The Experts below are selected from a list of 7410 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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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
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 (Ito) in Purkinje Fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Ito and that its overexpression might specifically alter PF Ito properties 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 Ito had similar density, but PF Ito differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Ito 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, essenti...
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Unique Cardiac Purkinje Fiber Transient Outward Current β-Subunit CompositionNovelty and Significance
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. # Novelty and Significance {#article-title-55}
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unique cardiac Purkinje Fiber transient outward current beta 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 (IVF). 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 Ito-properties and repolarization. Objective: To assess the potential role of DPP6 in PF-I to . Methods and Results: Clinical data in 5 IVF-patients suggested arrhythmia-origin in the PF conducting-system. PF and ventricular-muscle (VM) I to had similar density, but PF I to differed from VM in having tetraethylammonium-sensitivity and slower recovery. DPP6-overexpression significantly increased, whereas DPP6-kockdown reduced, I to -density and tetraethylammonium-sensitivity in canine PF, but not VM-cells. The K + -channel interacting β-subunit KChIP2, essential for normal expression of transient outward current (I to ) in VM, was weakly-expressed in human PFs, whereas DPP6 and frequenin (NCS-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary (CHO)-cells produced very small I to ; I to -amplitude was greatly enhanced by co-expression with KChIP2 or DPP6. Co expression of DPP6 with Kv4.3 and KChIP2 failed to alter I to versus Kv4.3/KChIP2 alone, but DPP6 expression with Kv4.3 and NCS-1 (to mimic PF I to -composition), greatly enhanced I to versus Kv4.3/NCS-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 IVF.
Arie O. Verkerk - One of the best experts on this subject based on the ideXlab platform.
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Embryonic Tbx3 + cardiomyocytes form the mature cardiac conduction system by progressive fate restriction
Development (Cambridge England), 2018Co-Authors: Rajiv Mohan, Lucile Miquerol, Mathilda Mommersteeg, Jorge Domínguez, Caroline Choquet, Vincent Wakker, Corrie De Gier-de Vries, Gerard Boink, Bastiaan Boukens, Arie O. VerkerkAbstract:A small network of spontaneously active Tbx3+ cardiomyocytes forms the cardiac conduction system (CCS) in adults. Understanding the origin and mechanism of development of the CCS network are important steps towards disease modeling and the development of biological pacemakers to treat arrhythmias. We found that Tbx3 expression in the embryonic mouse heart is associated with automaticity. Genetic inducible fate mapping revealed that Tbx3+ cells in the early heart tube are fated to form the definitive CCS components, except the Purkinje Fiber network. At mid-fetal stages, contribution of Tbx3+ cells was restricted to the definitive CCS. We identified a Tbx3+ population in the outflow tract of the early heart tube that formed the atrioventricular bundle. Whereas Tbx3+ cardiomyocytes also contributed to the adjacent Gja5+ atrial and ventricular chamber myocardium, embryonic Gja5+ chamber cardiomyocytes did not contribute to the Tbx3+ sinus node or to atrioventricular ring bundles. In conclusion, the CCS is established by progressive fate restriction of a Tbx3+ cell population in the early developing heart, which implicates Tbx3 as a useful tool for developing strategies to study and treat CCS diseases.
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unique cardiac Purkinje Fiber transient outward current β subunit composition
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 (Ito) in Purkinje Fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Ito and that its overexpression might specifically alter PF Ito properties 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 Ito had similar density, but PF Ito differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Ito 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, essenti...
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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
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. # Novelty and Significance {#article-title-55}
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unique cardiac Purkinje Fiber transient outward current beta 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 (IVF). 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 Ito-properties and repolarization. Objective: To assess the potential role of DPP6 in PF-I to . Methods and Results: Clinical data in 5 IVF-patients suggested arrhythmia-origin in the PF conducting-system. PF and ventricular-muscle (VM) I to had similar density, but PF I to differed from VM in having tetraethylammonium-sensitivity and slower recovery. DPP6-overexpression significantly increased, whereas DPP6-kockdown reduced, I to -density and tetraethylammonium-sensitivity in canine PF, but not VM-cells. The K + -channel interacting β-subunit KChIP2, essential for normal expression of transient outward current (I to ) in VM, was weakly-expressed in human PFs, whereas DPP6 and frequenin (NCS-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary (CHO)-cells produced very small I to ; I to -amplitude was greatly enhanced by co-expression with KChIP2 or DPP6. Co expression of DPP6 with Kv4.3 and KChIP2 failed to alter I to versus Kv4.3/KChIP2 alone, but DPP6 expression with Kv4.3 and NCS-1 (to mimic PF I to -composition), greatly enhanced I to versus Kv4.3/NCS-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 IVF.
