Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene

<p>Abstract</p> <p>Background</p> <p>Mutations in <it>MYBPC3 </it>encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM) and may also lead to dilated cardiomyopathy (DCM). <it>MYBPC3 </it>mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different <it>MYBPC3 </it>mutations.</p> <p>Methods</p> <p>87 patients with HCM and 71 patients with DCM were screened for <it>MYBPC3 </it>mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded.</p> <p>Results</p> <p>In 16 HCM (18.4%) and two DCM (2.8%) index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes <it>MYH7</it>, <it>TNNT2</it>, <it>TNNI3</it>, <it>ACTC </it>and <it>TPM1</it>. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2%) had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1%) suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families.</p> <p>Conclusion</p> <p><it>MYBPC3 </it>mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with <it>MYBPC3 </it>mutations require thorough clinical risk assessment.</p

Precise voltage measurement for power electronics with high switching frequencies

In this paper different approaches in precise measurement of gate voltages as well as drain-source voltages of modern SiC and GaN transistors are compared. An approach to calculate the necessary bandwidth of a voltage probe to reproduce the voltage slope is presented. Furthermore, state-of-the-art voltage probes are compared in means of bandwidth, common mode reduction and response on EMI

Expression of the IKr components KCNH2 (rERG) and KCNE2 (rMiRP1) during late rat heart development

To understand molecular mechanisms that regulate formation and maintenance of cardiac IKr (rapidly activating component of the delayed rectifier K+ current), we have investigated the spatiotemporal expression pattern of two rat potassium voltage−gated channels, namely subfamily H (eag−related), member2 (KCNH2) (alias name: rERG) and Isk−related family, member2 (KCNE2) (alias name: rMiRP1) during late embryonic development by means of the in situ hybridization technique. KCNE2 is transcribed predominantly in atrial und ventricular myocardium at stages E14.5−E18.5dpc and only a minor signal emerged in the tongue at E16.5dpc. In contrast, KCNH2 transcripts appeared in a less confined pattern with intense signals in atrial and ventricular myocardium, somites, spinal cord, bowel system, central nervous system and thymus at stages E14.5−E18.5dpc. Non−cardiac expression even exceeds the intensity of the cardiac signal, indicating that KCNH2 contributes to K+ currents in non−cardiac tissue as well. Transcription of the rat b−subunit KCNE2 is present in all regions of the fetal myocardium and co−distributes perfectly with transcription of the pore forming a−subunit KCNH2. It seems likely that KCNH2 and KCNE2 are linked to form cardiac IKr channels, associated to cardiogenesis and cardiomyocyte excitability

Identification and characterisation of a novel KCNQ1 mutation in a family with Romano−Ward syndrome

Romano−Ward syndromenext term (RWS), the autosomal dominant form of the congenital long QT previous termsyndrome,next term is characterised by prolongation of the cardiac repolarisation process associated with ventricular tachyarrhythmias of the torsades de pointes type. Genetic studies have identified previous termmutations innext term six ion channel genes, previous termKCNQ1,next term KCNH2, SCN5A, KCNE1 and KCNE2 and the accessory protein Ankyrin−B gene, to be responsible for this disorder. Single−strand conformation polymorphism (SSCP) analysis and subsequent DNA sequence analysis have identified previous terma KCNQ1 mutation in a familynext term that were clinically conspicuous due to several syncopes and prolonged QTc intervals previous terminnext term the ECG. The mutant subunit was expressed and functionally characterised previous terminnext term the Xenopus oocyte expression system. previous termA novelnext term heterozygous missense previous termmutation with anext term C to T transition at the first position of codon 343 (CCA) of the previous termKCNQ1next term gene was identified previous terminnext term three concerned previous termfamilynext term members (QTc intervals: 500, 510 and 530 ms, respectively). As previous termanext term result, proline 343 localised within the highly conserved transmembrane segment S6 of the previous termKCNQ1next term channel is replaced by previous termanext term serine. Co−expression of mutant (previous termKCNQ1next term−P343S) and wild−type (previous termKCNQ1)next term cRNA previous terminnext term Xenopus oocytes produced potassium currents reduced by &#8776;92%, while IKs reconstitution experiments with previous termanext term combination of previous termKCNQ1next term mutant, wild−type and KCNE1 subunits yielded currents reduced by &#8776;60%. previous termA novel mutationnext term (P343S) identified previous termin the KCNQ1next term subunit gene of three members of previous termanext term RWS previous termfamilynext term showed previous termanext term dominant−negative effect on native IKs currents leading to prolongation of the heart repolarisation and possibly increases the risk of malign arrhythmias with sudden cardiac death