LAUSR

Circulation. 2020;142:e372–e373. DOI: 10.1161/CIRCULATIONAHA.120.050611 e372 Jin Li, MD In Response: We appreciate the interest by Lazzerini et al regarding our recent publication1 and their thoughts on the anti-Cav1.2 autoantibody we discovered and identified as a biomarker of idiopathic cardiac arrest. The anti-Cav1.2 autoantibody inhibits the L-type Ca2+ current and shortens the action potential duration in human induced pluripotent stem cell–derived cardiomyocytes. Although we could have expected a shortened QT interval on ECG on the basis of the action potential duration shortening, our cohort of patients with anti-Cav1.2 autoantibodies presented a normal QT length (see the Table in reference1). After heart rate correction, the QTc value of patients with idiopathic cardiac arrest is slightly longer compared with that of the healthy controls, but still within the normal range (see the Table in reference1). Statistical significance is only found when using the Bazett formula, an equation well-known to have limitations despite its wide use.2 Lazzerini et al claim that our newly identified anti-Cav1.2 autoantibodies are actually anti-Ro/SSA autoantibodies. This hypothesis cannot be supported for several reasons. Anti-Ro/SSA autoantibodies target a cytoplasmic linker between domains II and III of the α1c subunit of Cav1.2 channels, 3,4 whereas our anti-Cav1.2 autoantibody targets an extracellular sequence of domain III between the transmembrane segments S5 and S6 (DFDNVLAAMMALFTVSTFEG); ie, the pore-forming part of Cav1.2 channels. Also, because anti-Ro/SSA (particularly 52 kD) cross-reacts with the extracellular pore domain of the hERG (human ether-a-go-go-related gene) channel,5 our microarray assay would have detected immunoglobulin G responses specific to this sequence (DSRIGWLHNLGDQIGKPYNS), which is not the case. We therefore can exclude the presence of anti-Ro/SSA autoantibodies in the study patients. In this context, because our anti-Cav1.2 immunoglobulin G was purified from patient plasma using affinity chromatography (matrix coupled to the DFDNVLAAMMALFTVSTFEG peptide), the action potential duration shortening recorded in human induced pluripotent stem cell–derived cardiomyocytes cannot be the result of an anti-Ro/SSA–mediated inhibition of Cav1.2 and hERG channels as suggested by Lazzerini et al.