title: Subclinical abnormalities in sarcoplasmic reticulum Ca(2+) release promote eccentric myocardial remodeling and pump failure death in response to pressure overload.
abstract: OBJECTIVE
  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: 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.
authors: Simon
authors: S
authors: Sedej
authors: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors: Albrecht
authors: A
authors: Schmidt
authors: IRCCS Salvatore Maugeri Foundation and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors: Marco
authors: M
authors: Denegri
authors: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors: Stefanie
authors: S
authors: Walther
authors: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors: Marinko
authors: M
authors: Matovina
authors: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors: Georg
authors: G
authors: Arnstein
authors: Department of Cardiology, Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria.
authors: Eva-Maria
authors: EM
authors: Gutschi
authors: Department of Cardiology, Medical University of Graz, Graz, Austria.
authors: Isabella
authors: I
authors: Windhager
authors: Department of Cardiology, Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria.
authors: Senka
authors: S
authors: Ljubojević
authors: IRCCS Salvatore Maugeri Foundation and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors: Sara
authors: S
authors: Negri
authors: Department of Cardiology, Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria.
authors: Frank R
authors: FR
authors: Heinzel
authors: Department of Cardiology, Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Translational Heart Failure Research, Graz, Austria.
authors: Egbert
authors: E
authors: Bisping
authors: Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Marc A
authors: MA
authors: Vos
authors: 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.
authors: Carlo
authors: C
authors: Napolitano
authors: 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.
authors: Silvia G
authors: SG
authors: Priori
authors: Institute of Pharmacology and Clinical Pharmacy, Philipps-University of Marburg, Marburg, Germany.
authors: Jens
authors: J
authors: Kockskämper
authors: 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.
authors: Burkert
authors: B
authors: Pieske
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D017725:Ventricular Pressure; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D004247:DNA
keywords: calcium; heart failure; hypertension; remodeling; sarcoplasmic reticulum