. Objective: To assess the potential role of DPP6 in PF I to . Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle I to had similar density, but PF I to differed from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I to density and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K + -channel interacting β-subunit K + -channel interacting protein type-2, essential for normal expression of I to in Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I to ; I to amplitude was greatly enhanced by coexpression with K + -channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K + -channel interacting protein type-2 failed to alter I to compared with Kv4.3/K + -channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I to composition) greatly enhanced I to compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I to enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF I to , with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
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Unique Cardiac Purkinje Fiber Transient Outward Current β-Subunit Composition: A Potential Molecular Link to Idiopathic Ventricular Fibrillation
Circulation research, 2013Co-Authors: Ling Xiao, Balázs Ördög, Maya A. Mamarbachi, Tamara T. Koopmann, Kevin J Sampson, Vivek Iyer, Gerard J.j. Boink, Pieter G Postema, Arie O. Verkerk, András VarróAbstract:Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial Idiopathic Ventricular Fibrillation. The molecular basis of transient outward current ( I to ) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I to and that its overexpression might specifically alter PF I to properties and repolarization. Objective: To assess the potential role of DPP6 in PF I to . Methods and Results: Clinical data in 5 Idiopathic Ventricular Fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and Ventricular muscle I to had similar density, but PF I to differed from Ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I to density and tetraethylammonium sensitivity in canine PF but not in Ventricular muscle cells. The K + -channel interacting β-subunit K + -channel interacting protein type-2, essential for normal expression of I to in Ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I to ; I to amplitude was greatly enhanced by coexpression with K + -channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K + -channel interacting protein type-2 failed to alter I to compared with Kv4.3/K + -channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I to composition) greatly enhanced I to compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I to enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF I to , with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of Idiopathic Ventricular Fibrillation.
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Founder mutations in the Netherlands: familial Idiopathic Ventricular Fibrillation and DPP6
Netherlands Heart Journal, 2011Co-Authors: Pieter G Postema, Imke Christiaans, Katja Zeppenfeld, N. Hofman, Paul G A Volders, Tamara T. Koopmann, Connie R Bezzina, Marielle Alders, A A M WildeAbstract:In this part of a series on founder mutations in the Netherlands, we review familial Idiopathic Ventricular Fibrillation linked to the DPP6 gene. Familial Idiopathic Ventricular Fibrillation determines an intriguing subset of the inheritable arrhythmia syndromes as there is no recognisable phenotype during cardiological investigation other than Ventricular arrhythmias highly associated with sudden cardiac death. Until recently, it was impossible to identify presymptomatic family members at risk for fatal events. We uncovered several genealogically linked families affected by numerous sudden cardiac deaths over the past centuries, attributed to familial Idiopathic Ventricular Fibrillation. Notably, Ventricular Fibrillation in these families was provoked by very short coupled monomorphic extrasystoles. We were able to associate their phenotype of lethal arrhythmic events with a haplotype harbouring the DPP6 gene. While this gene has not earlier been related to cardiac arrhythmias, we are now able, for the first time, to identify and to offer timely treatment to presymptomatic family members at risk for future fatal events solely by genetic analysis. Therefore, when there is a familial history of unexplained sudden cardiac deaths, a link to the DPP6 gene may be explored as it may enable risk evaluation of the remaining family members. In addition, when closely coupled extrasystoles initiate Ventricular Fibrillation in the absence of other identifiable causes, a link to the DPP6 gene should be suspected.
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familial Idiopathic Ventricular Fibrillation linked to chromosome 7q36 harboring dpp6
Journal of Arrhythmia, 2011Co-Authors: Pieter G Postema, Imke Christiaans, Tamara T. Koopmann, Connie R Bezzina, Marielle Alders, Stanley Nattel, András Varró, Ling Xiao, A A M WildeAbstract:Background: Until recently it was impossible to identify presymptomatic family members at risk for fatal events in familial Idiopathic Ventricular Fibrillation (IVF). We uncovered a large IVF-family and linked their arrhythmic events to a new arrhythmia gene on chromosome 7q36: DPP6. Methods and Results: We studied 169 carriers and 195 non-carriers. ECGs and echocardiography were normal. All-cause mortality or IVF/resuscitation occurred in 67 carriers and 7 non-carriers (no IVF/resuscitation). At 62 years of age, 50% of carriers had an event (p<0.001), the youngest 16 years old, males earlier than females (56 vs. 72 years, p<0.001). IVF was always elicited by monomorphic short-coupled extrasystoles from the right Ventricular apex/lower free wall and an origin in the Purkinje network was suspected. Expression-studies showed overexpression of DPP6 mRNA in carriers (p<0.01). Expression-studies in non-diseased explanted human hearts showed higher DPP6 mRNA expression in Purkinje fiber than in any other region (p<0.01). Conclusions: A new arrhythmia gene on chromosome 7q36, DPP6, is linked to familial IVF and shows a very malignant phenotype. Short-coupled extrasystoles from the right-Ventricular apex/free wall, presumably originating from the Purkinje network, trigger IVF. For the first time, only genetic predisposition can be used as a risk-marker for future events in IVF.
