title: Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model.
abstract: Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Retrograde application of AAV6-S100A1 (1.5 × 10(13) tvp) via the anterior cardiac vein (ACV) resulted in high-level myocardial S100A1 protein peak expression of up to 95-fold above control. At 14 weeks, pigs with high-level myocardial S100A1 protein overexpression did not show abnormalities in the electrocardiogram. Electrophysiological right ventricular stimulation ruled out an increased susceptibility to monomorphic ventricular arrhythmia. High-level S100A1 protein overexpression in the LV myocardium resulted in a significant increase in LV ejection fraction (LVEF), albeit to a lesser extent than previously reported with low S100A1 protein overexpression. Cardiac remodeling was, however, equally reversed. High myocardial S100A1 protein overexpression neither increases the occurrence of cardiac arrhythmia nor causes detrimental effects on myocardial contractile function in vivo. In contrast, this study demonstrates a broad therapeutic range of S100A1 gene therapy in post-ischemic HF using a preclinical large animal model.
authors.affiliation: 1] Center for Molecular and Translational Cardiology, Heidelberg University Hospital, Heidelberg, Germany [2] Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Weber
authors.affiliation: 1] Center for Molecular and Translational Cardiology, Heidelberg University Hospital, Heidelberg, Germany [2] Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Neacsu
authors.affiliation: 1] Center for Molecular and Translational Cardiology, Heidelberg University Hospital, Heidelberg, Germany [2] Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Krautz
authors.affiliation: Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Schlegel
authors.affiliation: Department of Pediatrics, University of Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Raake
authors.affiliation: 1] Center for Molecular and Translational Cardiology, Heidelberg University Hospital, Heidelberg, Germany [2] Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Ritterhoff
authors.affiliation: Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Jungmann
authors.affiliation: Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: A B
authors.initials: AB
authors.lastname: Remppis
authors.affiliation: Institute for Animal Physiology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Stangassinger
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: 1] Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany [2] Deutsches Zentrum für Herz-/Kreislaufforschung, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: H A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: O J
authors.initials: OJ
authors.lastname: Müller
authors.affiliation: 1] Center for Molecular and Translational Cardiology, Heidelberg University Hospital, Heidelberg, Germany [2] Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany [3] Deutsches Zentrum für Herz-/Kreislaufforschung, University Hospital Heidelberg, Heidelberg, Germany [4] Laboratory for Cardiac Stem Cell and Gene Therapy, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Most
authors.affiliation: 1] Center for Molecular and Translational Cardiology, Heidelberg University Hospital, Heidelberg, Germany [2] Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: S T
authors.initials: ST
authors.lastname: Pleger
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology / Q000628:therapy; D017202:Myocardial Ischemia / Q000150:complications* / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D013318:Stroke Volume / Q000502:physiology; D013552:Swine
chemical_list: D009418:S100 Proteins; C110294:S100A1 protein