KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation

Abstract

Background: A 53-year-old female presented with a 10-year history of paroxysmal atrial fibrillation (AF), precipitated by activity and refractory to medical therapy. In the absence of traditional risk factors for disease, a genetic defect in electrical homeostasis underlying stress-induced AF was explored.

Investigations: Echocardiography, cardiac perfusion stress imaging, invasive electrophysiology with isoproterenol provocation, genomic DNA sequencing of K(ATP) channel genes, exclusion of mutation in 2,000 individuals free of AF, reconstitution of channel defect with molecular phenotyping, and verification of pathogenic link in targeted knockout.

Diagnosis: K(ATP) channelopathy caused by missense mutation (Thr1547Ile) of the ABCC9 gene conferring predisposition to adrenergic AF originating from the vein of Marshall.

Management: Disruption of arrhythmogenic gene-environment substrate at the vein of Marshall by radiofrequency ablation.

Figure 1

Mutation in ABCC9, which encodes the SUR2A K_ATP channel subunit, in a patient with AF originating from the vein of Marshall. (A) AF with variable ventricular rate response was provoked by isoproterenol infusion (2 μg/min). (B,C) Intracardiac mapping localized the site of earliest activation of premature AF-initiating beats to the vein of Marshall (arrow, C). (D) Sequencing of the patient’s DNA identified a heterozygous missense mutation (4640C>T) causing substitution of the 1547 threonine residue for isoleucine (Thr1547Ile) in exon 38 of ABCC9. Exon 38 encodes the carboxy-terminus of SUR2A. (E) Alignment of the human SUR2A carboxy-terminal domain with orthologs from other species demonstrated the conserved Thr1547 and surrounding region. (F) Model of SUR2A NBD2 with carboxy-terminal tail. Red denotes α-helix, blue-green β-strand, and yellow W_A or W_B (left panel). Thr1547, found to be substituted in the patient, mapped to the SUR2A tail region adjacent to Walker motifs. Dashed lines indicate hydrogen bonds that stabilize Walker A and the associated carboxy-terminus. Red denotes oxygen atoms, royal blue denotes nitrogen, and mustard denotes sulfur (right panel). (G) Alignment of human SUR isoforms indicated that the carboxy-terminal tail, including Thr1547 (arrow), is unique to cardiac SUR2A. Abbreviations: aa, amino acid; AF, atrial fibrillation; CS, coronary sinus; HIS, His bundle; HRA, high right atrial; Map, mapping; Map d, distal mapping catheter; Map p, proximal mapping catheter; NBD, nucleotide-binding domain; RVA, right ventricular apex; V1, surface electrocardiogram; W_A, Walker A motif; W_B, Walker B motif.

Figure 2

The ABCC9 mutation disrupts K_ATP channel function, with the disease phenotype verified in an adrenergically stressed gene knockout model. (A) Cardiac K_ATP channels comprise the ABCC9-encoded SUR2A subunit (containing NBD1 and NBD2, each with W_A, W_B motifs and linker region), and the KCNJ11-encoded Kir6.2 pore. Intracellular ATP normally keeps K_ATP channels closed. Stress-induced build-up of MgADP at NBD2 of SUR2A antagonizes ATP-induced channel inhibition, promoting K⁺ efflux. (B) Compared with the WT subunit, mutant SUR2A (Thr1547Ile) coexpressed with Kir6.2 demonstrated aberrant K_ATP channel function, characterized by defective response to ADP in patch-clamp recordings. (C) Reduced K⁺ current response to escalating ADP concentrations in mutant (Thr1547Ile) versus WT K_ATP channels. (D) ATP-induced channel inhibition was retained in mutant channels. Channel inhibition was expressed relative to activity recorded in the absence of ATP at -60 mV, in inside-out patches. Curves represent Hill equation fits of data. (E) The Thr1547Ile mutation did not prevent ATP-induced K_ATP channel closure, but compromised ADP-dependent channel opening. (F) During telemetry in the conscious state, WT mice maintained sinus rhythm following isoproterenol (10 mg/kg) injection, whereas Kir6.2^-/- knockout mice lacking functional K_ATP channels demonstrated—with sympathomimetic challenge—electrical vulnerability manifested by AF. (G) K_ATP channel deficit led to AF in 70% of knockout mice within 20 min of adrenergically medicated stress. Sinus rhythm was maintained in all WT mice with intact K_ATP channels. Abbreviations: AF, atrial fibrillation; L, linker region; NBD, nucleotide-binding domain; pA, picoAmps; W_A, Walker A motif; W_B, Walker B motif; WT, wild type.

Figure 3

Ablation of the vein of Marshall eliminated adrenergic AF in a patient with mutated K_ATP channels. (A) Fluoroscopic view of mapping catheter within the vein of Marshall at the site of the earliest atrial activation during isoproterenol-induced ectopy initiating AF. (B) Multilead intracardiac tracings before, during, and after radiofrequency ablation. Mapping: spontaneous atrial ectopy was first recorded (dotted and dashed line) in the ablation catheter, overlaying the vein of Marshall, where an abnormal potential (arrow) preceded atrial activation. Ablation: radiofrequency ablation eliminated the vein of Marshall potential and atrial ectopy. Postablation: despite isoproterenol infusion (2 μg/min), the vein of Marshall potential or ectopy could no longer be induced and the patient remained in sinus rhythm. (C) Adrenergic challenge provoked ectopy from the vein of Marshall, triggering transition from sinus rhythm to AF in the susceptible patient with inadequate adaptation to imposed stress load. As stress-responsive K_ATP channels preserve electrical homeostasis, channel malfunction resulting from gene mutation creates a risk-conferring substrate, predisposing to arrhythmia. Ablation of the arrhythmia-triggering source disrupted the arrhythmogenic gene-environment interaction. Abbreviations: ABL d, distal electrodes of ablation catheter; ABL p, proximal electrodes of ablation catheter; AF, atrial fibrillation; CS, coronary sinus catheter (distal, proximal); HIS, His bundle recording catheter; HRA, high right atrial catheter; LS, left superior pulmonary vein catheter (distal, proximal); Map, mapping catheter; RVA, right ventricular apex catheter; SR, sinus rhythm; V1, surface electrocardiogram.