title: The calcium-frequency response in the rat ventricular myocyte: an experimental and modelling study.
abstract: In the majority of species, including humans, increased heart rate increases cardiac contractility. This change is known as the force-frequency response (FFR). The majority of mammals have a positive force-frequency relationship (FFR). In rat the FFR is controversial. We derive a species- and temperature-specific data-driven model of the rat ventricular myocyte. As a measure of the FFR, we test the effects of changes in frequency and extracellular calcium on the calcium-frequency response (CFR) in our model and three altered models. The results show a biphasic peak calcium-frequency response, due to biphasic behaviour of the ryanodine receptor and the combined effect of the rapid calmodulin buffer and the frequency-dependent increase in diastolic calcium. Alterations to the model reveal that inclusion of Ca(2+) /calmodulin-dependent protein kinase II (CAMKII)-mediated L-type channel and transient outward K(+) current activity enhances the positive magnitude calcium-frequency response, and the absence of CAMKII-mediated increase in activity of the sarco/endoplasmic reticulum Ca(2+) -ATPase induces a negative magnitude calcium-frequency response.
  
  
  
  An increase in heart rate affects the strength of cardiac contraction by altering the Ca(2+) transient as a response to physiological demands. This is described by the force-frequency response (FFR), a change in developed force with pacing frequency. The majority of mammals, including humans, have a positive FFR, and cardiac contraction strength increases with heart rate. However, the rat and mouse are exceptions, with the majority of studies reporting a negative FFR, while others report either a biphasic or a positive FFR. Understanding the differences in the FFR between humans and rats is fundamental to interpreting rat-based experimental findings in the context of human physiology. We have developed a novel model of rat ventricular electrophysiology and calcium dynamics, derived predominantly from experimental data recorded under physiological conditions. As a measure of FFR, we tested the effects of changes in stimulation frequency and extracellular calcium concentration on the simulated Ca(2+) transient characteristics and showed a biphasic peak calcium-frequency relationship, consistent with recent observations of a shift from negative to positive FFR when approaching the rat physiological frequency range. We tested the hypotheses that (1) inhibition of Ca(2+) /calmodulin-dependent protein kinase II (CAMKII)-mediated increase in sarco/endoplasmic reticulum Ca(2+) -ATPase (SERCA) activity, (2) CAMKII modulation of SERCA, L-type channel and transient outward K(+) current activity and (3) Na(+) /K(+) pump dynamics play a significant role in the rat FFR. The results reveal a major role for CAMKII modulation of SERCA in the peak Ca(2+) -frequency response, driven most significantly by the cytosolic calcium buffering system and changes in diastolic Ca(2+) .
authors.affiliation: King's College London, Department of Biomedical Engineering and Imaging Sciences, St. Thomas' Hospital, London, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Gattoni
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|K. G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Åsmund Treu
authors.initials: ÅT
authors.lastname: Røe
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|K. G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Michael
authors.initials: M
authors.lastname: Frisk
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|K. G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: William E
authors.initials: WE
authors.lastname: Louch
authors.affiliation: King's College London, Department of Biomedical Engineering and Imaging Sciences, St. Thomas' Hospital, London, UK.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Niederer
authors.affiliation: King's College London, Department of Biomedical Engineering and Imaging Sciences, St. Thomas' Hospital, London, UK.|University of Auckland, Engineering School Block 1, Level 5, 20 Symonds St, Auckland, 101, New Zealand.
authors.forename: Nicolas P
authors.initials: NP
authors.lastname: Smith
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000502:physiology*; D017208:Rats, Wistar; D013696:Temperature
chemical_list: D002118:Calcium