Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.

Background: Mutations in the human desmin gene cause myopathies and cardiomyopathies. Aim of this study was to elucidate molecular mechanisms initiated by the heterozygous R406W-desmin mutation in the development of a severe and early-onset cardiac phenotype. Methods: We report an adolescent patient, who underwent cardiac transplantation due to restrictive cardiomyopathy caused by a heterozygous R406W-desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin and to intercalated disc proteins. Effects of the R406W mutation on the molecular properties of desmin were addressed by cell transfection and in vitro assembly experiments. To prove the genuine deleterious impact of the mutation on heart tissue, we further generated and analyzed R405W-desmin knock-in mice harboring the orthologous form of the human R406W-desmin. Results: Microscopic analysis of the explanted heart revealed desmin aggregates and the absence of desmin filaments at intercalated discs. Structural changes within intercalated discs were revealed by the abnormal organization of desmoplakin, plectin, N-cadherin, and connexin-43. Next generation sequencing confirmed the DES variant c.1216C>T (p.R406W) as the sole disease-causing mutation. Cell transfection studies disclosed a dual behavior of R406W-desmin with both its integration into the endogenous intermediate filament system and segregation into protein aggregates. In vitro , R406W-desmin formed unusually thick filaments that organized into complex filament aggregates and fibrillar sheets. In contrast, assembly of equimolar mixtures of mutant and wild-type desmin generated chimeric filaments of seemingly normal morphology but with occasional prominent irregularities. Heterozygous and homozygous R405W-desmin knock-in mice develop both a myopathy and a cardiomyopathy. In particular, the main histopathological results from the patient are recapitulated in the hearts from R405W-desmin knock-in mice of both genotypes. Moreover, while heterozygous knock-in mice have a normal life span, homozygous animals die at three months of age due to a smooth muscle-related gastrointestinal phenotype. Conclusions: We demonstrate that R406W-desmin provokes its severe cardiotoxic potential by a novel pathomechanism, where the concurrent dual functional states of mutant desmin assembly complexes underlie the uncoupling of desmin filaments from intercalated discs and their structural disorganization.

BackgroundPostoperative fluid management in critically ill neonates and infants with capillary leak syndrome (CLS) and extensive volume overload after cardiac surgery on cardiopulmonary bypass is challenging. CLS is often resistant to conventional diuretic therapy, aggravating the course of weaning from invasive ventilation, increasing length of stay on ICU and morbidity and mortality.MethodsTolvaptan (TLV, vasopressin type 2 receptor antagonist) was used as an additive diuretic in neonates and infants with CLS after cardiac surgery. Retrospective analysis of 25 patients with CLS including preoperative and postoperative parameters was performed. Multivariate regression analysis was performed to identify predictors for TLV response.ResultsMultivariate analysis identified urinary output during 24 h after TLV administration and mean blood pressure (BP) on day 2 of TLV treatment as predictors for TLV response (AUC = 0.956). Responder showed greater weight reduction (p < 0.0001), earlier weaning from ventilator during TLV (p = 0.0421) and shorter time in the ICU after TLV treatment (p = 0.0155). Serum sodium and serum osmolality increased significantly over time in all patients treated with TLV.ConclusionIn neonates and infants with diuretic-refractory CLS after cardiac surgery, additional aquaretic therapy with TLV showed an increase in urinary output and reduction in bodyweight in patients classified as TLV responder. Increase in urinary output and mean BP on day 2 of treatment were strong predictors for TLV response.Electronic supplementary materialThe online version of this article (10.1186/s12887-019-1418-6) contains supplementary material, which is available to authorized users.

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