Nour Raad1,2,3, Philip Bittihn4,5, Marine Cacheux1, Dongtak Jeong1, Zeki Ilkan1, Delaine Ceholski1, Erik Kohlbrenner1, Lu Zhang6, Chen-Leng Cai6, Evangelia G Kranias7, Roger J Hajjar8, Francesca Stillitano1, Fadi G Akar1,9,10. 1. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (N.R., M.C., D.J., Z.I., D.C., E.K., F.S., F.G.A.). 2. Poliklinik für Innere Medizin I, Rechts der Isar Hospital, Technical University Munich, Germany (N.R.). 3. German Center for Cardiovascular Research, Munich Heart Alliance (N.R.). 4. BioCircuits Institute, University of California, San Diego (P.B.). 5. Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany (P.B.). 6. Indiana University School of Medicine, Indianapolis (L.Z., C.C.). 7. University of Cincinnati College of Medicine, OH (E.G.K.). 8. Phospholamban Foundation, Middenmeer, The Netherlands (R.J.H.). 9. School of Medicine (F.G.A.), Yale University, New Haven, CT. 10. Department of Biomedical Engineering (F.G.A.). Yale University, New Haven, CT.
Abstract
BACKGROUND: Arginine (Arg) 14 deletion (R14del) in the calcium regulatory protein phospholamban (hPLNR14del) has been identified as a disease-causing mutation in patients with an inherited cardiomyopathy. Mechanisms underlying the early arrhythmogenic phenotype that predisposes carriers of this mutation to sudden death with no apparent structural remodeling remain unclear. METHODS: To address this, we performed high spatiotemporal resolution optical mapping of intact hearts from adult knock-in mice harboring the human PLNWT (wildtype [WT], n=12) or the heterozygous human PLNR14del mutation (R14del, n=12) before and after ex vivo challenge with isoproterenol and rapid pacing. RESULTS: Adverse electrophysiological remodeling was evident in the absence of significant structural or hemodynamic changes. R14del hearts exhibited increased arrhythmia susceptibility compared with wildtype. Underlying this susceptibility was preferential right ventricular action potential prolongation that was unresponsive to β-adrenergic stimulation. A steep repolarization gradient at the left ventricular/right ventricular interface provided the substrate for interventricular activation delays and ultimately local conduction block during rapid pacing. This was followed by the initiation of macroreentrant circuits supporting the onset of ventricular tachycardia. Once sustained, these circuits evolved into high-frequency rotors, which in their majority were pinned to the right ventricle. These rotors exhibited unique spatiotemporal dynamics that promoted their increased stability in R14del compared with wildtype hearts. CONCLUSIONS: Our findings highlight the crucial role of primary electric remodeling caused by the hPLNR14del mutation. These inherently arrhythmogenic features form the substrate for adrenergic-mediated VT at early stages of PLNR14del induced cardiomyopathy.
BACKGROUND: Arginine (Arg) 14 deletion (R14del) in the calcium regulatory protein phospholamban (hPLNR14del) has been identified as a disease-causing mutation in patients with an inherited cardiomyopathy. Mechanisms underlying the early arrhythmogenic phenotype that predisposes carriers of this mutation to sudden death with no apparent structural remodeling remain unclear. METHODS: To address this, we performed high spatiotemporal resolution optical mapping of intact hearts from adult knock-in mice harboring the human PLNWT (wildtype [WT], n=12) or the heterozygous human PLNR14del mutation (R14del, n=12) before and after ex vivo challenge with isoproterenol and rapid pacing. RESULTS: Adverse electrophysiological remodeling was evident in the absence of significant structural or hemodynamic changes. R14del hearts exhibited increased arrhythmia susceptibility compared with wildtype. Underlying this susceptibility was preferential right ventricular action potential prolongation that was unresponsive to β-adrenergic stimulation. A steep repolarization gradient at the left ventricular/right ventricular interface provided the substrate for interventricular activation delays and ultimately local conduction block during rapid pacing. This was followed by the initiation of macroreentrant circuits supporting the onset of ventricular tachycardia. Once sustained, these circuits evolved into high-frequency rotors, which in their majority were pinned to the right ventricle. These rotors exhibited unique spatiotemporal dynamics that promoted their increased stability in R14del compared with wildtype hearts. CONCLUSIONS: Our findings highlight the crucial role of primary electric remodeling caused by the hPLNR14del mutation. These inherently arrhythmogenic features form the substrate for adrenergic-mediated VT at early stages of PLNR14del induced cardiomyopathy.
Authors: Judith A Groeneweg; Paul A van der Zwaag; Jan D H Jongbloed; Moniek G P J Cox; Arnold Vreeker; Rudolf A de Boer; Jeroen F van der Heijden; Toon A B van Veen; William J McKenna; J Peter van Tintelen; Dennis Dooijes; Richard N W Hauer Journal: Heart Rhythm Date: 2012-12-25 Impact factor: 6.343
Authors: Kobra Haghighi; Tracy Pritchard; Julie Bossuyt; Jason R Waggoner; Qunying Yuan; Guo-Chang Fan; Hanna Osinska; Ahmad Anjak; Jack Rubinstein; Jeffrey Robbins; Donald M Bers; Evangelia G Kranias Journal: J Mol Cell Cardiol Date: 2011-12-01 Impact factor: 5.000
Authors: Sami F Noujaim; Sandeep V Pandit; Omer Berenfeld; Karen Vikstrom; Marina Cerrone; Sergey Mironov; Michelle Zugermayr; Anatoli N Lopatin; José Jalife Journal: J Physiol Date: 2006-11-09 Impact factor: 5.182
Authors: D Corrado; C Basso; G Thiene; W J McKenna; M J Davies; F Fontaliran; A Nava; F Silvestri; C Blomstrom-Lundqvist; E K Wlodarska; G Fontaine; F Camerini Journal: J Am Coll Cardiol Date: 1997-11-15 Impact factor: 24.094
Authors: Chantal J M van Opbergen; Navratan Bagwan; Alicia Lundby; Mario Delmar; Svetlana R Maurya; Joon-Chul Kim; Abigail N Smith; Daniel J Blackwell; Jeffrey N Johnston; Björn C Knollmann; Marina Cerrone Journal: Circulation Date: 2022-05-01 Impact factor: 39.918