Steroid sulfatase deficiency increases the frequency and persistence of ventricular arrhythmias in mice
BackgroundEmerging evidence in humans has linked Xp22.31 genetic deletions to an increased risk of stress-induced arrhythmias, and association analysis across Xp22.31 has shown enrichment for atrial fibrillation genetic risk variants around STS (steroid sulfatase). MethodsWe compared heart rhythm in homozygous STS-knockout (STS-KO) adult mice (n=19) to wildtype (WT) mice (n=11) under baseline (Tyrodes solution), and {beta}-adrenergic stimulation (stress), conditions using ex vivo perfused-heart electrocardiography (ECG). Ventricular ectopic beats (VEBs) were manually-identified, and rhythm abnormalities were quantified using a semi-automated approach. ResultsAt baseline, the groups displayed comparable sinus cycle length and ECG intervals; all WT hearts showed stable sinus rhythm, whereas [~]30% of STS-KO hearts developed spontaneous VEBs. WT hearts typically maintained steady rhythm under {beta}-adrenergic stimulation; in contrast, [~]60% of STS-KO hearts displayed VEBs. Under baseline and stimulated conditions the QRS interval was greater during VEBs than normal beats in STS-KO hearts, consistent with a ventricular origin. We identified a higher frequency of any abnormal beats in STS-KO hearts than in WT hearts under baseline (1.9{+/-}0.7% vs. 0.3{+/-}0.1%, p=0.038) and stimulated (5.3{+/-}2.2% vs. 0.5{+/-}0.3%, p=0.047) conditions. Under stimulated conditions, abnormal beats only occurred singly in WT hearts, whereas in STS-KO hearts, [~]50% of the time they occurred in runs of two or more. ConclusionSTS deficiency in mice predisposes to arrhythmias, and the STS-KO mouse represents a tractable model for mechanistic investigation. These data support the contention that STS activity influences arrhythmic vulnerability in humans and that STS should be considered for inclusion in arrhythmia-related gene panels.