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 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
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 (Ito) in Purkinje Fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Ito and that its overexpression might specifically alter PF Ito properties 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 Ito had similar density, but PF Ito differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Ito 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, essenti...
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Unique Cardiac Purkinje Fiber Transient Outward Current β-Subunit CompositionNovelty and Significance
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. # Novelty and Significance {#article-title-55}
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unique cardiac Purkinje Fiber transient outward current beta 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 (IVF). 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 Ito-properties and repolarization. Objective: To assess the potential role of DPP6 in PF-I to . Methods and Results: Clinical data in 5 IVF-patients suggested arrhythmia-origin in the PF conducting-system. PF and ventricular-muscle (VM) I to had similar density, but PF I to differed from VM in having tetraethylammonium-sensitivity and slower recovery. DPP6-overexpression significantly increased, whereas DPP6-kockdown reduced, I to -density and tetraethylammonium-sensitivity in canine PF, but not VM-cells. The K + -channel interacting β-subunit KChIP2, essential for normal expression of transient outward current (I to ) in VM, was weakly-expressed in human PFs, whereas DPP6 and frequenin (NCS-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary (CHO)-cells produced very small I to ; I to -amplitude was greatly enhanced by co-expression with KChIP2 or DPP6. Co expression of DPP6 with Kv4.3 and KChIP2 failed to alter I to versus Kv4.3/KChIP2 alone, but DPP6 expression with Kv4.3 and NCS-1 (to mimic PF I to -composition), greatly enhanced I to versus Kv4.3/NCS-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 IVF.
Vivek Iyer - One of the best experts on this subject based on the ideXlab platform.
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Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje Fiber.
PLOS ONE, 2014Co-Authors: Vivek Iyer, Kevin J Sampson, Robert S. KassAbstract:Congenital long QT syndrome is a heritable family of arrhythmias caused by mutations in 13 genes encoding ion channel complex proteins. Mounting evidence has implicated the Purkinje Fiber network in the genesis of ventricular arrhythmias. In this study, we explore the hypothesis that long QT mutations can demonstrate different phenotypes depending on the tissue type of expression. Using computational models of the human ventricular myocyte and the Purkinje Fiber cell, the biophysical alteration in channel function in LQT1, LQT2, LQT3, and LQT7 are modeled. We identified that the plateau potential was important in LQT1 and LQT2, in which mutation led to minimal action potential prolongation in Purkinje Fiber cells. The phenotype of LQT3 mutation was dependent on the biophysical alteration induced as well as tissue type. The canonical ΔKPQ mutation causes severe action potential prolongation in both tissue types. For LQT3 mutation F1473C, characterized by shifted channel availability, a more severe phenotype was seen in Purkinje Fiber cells with action potential prolongation and early afterdepolarizations. The LQT3 mutation S1904L demonstrated striking effects on action potential duration restitution and more severe action potential prolongation in Purkinje Fiber cells at higher heart rates. Voltage clamp simulations highlight the mechanism of effect of these mutations in different tissue types, and impact of drug therapy is explored. We conclude that arrhythmia formation in long QT syndrome may depend not only on the basis of mutation and biophysical alteration, but also upon tissue of expression. The Purkinje Fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies.
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unique cardiac Purkinje Fiber transient outward current β subunit composition
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 (Ito) in Purkinje Fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Ito and that its overexpression might specifically alter PF Ito properties 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 Ito had similar density, but PF Ito differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Ito 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, essenti...
