Simon Sedej1, Albrecht Schmidt2, Marco Denegri3, Stefanie Walther2, Marinko Matovina2, Georg Arnstein2, Eva-Maria Gutschi4, Isabella Windhager2, Senka Ljubojević4, Sara Negri3, Frank R Heinzel4, Egbert Bisping4, Marc A Vos5, Carlo Napolitano6, Silvia G Priori6, Jens Kockskämper7, Burkert Pieske8. 1. Department of Cardiology, Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria. Electronic address: simon.sedej@medunigraz.at. 2. Department of Cardiology, Medical University of Graz, Graz, Austria. 3. IRCCS Salvatore Maugeri Foundation and Department of Molecular Medicine, University of Pavia, Pavia, Italy. 4. Department of Cardiology, Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria. 5. Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands. 6. IRCCS Salvatore Maugeri Foundation and Department of Molecular Medicine, University of Pavia, Pavia, Italy; Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York. 7. Institute of Pharmacology and Clinical Pharmacy, Philipps-University of Marburg, Marburg, Germany. 8. Department of Cardiology, Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria. Electronic address: burkert.pieske@medunigraz.at.
Abstract
OBJECTIVES: 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. BACKGROUND: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVES: 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. BACKGROUND: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
Authors: Ketaki N Mhatre; Paulina Wakula; Oliver Klein; Egbert Bisping; Jakob Völkl; Burkert Pieske; Frank R Heinzel Journal: Cell Mol Life Sci Date: 2018-07-30 Impact factor: 9.261
Authors: Julia Schipke; Clara Grimm; Georg Arnstein; Jens Kockskämper; Simon Sedej; Christian Mühlfeld Journal: J Anat Date: 2016-03-17 Impact factor: 2.610
Authors: Carsten Tschöpe; Christoph Birner; Michael Böhm; Oliver Bruder; Stefan Frantz; Andreas Luchner; Lars Maier; Stefan Störk; Behrouz Kherad; Ulrich Laufs Journal: Clin Res Cardiol Date: 2017-10-10 Impact factor: 5.460
Authors: Vander José das Neves; Tiago Fernandes; Fernanda Roberta Roque; Ursula Paula Renó Soci; Stéphano Freitas Soares Melo; Edilamar Menezes de Oliveira Journal: World J Cardiol Date: 2014-08-26
Authors: Tobias Eisenberg; Mahmoud Abdellatif; Sabrina Schroeder; Uwe Primessnig; Slaven Stekovic; Tobias Pendl; Alexandra Harger; Julia Schipke; Andreas Zimmermann; Albrecht Schmidt; Mingming Tong; Christoph Ruckenstuhl; Christopher Dammbrueck; Angelina S Gross; Viktoria Herbst; Christoph Magnes; Gert Trausinger; Sophie Narath; Andreas Meinitzer; Zehan Hu; Alexander Kirsch; Kathrin Eller; Didac Carmona-Gutierrez; Sabrina Büttner; Federico Pietrocola; Oskar Knittelfelder; Emilie Schrepfer; Patrick Rockenfeller; Corinna Simonini; Alexandros Rahn; Marion Horsch; Kristin Moreth; Johannes Beckers; Helmut Fuchs; Valerie Gailus-Durner; Frauke Neff; Dirk Janik; Birgit Rathkolb; Jan Rozman; Martin Hrabe de Angelis; Tarek Moustafa; Guenter Haemmerle; Manuel Mayr; Peter Willeit; Marion von Frieling-Salewsky; Burkert Pieske; Luca Scorrano; Thomas Pieber; Raimund Pechlaner; Johann Willeit; Stephan J Sigrist; Wolfgang A Linke; Christian Mühlfeld; Junichi Sadoshima; Joern Dengjel; Stefan Kiechl; Guido Kroemer; Simon Sedej; Frank Madeo Journal: Nat Med Date: 2016-11-14 Impact factor: 53.440