Mutations in a variety of myofibrillar genes cause dilated cardiomyopathy (DCM) in humans, usually with dominant inheritance and incomplete penetrance. Here, we sought to clarify the functional effects of the previously identified DCM-causing TTN 2-bp insertion mutation (c. 43628insAT) and generated a titin knock-in mouse model mimicking the c.43628insAT allele.Mutant embryos homozygous for the Ttn knock-in mutation developed defects in sarcomere formation and consequently died before E9.5. Heterozygous mice were viable and demonstrated normal cardiac morphology, function and muscle mechanics. mRNA and protein expression studies on heterozygous hearts demonstrated elevated wild-type titin mRNA under resting conditions, suggesting that up-regulation of the wild-type titin allele compensates for the unstable mutated titin under these conditions. When chronically exposed to angiotensin II or isoproterenol, heterozygous mice developed marked left ventricular dilatation (p<0.05) with impaired fractional shortening (p<0.001) and diffuse myocardial fibrosis (11.95 ± 2.8% versus 3.7 ±1.1%). Thus, this model mimics typical features of human dilated cardiomyopathy and may further our understanding of how titin mutations perturb cardiac function and remodel the heart.

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Hashtag Gesundheit e. V diskutierte im Rahmen seines Formates #Politik_Talk die Frage „Was bringt das DVG?“ mit Selfapy-Gründerin Nora Blum, Chris Berger, Referent Politik bvitg, und Dr. Gottfried Ludewig, Abteilungsleiter Digitalisierung im Bundesministerium für Gesundheit und maßgeblicher Antreiber des Digitale-Versorgung-Gesetzes.

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial diseases and the third most common cause of heart failure. Familial occurrence, mostly as an autosomal dominant trait, is responsible for 20 –30% of all DCM cases. We have previously shown that mutations in the giant muscle filament titin ( TTN ) cause dilated cardiomyopathy. In a large DCM kindred (A1) with autosomal dominant inherited DCM, we could identify a 2 bp insertion mutation in exon 326 of TTN . This heterozygous nonsense mutation leads to a framshift generating a premature stop codon after the addition of 4 novel amino acid residues. We have recently evaluated a cardiac biopsy sample from an affected family member of kindred A1 showing that no truncated protein is observed in a western blot analysis. To further investigate the functional consequences of the identified human TTN mutation, we now generated a mouse model that includes the 2bp insertion at the corresponding site in the mouse genome. Heterozygous mice are viable and fertile. As in the human situation, the truncated titin is not detectable in western blot analysis of cardiac tissue indicating haploinsufficiency. The ventricles of the heterozygous animals show a decrease in ventricular stiffness as seen in isolated working heart pressure measurements and transmitral Doppler echocardiography (E:A 1.34 vs. 1.075, p<0.01; IVRT 13.57ms vs. 17.01ms, p<0.05). When exposed to angiotensin II (1.4 mg/kg/d for 14d) as a cardiac stressor, heterozygous animals develop dilatation of the left ventricles (4.45mm vs. 3.77 mm, p<0.05) with impaired fractional shortening (25.12% vs. 32.86%, p<0.01) and a diffuse myocardial fibrosis. Homozygous mice die in utero before E8.0. Whether a defect in the formation of sarcomeres or, alternatively, a defect in yet unknown non-muscle functions of titin account for this early embryonic lethality remains to be determined. Conclusion: Our mouse model shows that a mutation in TTN leads to impaired biomechanical properties of the heart, resulting in left ventricular dilatation and decreased systolic function, thereby recapitulating the human phenotype.

Häufig wirkte es im ersten Jahr der GroKo so, als wäre Bundesgesundheitsminister Jens Spahn der Einzige, der so richtig Lust aufs Regieren hätte.

Eine gute Notfallversorgung kann im Zweifel über Leben und Tod entscheiden und dennoch wurde sie in der Vergangenheit nur als Nischenthema behandelt.

Der Krankenhausplan von Nordrhein-Westfalens Gesundheitsminister Karl-Josef Laumann wurde von vielen Seiten überraschend positiv aufgenommen. Die Versorgung in Nordrhein-Westfalen (NRW) soll durch mutige Umstrukturierungsmaßnahmen deutlich verbessert werden.