Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Sedej, S; Schmidt, A; Denegri, M; Walther, S; Matovina, M; Arnstein, G; Gutschi, EM; Windhager, I; Ljubojević, S; Negri, S; Heinzel, FR; Bisping, E; Vos, MA; Napolitano, C; Priori, SG; Kockskämper, J; Pieske, B.
Subclinical abnormalities in sarcoplasmic reticulum Ca(2+) release promote eccentric myocardial remodeling and pump failure death in response to pressure overload.
J Am Coll Cardiol. 2014; 63(15):1569-1579
Doi: 10.1016/j.jacc.2013.11.010
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- Führende Autor*innen der Med Uni Graz
- Pieske Burkert Mathias
- Sedej Simon
- Co-Autor*innen der Med Uni Graz
- Arnstein Georg
- Bisping Egbert Hubertus
- Heinzel Frank
- Holzer Senka
- Schmidt Albrecht
- Thon-Gutschi Eva-Maria
- Walther Stefanie
- Windhager Isabella
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- Abstract:
- This study sought to explore whether subclinical alterations of sarcoplasmic reticulum (SR) Ca(2+) release through cardiac ryanodine receptors (RyR2) aggravate cardiac remodeling in mice carrying a human RyR2(R4496C+/-) gain-of-function mutation in response to pressure overload. RyR2 dysfunction causes increased diastolic SR Ca(2+) release associated with arrhythmias and contractile dysfunction in inherited and acquired cardiac diseases, such as catecholaminergic polymorphic ventricular tachycardia and heart failure (HF). Functional and structural properties of wild-type and catecholaminergic polymorphic ventricular tachycardia-associated RyR2(R4496C+/-) hearts were characterized under conditions of pressure overload induced by transverse aortic constriction (TAC). Wild-type and RyR2(R4496C+/-) hearts had comparable structural and functional properties at baseline. After TAC, RyR2(R4496C+/-) hearts responded with eccentric hypertrophy, substantial fibrosis, ventricular dilation, and reduced fractional shortening, ultimately resulting in overt HF. RyR2(R4496C+/-)-TAC cardiomyocytes showed increased incidence of spontaneous SR Ca(2+) release events, reduced Ca(2+) transient peak amplitude, and SR Ca(2+) content as well as reduced SR Ca(2+)-ATPase 2a and increased Na(+)/Ca(2+)-exchanger protein expression. HF phenotype in RyR2(R4496C+/-)-TAC mice was associated with increased mortality due to pump failure but not tachyarrhythmic events. RyR2-stabilizer K201 markedly reduced Ca(2+) spark frequency in RyR2(R4496C+/-)-TAC cardiomyocytes. Mini-osmotic pump infusion of K201 prevented deleterious remodeling and improved survival in RyR2(R4496C+/-)-TAC mice. The combination of subclinical congenital alteration of SR Ca(2+) release and pressure overload promoted eccentric remodeling and HF death in RyR2(R4496C+/-) mice, and pharmacological RyR2 stabilization prevented this deleterious interaction. These findings suggest potential clinical relevance for patients with acquired or inherited gain-of-function of RyR2-mediated SR Ca(2+) release. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Calcium Signaling - genetics
- DNA - genetics
- DNA Mutational Analysis -
- Disease Models, Animal -
- Disease Progression -
- Heart Failure - genetics
- Mice -
- Mice, Knockout -
- Mutation -
- Myocytes, Cardiac - metabolism
- Ryanodine Receptor Calcium Release Channel - genetics
- Sarcoplasmic Reticulum - metabolism
- Ventricular Pressure -
- Ventricular Remodeling - genetics
- Find related publications in this database (Keywords)
- calcium
- heart failure
- hypertension
- remodeling
- sarcoplasmic reticulum