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Background: While the cardiac sodium channel ( SCN5A ) variants S1103Y and R1193Q have been associated with LQT3 and drug-induced arrhythmia, they are too common to be highly arrhythmogenic: S1103Y allele frequency is 8.1% in Africans and R1193Q 6.1% in East Asians. We have previously reported that S1103Y had no effect on QT in a large biobank or on action potential duration (APD) in iPSC-CMs. Here, we identify a mechanism underlying control of normal baseline repolarization with these variants and study whether the mechanism is generalizable. Methods: Late sodium current (I Na-L ), I Kr , and sensitivity to the blockers dofetilide (I Kr ) and GS967 (I Na-L ) were measured in natural or genome-edited iPSC-CMs carrying S1103Y, R1193Q, or R518X, a common KCNQ1 nonsense variant in the Jervell Lange-Nielsen (JLN) syndrome and unaffected family members. Results: Although APD was unaffected by S1103Y, I Na-L was increased 2~16-fold in SY/YY compared to SS cells (pKr was increased in SY/YY ([SY] 1.2 pA/pF, n=17, pKr and I Na-L and increased dofetilide sensitivity. In R518X JLN iPSC-CMs, I Ks was absent as expected but I Kr was increased (1.9 pA/pF, n=5), and editing R518X to wild-type increased I Ks (1.3 pA/pF, n=10) and dramatically decreased I Kr (0.2 pA/pF, n=4). Conclusions: S1103Y and R1193Q increase I Na-L but unexpectedly do not affect baseline repolarization. We hypothesize that increased I Kr through as yet undetermined mechanisms maintains normal repolarization but at the cost of increased sensitivity to I Kr block. The findings with R518X suggest this may be a general mechanism. Our data show that preposition to genetically- or drug-mediated arrhythmias is determined by a complex interaction among multiple repolarizing currents that is not fully captured by heterologous expression systems.

Increased low density lipoprotein (LDL) cholesterol and triglycerides, and decreased high density lipoprotein (HDL) cholesterol concentrations are associated with adverse cardiovascular risk in the general population. Patients with systemic lupus erythematosus (SLE) have an altered lipid profile characterized by increased triglycerides and decreased HDL cholesterol concentrations. We examined the relationships between lipid concentrations, cytokines, and inflammatory markers in patients with SLE.Fasting lipid concentrations, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were measured in 110 patients with SLE. Disease activity was quantified by the SLE Disease Activity Index (SLEDAI), and disease damage by the Systemic Lupus International Collaborating Clinics (SLICC) score. Concentrations of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and insulin were measured and insulin sensitivity calculated.Lower concentrations of HDL cholesterol were independently associated with higher ESR (p0.001), IL-6 (p = 0.02), SLEDAI (p = 0.04), and TNF-alpha (p = 0.04) after adjustment for age, sex, race, body mass index, insulin sensitivity, and current use of corticosteroids or hydroxychloroquine. Triglyceride concentrations were associated with higher CRP concentrations (p = 0.02) and SLICC score (p = 0.04).Deleterious changes in lipid profile are independently associated with higher concentrations of markers and mediators of inflammation and disease activity and damage in patients with SLE.