Dataset Information

Sodium current reduction unmasks a structure-dependent substrate for arrhythmogenesis in the normal ventricles.

ABSTRACT:

Background

Organ-scale arrhythmogenic consequences of source-sink mismatch caused by impaired excitability remain unknown, hindering the understanding of pathophysiology in disease states like Brugada syndrome and ischemia.

Objective

We sought to determine whether sodium current (INa) reduction in the structurally normal heart unmasks a regionally heterogeneous substrate for the induction of sustained arrhythmia by premature ventricular contractions (PVCs).

Methods

We conducted simulations in rabbit ventricular computer models with 930 unique combinations of PVC location (10 sites) and coupling interval (250-400 ms), INa reduction (30 or 40% of normal levels), and post-PVC sinus rhythm (arrested or persistent). Geometric characteristics and source-sink mismatch were quantitatively analyzed by calculating ventricular wall thickness and a newly formulated 3D safety factor (SF), respectively.

Results

Reducing INa to 30% of its normal level created a substrate for sustained arrhythmia induction by establishing large regions of critical source-sink mismatch (SF<1) for ectopic wavefronts propagating from thin to thick tissue. In the same simulations but with 40% of normal INa, PVCs did not induce reentry because the volume of tissue with SF<1 was >95% smaller. Likewise, when post-PVC sinus activations were persistent instead of arrested, no ectopic excitations initiated sustained reentry because sinus activation breakthroughs engulfed the excitable gap.

Conclusion

Our new SF formulation can quantify ectopic wavefront propagation robustness in geometrically complex 3D tissue with impaired excitability. This novel methodology was applied to show that INa reduction precipitates source-sink mismatch, creating a potent substrate for sustained arrhythmia induction by PVCs originating near regions of ventricular wall expansion, such as the RV outflow tract.

SUBMITTER: Boyle PM

PROVIDER: S-EPMC3904970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mutations in CACNA1C that increase current through the CaV1.2 L-type Ca2+ channel underlie rare forms of long QT syndrome (LQTS), and Timothy syndrome (TS). We identified a variant in CACNA1C in a male child of Filipino descent with arrhythmias and extracardiac features by candidate gene sequencing and performed functional expression studies to electrophysiologically characterize the effects of the variant on CaV1.2 channels. As a baby, the subject developed seizures and displayed developmental delays at 30 months of age. At age 5 years, he displayed a QTc of 520 ms and experienced recurrent VT. Physical exam at 17 years of age was notable for microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis. Candidate gene sequencing identified a G>C transversion at position 5731 of CACNA1C (rs374528680) predicting a glycine>arginine substitution at residue 1911 (p.G1911R) of CaV1.2. The allele frequency of this variant is 0.01 in Malays, but absent in 984 Caucasian alleles and in the 1000 genomes project. In electrophysiological analyses, the variant decreased voltage-dependent inactivation, thus causing a gain of function of CaV1.2. We also observed a negative shift of V1/2 of activation and positive shift of V1/2 of channel inactivation, resulting in an increase of the window current. Together, these suggest a gain-of-function effect on CaV1.2 and suggest increased susceptibility for arrhythmias in certain clinical settings. The p.G1911R variant was also identified in a case of sudden unexplained infant death (SUID), for which an increasing number of clinical observations have demonstrated can be associated with arrhythmogenic mutations in cardiac ion channels. In summary, the combined effects of the CACNA1C variant to diminish voltage-dependent inactivation of CaV1.2 and increase window current expand our appreciation of mechanisms by which a gain of function of CaV1.2 can contribute to QT prolongation.