A A M Wilde - One of the best experts on this subject based on the ideXlab platform.
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Life-long tailoring of diagnosis and management of patients with Idiopathic Ventricular Fibrillation : future perspectives in research
Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation, 2018Co-Authors: L. J. Blom, Paul G A Volders, A A M Wilde, R. J. HassinkAbstract:The diagnosis and management of Idiopathic Ventricular Fibrillation is challenging, as it requires extensive diagnostic testing and offers few curative options due to unknown underlying disease. The resulting population is a heterogeneous group of patients with a largely unknown natural history. Structural patient characterisation, follow-up and innovations in diagnostic testing can improve our understanding of the disease mechanisms of Idiopathic Ventricular Fibrillation, detect underlying disease during follow-up and aid in therapeutic management. Recently, initiatives have been launched in the Netherlands to investigate the role of high-resolution non-invasive electrocardiographic imaging and genetic and familial screening in Idiopathic Ventricular Fibrillation.
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Characterisation of familial Idiopathic Ventricular Fibrillation linked to DPP6
European Heart Journal, 2013Co-Authors: Pieter G Postema, J Ten N Sande, Imke Christiaans, M Boekholdt, Connie R Bezzina, Marielle Alders, Stanley Nattel, András Varró, X Ling, A A M WildeAbstract:Purpose: Idiopathic Ventricular Fibrillation (IVF) is a rare but notoriously difficult to manage arrhythmia syndrome as there are no clinical identifiers to establish the risk for a premature cardiac arrest. However, we recently uncovered a link between familial IVF and a risk haplotype on the new arrhythmia gene DPP6 on chromosome 7q36 in several related IVF families. DPP6 is putatively involved in the Ito current in heart. In this study we characterise both the extended bench and bedside evaluations in IVF linked to DPP6. Methods: We studied 235 carriers and 267 non-carriers of the DPP6 risk haplotype. Clinical parameters and a combination of all cause mortality and cardiac arrest were evaluated. Additional expression studies in human cardiac tissue samples and adenovirus-mediated gene transfer studies in cultured canine Purkinje cells and cardiomyocytes were performed. Results: Successfully resuscitated patients did not have any sign of other inheritable arrhythmia syndromes. Recorded IVF was always initiated by monomorphic short-coupled extrasystoles from the right Ventricular apex/lower free wall. Ablation of extrasystole preceding Purkinje potentials and/or the administration quinidine led to suppression of subsequent arrhythmias. Carriers and non-carriers had normal and similar electrocardiographic and echocardiographic indices. Cardiac MRI showed a trend to slightly larger right Ventricular volumes in carriers, but these were still within normal limits and not clinically useful. Death and/or cardiac arrest occurred in 84 carriers and 10 non-carriers. Median survival of carriers was 68 years (p
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Founder mutations in the Netherlands: familial Idiopathic Ventricular Fibrillation and DPP6
Netherlands Heart Journal, 2011Co-Authors: Pieter G Postema, Imke Christiaans, Katja Zeppenfeld, N. Hofman, Paul G A Volders, Tamara T. Koopmann, Connie R Bezzina, Marielle Alders, A A M WildeAbstract:In this part of a series on founder mutations in the Netherlands, we review familial Idiopathic Ventricular Fibrillation linked to the DPP6 gene. Familial Idiopathic Ventricular Fibrillation determines an intriguing subset of the inheritable arrhythmia syndromes as there is no recognisable phenotype during cardiological investigation other than Ventricular arrhythmias highly associated with sudden cardiac death. Until recently, it was impossible to identify presymptomatic family members at risk for fatal events. We uncovered several genealogically linked families affected by numerous sudden cardiac deaths over the past centuries, attributed to familial Idiopathic Ventricular Fibrillation. Notably, Ventricular Fibrillation in these families was provoked by very short coupled monomorphic extrasystoles. We were able to associate their phenotype of lethal arrhythmic events with a haplotype harbouring the DPP6 gene. While this gene has not earlier been related to cardiac arrhythmias, we are now able, for the first time, to identify and to offer timely treatment to presymptomatic family members at risk for future fatal events solely by genetic analysis. Therefore, when there is a familial history of unexplained sudden cardiac deaths, a link to the DPP6 gene may be explored as it may enable risk evaluation of the remaining family members. In addition, when closely coupled extrasystoles initiate Ventricular Fibrillation in the absence of other identifiable causes, a link to the DPP6 gene should be suspected.
