Unique Cardiac Purkinje Fiber Transient Outward Current β-Subunit Composition

Abstract

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, essential for normal expression of Ito 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 Ito; Ito 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 Ito 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 Ito composition) greatly enhanced Ito 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 Ito enhancement 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.

Idiopathic Ventricular Fibrillation

“…16 A subgroup of IVF patients show short-coupled VPBs causing TdP/ VF. In these patients, mapping and ablation proved effective to prevent recurrence of short coupled TdP (scTdP)/VF.…”

“…VPBs with a short-coupled interval (ie, R-on-T phenomenon) can cause phase 2 reentry and hereby elicit VF. 16 …”

Cardiac Purkinje fibers and arrhythmias; The GK Moe Award Lecture 2015

“…In normal canine Purkinje cells, the transient outward current is very large, rate and age dependent and easily remodeled 35,36,37 (Figure S3). It is sensitive to block with 4 aminopyridine which inhibits both the transient and sustained component of the current.…”

Miocardiocitos conducentes ventriculares

“…[30][31][32][33][34] Los procesos arritmogénicos en los que están involucradas las células miocárdicas conducentes ventriculares incluyen la insuficiencia cardiaca congestiva, el síndrome de QT prolongado y la taquicardia ventricular. [35][36][37][38] Los modelos matemáticos, experimentos con células madre y matrices para regeneración de tejidos en el campo de la ingeniería tisular, han reproducido los procesos fisiológicos de intercambio iónico y características de las corrientes de entrada y salida, para simular los mecanismos de patogénesis. 39 Por ejemplo, el modelo establecido por Iyer et al, en el año 2014, evidencia la influencia de los miocardiocitos conducentes ventriculares en este tipo de alteraciones por canalopatías debidas a mutaciones genéticas en los canales de sodio, en lo que se observan intervalos QT prolongados, más de lo normal que predispone a fibrilación ventricular maligna.…”