Chronic administration of ivabradine improves cardiac Ca handling and function in a rat model of Duchenne muscular dystrophy.
Jessica Marksteiner, Christopher Dostal, Janine Ebner, Petra Lujza Szabó, Bruno K Podesser, Simge Baydar, Ana I A Goncalves, Anja Wagner, Klaus Kratochwill, Petra Fichtinger, Dietmar Abraham, Isabella Salzer, Helmut Kubista, Elena Lilliu, Benjamin Hackl, Jakob Sauer, Hannes Todt, Xaver Koenig, Karlheinz Hilber, Attila Kiss
Author Information
Jessica Marksteiner: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
Christopher Dostal: Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria.
Janine Ebner: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
Petra Lujza Szabó: Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria.
Bruno K Podesser: Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria.
Simge Baydar: Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria.
Ana I A Goncalves: Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria.
Anja Wagner: Core Facility Proteomics, Medical University of Vienna, 1090, Vienna, Austria.
Klaus Kratochwill: Core Facility Proteomics, Medical University of Vienna, 1090, Vienna, Austria.
Petra Fichtinger: Center for Anatomy and Cell Biology, Medical University of Vienna, 1090, Vienna, Austria.
Dietmar Abraham: Center for Anatomy and Cell Biology, Medical University of Vienna, 1090, Vienna, Austria.
Isabella Salzer: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
Helmut Kubista: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
Elena Lilliu: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
Benjamin Hackl: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
Jakob Sauer: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
Hannes Todt: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
Xaver Koenig: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
Karlheinz Hilber: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria. karlheinz.hilber@meduniwien.ac.at.
Attila Kiss: Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090, Vienna, Austria.
Duchenne muscular dystrophy (DMD), a severe muscle disease caused by mutations in the gene encoding for the intracellular protein dystrophin, is associated with impaired cardiac function and arrhythmias. A causative factor for complications in the dystrophic heart is abnormal calcium (Ca) handling in ventricular cardiomyocytes, and restoration of normal Ca homeostasis has emerged as therapeutic strategy. Here, we used a rodent model of DMD, the dystrophin-deficient DMD rat, to test the following hypothesis: chronic administration of ivabradine (IVA), a drug clinically approved for the treatment of heart failure, improves Ca handling in dystrophic ventricular cardiomyocytes and thereby enhances contractile performance in the dystrophic heart. Intracellular Ca measurements revealed that 4-months administration of IVA to DMD rats significantly improves Ca handling properties in dystrophic ventricular cardiomyocytes. In particular, IVA treatment increased electrically-evoked Ca transients and speeded their decay. This suggested enhanced sarcoplasmic reticulum Ca release and faster removal of Ca from the cytosol. Chronic IVA administration also enhanced the sarcoplasmic reticulum Ca load. Transthoracic echocardiography revealed a significant improvement of cardiac systolic function in IVA-treated DMD rats. Thus, left ventricular ejection fraction and fractional shortening were enhanced, and end-systolic as well as end-diastolic diameters were diminished by the drug. Finally, chronic IVA administration neither significantly attenuated cardiac fibrosis and apoptosis, nor was vascular function improved by the drug. Collectively our findings suggest that long-term IVA administration enhances contractile function in the dystrophic heart by improvement of Ca handling in ventricular cardiomyocytes. Chronic IVA administration may be beneficial for DMD patients.
