Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance. In 3 branches of a large South African Afrikaner pedigree with an autosomal-dominant form of PFHBI, we identified the mutation c.19G→A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4) at chromosomal locus 19q13.3. This mutation predicted the amino acid substitution p.E7K in the TRPM4 amino terminus. TRPM4 encodes a Ca 2+ -activated nonselective cation (CAN) channel that belongs to the transient receptor potential melastatin ion channel family. Quantitative analysis of TRPM4 mRNA content in human cardiac tissue showed the highest expression level in Purkinje fibers. Cellular expression studies showed that the c.19G→A missense mutation attenuated deSUMOylation of the TRPM4 channel. The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface. Our data therefore revealed a gain-of-function mechanism underlying this type of familial heart block.

Endovascular implants currently used after cardiovascular events have proven their efficacy. However, strategies are in quest to optimize clinical outcomes. One possibility is the development of polymer surfaces imitating extracellular matrix in order to promote vascular integration of an implanted device. The aim of this study was to develop and investigate methods for covalent immobilization of a synthesized elastin-like protein (ELP) additionally modified with functional domains (RGD, CS5 and P15) promoting endothelial cell proliferation on biodegradable poly (L-lactide) (PLLA) as model endovascular implant surface. Evaluation of the impact of different ELP immobilization methods on PLLA regarding the achievable surface load evidences that the amino activation of PLLA does not have considerable influence, while the reaction sequence as well as the used crosslinker presents determining factors in ELP immobilization. Biocompatibility regarding selective promotion of endothelial cell (EC) adherence and proliferation especially in contrast to smooth muscle cells (SMC) was improved on covalently immobilized but not on physically adsorbed ELP. In summary, we could underline the applicability of a modified ELP-coating for endovascular implant surfaces in vitro and provide information on applicable immobilization procedures. Moreover, the latter builds the basis for a wide variety of implant applications, because the developed immobilization strategy should be easily transferable to any ELP with tailored biological functionality by exchange of the integrated active sequences.

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