TY  - JOUR
A1  - Böhm, Johann
A1  - Vasli, Nasim
A1  - Maurer, Marie
A1  - Cowling, Belinda
A1  - Shelton, G. Diane
A1  - Kress, Wolfram
A1  - Toussaint, Anne
A1  - Prokic, Ivana
A1  - Schara, Ulrike
A1  - Anderson, Thomas James
A1  - Weis, Joachim
A1  - Tiret, Laurent
A1  - Laporte, Jocelyn
T1  - Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy
JF  - PLOS Genetics
N2  - Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.
KW  - linked myotubular myopathy
KW  - skeletal muscle
KW  - inherited myopathy
KW  - SH3 domain
KW  - amphiphysin-2 BIN1
KW  - membrane curvature
KW  - tumor-suppressor
KW  - great dane
KW  - mutation
KW  - gene
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127590
SN  - 1553-7404
VL  - 9
IS  - 6
ER  - 
TY  - JOUR
A1  - Bavendiek, Udo
A1  - Berliner, Dominik
A1  - Aguirre Dávila, Lukas
A1  - Schwab, Johannes
A1  - Maier, Lars
A1  - Philipp, Sebastian A.
A1  - Rieth, Andreas
A1  - Westenfeld, Ralf
A1  - Piorkowski, Christopher
A1  - Weber, Kristina
A1  - Hänselmann, Anja
A1  - Oldhafer, Maximiliane
A1  - Schallhorn, Sven
A1  - von der Leyen, Heiko
A1  - Schröder, Christoph
A1  - Veltmann, Christian
A1  - Störk, Stefan
A1  - Böhm, Michael
A1  - Koch, Armin
A1  - Bauersachs, Johann
T1  - Rationale and design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double-blind, placebo-controlled study
JF  - European Journal of Heart Failure
N2  - Aims
Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides – although regularly used for HF treatment – remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF).

Methods
Patients with chronic HF, New York Heart Association (NYHA) functional class III–IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8–18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF.

Conclusion
The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.
KW  - heart failure
KW  - cardiac glycosides
KW  - digitalis
KW  - digitoxin
KW  - clinical trial
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221548
VL  - 21
ER  -