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familial Idiopathic Ventricular Fibrillation linked to chromosome 7q36 harboring dpp6
Journal of Arrhythmia, 2011Co-Authors: Pieter G Postema, Imke Christiaans, Tamara T. Koopmann, Connie R Bezzina, Marielle Alders, Stanley Nattel, András Varró, Ling Xiao, A A M WildeAbstract:Background: Until recently it was impossible to identify presymptomatic family members at risk for fatal events in familial Idiopathic Ventricular Fibrillation (IVF). We uncovered a large IVF-family and linked their arrhythmic events to a new arrhythmia gene on chromosome 7q36: DPP6. Methods and Results: We studied 169 carriers and 195 non-carriers. ECGs and echocardiography were normal. All-cause mortality or IVF/resuscitation occurred in 67 carriers and 7 non-carriers (no IVF/resuscitation). At 62 years of age, 50% of carriers had an event (p<0.001), the youngest 16 years old, males earlier than females (56 vs. 72 years, p<0.001). IVF was always elicited by monomorphic short-coupled extrasystoles from the right Ventricular apex/lower free wall and an origin in the Purkinje network was suspected. Expression-studies showed overexpression of DPP6 mRNA in carriers (p<0.01). Expression-studies in non-diseased explanted human hearts showed higher DPP6 mRNA expression in Purkinje fiber than in any other region (p<0.01). Conclusions: A new arrhythmia gene on chromosome 7q36, DPP6, is linked to familial IVF and shows a very malignant phenotype. Short-coupled extrasystoles from the right-Ventricular apex/free wall, presumably originating from the Purkinje network, trigger IVF. For the first time, only genetic predisposition can be used as a risk-marker for future events in IVF.
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Diagnosis and long-term follow-up of the Brugada syndrome in patients with Idiopathic Ventricular Fibrillation
European heart journal, 2001Co-Authors: Carol Ann Remme, A A M Wilde, Richard Derksen, Eric F.d. Wever, Rnw HauerAbstract:Aims Some patients with Idiopathic Ventricular Fibrillation may suffer from the Brugada syndrome. The diagnostic criteria for the Brugada syndrome are uncertain and arbitrarily set. Therefore, we studied the prevalence of the Brugada syndrome using various diagnostic criteria and long-term follow-up in 37 Idiopathic Ventricular Fibrillation patients. Methods and Results Idiopathic Ventricular Fibrillation was diagnosed after thorough clinical evaluation in 37 survivors of an out-of-hospital cardiac arrest referred to our institute (UMC Utrecht). Retrospectively, nine patients (24%, group I) were classified as potentially having the Brugada syndrome based on the presence of (in)complete right bundle branch block and ST-segment elevation in leads V1–V3of ≥1mm. Only three patients (8%, group II) showed (in)complete right bundle branch block and ≥2mm ST-segment elevation. With the intermittent presence of these ECG features and/or their (re)appearance with class I antiarrhythmic drugs included as criteria, the percentage of the Brugada syndrome was attenuated in group I (2/37; 5%) and group II (1/37; 3%). Sixteen (43%) of all Idiopathic Ventricular Fibrillation patients (mean follow-up 77±41 months) had a recurrent episode of syncope, Ventricular tachyarrhythmias or sudden death. Recurrence rate was 3/9 (33%) in Brugada patients group I, 2/3 (66%) in group II and 13/28 (46%) in patients without the Brugada syndrome ( P =ns). Conclusions Depending on the diagnostic criteria used, the Brugada syndrome was observed in 3% to 24% of patients with Idiopathic Ventricular Fibrillation, underlining the importance of defining the precise diagnostic criteria in these patients. For all Idiopathic Ventricular Fibrillation patients, the Ventricular tachyarrhythmia recurrence rate was substantial during an average follow-up of more than 6 years.
