Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
Jonas van den Brink
Simula Research Laboratory, Fornebu, Norway
Niall MacQuaide
Institute of Cardiovascular Sciences, University of Glasgow, Glasgow, United Kingdom
Per Kristian Lunde
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
Michael Frisk
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
Jan Magnus Aronsen
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; Bjørknes College, Oslo, Norway
Einar S Norden
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; Bjørknes College, Oslo, Norway
Alessandro Cataliotti
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
Ivar Sjaastad
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca2+ release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Ca2+ sparks (Ca2+ release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented ‘silent’ Ca2+ leak, not visible as sparks. Larger multi-cluster CRUs common in HF also exhibited low fidelity spark generation. When successfully triggered, sparks in failing cells displayed slow kinetics as Ca2+ spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca2+ transient. Thus, nanoscale RyR reorganization during HF augments Ca2+ leak and slows Ca2+ release kinetics, leading to weakened contraction in this disease.