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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
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. # Novelty and Significance {#article-title-55}
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unique cardiac Purkinje Fiber transient outward current beta 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 (IVF). 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 Ito-properties and repolarization. Objective: To assess the potential role of DPP6 in PF-I to . Methods and Results: Clinical data in 5 IVF-patients suggested arrhythmia-origin in the PF conducting-system. PF and ventricular-muscle (VM) I to had similar density, but PF I to differed from VM in having tetraethylammonium-sensitivity and slower recovery. DPP6-overexpression significantly increased, whereas DPP6-kockdown reduced, I to -density and tetraethylammonium-sensitivity in canine PF, but not VM-cells. The K + -channel interacting β-subunit KChIP2, essential for normal expression of transient outward current (I to ) in VM, was weakly-expressed in human PFs, whereas DPP6 and frequenin (NCS-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary (CHO)-cells produced very small I to ; I to -amplitude was greatly enhanced by co-expression with KChIP2 or DPP6. Co expression of DPP6 with Kv4.3 and KChIP2 failed to alter I to versus Kv4.3/KChIP2 alone, but DPP6 expression with Kv4.3 and NCS-1 (to mimic PF I to -composition), greatly enhanced I to versus Kv4.3/NCS-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 IVF.
Kevin J Sampson - One of the best experts on this subject based on the ideXlab platform.
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Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje Fiber.
PLOS ONE, 2014Co-Authors: Vivek Iyer, Kevin J Sampson, Robert S. KassAbstract:Congenital long QT syndrome is a heritable family of arrhythmias caused by mutations in 13 genes encoding ion channel complex proteins. Mounting evidence has implicated the Purkinje Fiber network in the genesis of ventricular arrhythmias. In this study, we explore the hypothesis that long QT mutations can demonstrate different phenotypes depending on the tissue type of expression. Using computational models of the human ventricular myocyte and the Purkinje Fiber cell, the biophysical alteration in channel function in LQT1, LQT2, LQT3, and LQT7 are modeled. We identified that the plateau potential was important in LQT1 and LQT2, in which mutation led to minimal action potential prolongation in Purkinje Fiber cells. The phenotype of LQT3 mutation was dependent on the biophysical alteration induced as well as tissue type. The canonical ΔKPQ mutation causes severe action potential prolongation in both tissue types. For LQT3 mutation F1473C, characterized by shifted channel availability, a more severe phenotype was seen in Purkinje Fiber cells with action potential prolongation and early afterdepolarizations. The LQT3 mutation S1904L demonstrated striking effects on action potential duration restitution and more severe action potential prolongation in Purkinje Fiber cells at higher heart rates. Voltage clamp simulations highlight the mechanism of effect of these mutations in different tissue types, and impact of drug therapy is explored. We conclude that arrhythmia formation in long QT syndrome may depend not only on the basis of mutation and biophysical alteration, but also upon tissue of expression. The Purkinje Fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies.
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unique cardiac Purkinje Fiber transient outward current β subunit composition
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 (Ito) in Purkinje Fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Ito and that its overexpression might specifically alter PF Ito properties 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 Ito had similar density, but PF Ito differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Ito 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, essenti...
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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
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. # Novelty and Significance {#article-title-55}
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unique cardiac Purkinje Fiber transient outward current beta 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 (IVF). 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 Ito-properties and repolarization. Objective: To assess the potential role of DPP6 in PF-I to . Methods and Results: Clinical data in 5 IVF-patients suggested arrhythmia-origin in the PF conducting-system. PF and ventricular-muscle (VM) I to had similar density, but PF I to differed from VM in having tetraethylammonium-sensitivity and slower recovery. DPP6-overexpression significantly increased, whereas DPP6-kockdown reduced, I to -density and tetraethylammonium-sensitivity in canine PF, but not VM-cells. The K + -channel interacting β-subunit KChIP2, essential for normal expression of transient outward current (I to ) in VM, was weakly-expressed in human PFs, whereas DPP6 and frequenin (NCS-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary (CHO)-cells produced very small I to ; I to -amplitude was greatly enhanced by co-expression with KChIP2 or DPP6. Co expression of DPP6 with Kv4.3 and KChIP2 failed to alter I to versus Kv4.3/KChIP2 alone, but DPP6 expression with Kv4.3 and NCS-1 (to mimic PF I to -composition), greatly enhanced I to versus Kv4.3/NCS-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 IVF.
