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S100A1 GENETICALLY TARGETED THERAPY REVERSES DYSFUNCTION OF HUMAN FAILING MYOCARDIUM
E188 JACC April 5, 2011 Volume 57, Issue 17
CARDIAC FUNCTION AND HEART FAILURE S100A1 GENETICALLY TARGETED THERAPY REVERSES DYSFUNCTION OF HUMAN FAILING MYOCARDIUM ACC Oral Contributions Ernest N. Morial Convention Center, Room 243 Monday, April 04, 2011, 11:15 a.m.-11:30 a.m.
Session Title: Translational Science in Heart Failure Abstract Category: 20. Myocardial Function/Heart Failure—Basic/Molecular Presentation Number: 911-5 Authors: Henriette L. Brinks, David Rohde, Mirko Voelkers, Gang Qiu, Sven T. Pleger, Nicole Herzog, Joseph Rabinowitz, Arjang Ruhparwar, Scott Silvestry, Carolin Kraus, Paul Mather, Hugo A. Katus, Walter J. Koch, Patrick Most, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, Department of Internal Medicine III, Center for Molecular and Translational Cardiology, Heidelberg, Germany Background: One pillar of heart failure (HF) is the depletion of the calcium (Ca2+) sensor protein S100A1 driving progressive deterioration of cardiac performance and transition to failure. Repairing this molecular defect by genetically-targeted S100A1 replacement in preclinical studies reversed the disease by restoring cardiomyocyte Ca2+ handling. Methods: This study sought to determine significance of S100A1 genetically-targeted therapy in human failing myocardium focusing on the key pathological features emanating from contractile dysfunction and negative force-frequency response (FFR), blunted contractile reserve, susceptibility to arrhythmogenic Ca2+ leakage and impaired energy homeomostasis in failing ventricular cardiomyocytes. Results: S100A1 genetically-targeted therapy of isolated human failing cardiomyocytes (HFCMs) employing the human S100A1 cDNA both reversed contractile dysfunction and negative FFR due to normalized S100A1 protein expression. Therapeutic effects of restored S100A1 expression extended into enhanced contractile reserve of HFCMs under `-adrenergic receptor (`-AR) stimulation occuring independent of cAMP-dependent (PKA) and calmodulin-dependent (CaMKII) kinase activity. S100A1 gene replacement reversed underlying Ca2+ handling abnormalities in HFCMs basally and under `-AR stimulation comprising of enhanced SR Ca2+ load and intracellular Ca2+ transients, decreased diastolic Ca2+ overload and susceptibility to arrhythmogenic SR Ca2+ leak. As a result of normalized diastolic Ca2+ handling, S100A1 improved compromised mitochondrial function illustrated by normalized phosphocreatine (CP)/Adenosine-tri-phosphate (ATP) ratio, predictive of superior clinical outcome. Conclusions: Our results demonstrate that S100A1 gene replacement exerts a favorable therapeutic profile reversing key pathological features characteristic of human failing myocardium and pave the way for S100A1 genetically-targeted therapy towards clinical application in human HF.
CARDIAC FUNCTION AND HEART FAILURE S100A1 GENETICALLY TARGETED THERAPY REVERSES DYSFUNCTION OF HUMAN FAILING MYOCARDIUM ACC Oral Contributions Ernest N. Morial Convention Center, Room 243 Monday, April 04, 2011, 11:15 a.m.-11:30 a.m.
Session Title: Translational Science in Heart Failure Abstract Category: 20. Myocardial Function/Heart Failure—Basic/Molecular Presentation Number: 911-5 Authors: Henriette L. Brinks, David Rohde, Mirko Voelkers, Gang Qiu, Sven T. Pleger, Nicole Herzog, Joseph Rabinowitz, Arjang Ruhparwar, Scott Silvestry, Carolin Kraus, Paul Mather, Hugo A. Katus, Walter J. Koch, Patrick Most, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, Department of Internal Medicine III, Center for Molecular and Translational Cardiology, Heidelberg, Germany Background: One pillar of heart failure (HF) is the depletion of the calcium (Ca2+) sensor protein S100A1 driving progressive deterioration of cardiac performance and transition to failure. Repairing this molecular defect by genetically-targeted S100A1 replacement in preclinical studies reversed the disease by restoring cardiomyocyte Ca2+ handling. Methods: This study sought to determine significance of S100A1 genetically-targeted therapy in human failing myocardium focusing on the key pathological features emanating from contractile dysfunction and negative force-frequency response (FFR), blunted contractile reserve, susceptibility to arrhythmogenic Ca2+ leakage and impaired energy homeomostasis in failing ventricular cardiomyocytes. Results: S100A1 genetically-targeted therapy of isolated human failing cardiomyocytes (HFCMs) employing the human S100A1 cDNA both reversed contractile dysfunction and negative FFR due to normalized S100A1 protein expression. Therapeutic effects of restored S100A1 expression extended into enhanced contractile reserve of HFCMs under `-adrenergic receptor (`-AR) stimulation occuring independent of cAMP-dependent (PKA) and calmodulin-dependent (CaMKII) kinase activity. S100A1 gene replacement reversed underlying Ca2+ handling abnormalities in HFCMs basally and under `-AR stimulation comprising of enhanced SR Ca2+ load and intracellular Ca2+ transients, decreased diastolic Ca2+ overload and susceptibility to arrhythmogenic SR Ca2+ leak. As a result of normalized diastolic Ca2+ handling, S100A1 improved compromised mitochondrial function illustrated by normalized phosphocreatine (CP)/Adenosine-tri-phosphate (ATP) ratio, predictive of superior clinical outcome. Conclusions: Our results demonstrate that S100A1 gene replacement exerts a favorable therapeutic profile reversing key pathological features characteristic of human failing myocardium and pave the way for S100A1 genetically-targeted therapy towards clinical application in human HF.