Ursula Doris1, Sanjay Kharche1,2, Maria Petkova1, Balint Borbas1, Sunil Jit R J Logantha1, Olga Fedorenko3,4, Michal Maczewski5, Urszula Mackiewicz5, Yu Zhang1, Anwar Chahal6,7, Alicia D'Souza1, Andrew J Atkinson1, Halina Dobrzynski8, Joseph Yanni1. 1. Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, England, UK. 2. Department of Biophysics and Lawson Health Research Institute, University of Western Ontario, London, Canada. 3. Mental Health Research Institute, Tomsk National Research Medical Centre, Tomsk, Russian Federation. 4. School of Non-Destructive Testing and Security, National Tomsk Polytechnic University, Tomsk, Russian Federation. 5. Medical Centre of Postgraduate Education, Warsaw, Poland. 6. Mayo Clinic, Rochester, Minnesota, USA. 7. Papworth Hospital NHS Trust, Cambridge, UK. 8. Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, England, UK. halina.dobrzynski@manchester.ac.uk.
Abstract
BACKGROUND: Functional properties of the sinoatrial node (SAN) are known to differ between sexes. Women have higher resting and intrinsic heart rates. Sex determines the risk of developing certain arrhythmias such as sick sinus syndrome, which occur more often in women. We believe that a major contributor to these differences is in gender specific ion channel expression. METHODS: qPCR was used to compare ion channel gene expression in the SAN and right atrium (RA) between male and female rats. Histology, immunohistochemistry and signal intensity analysis were used to locate the SAN and determine abundance of ion channels. The effect of nifedipine on extracellular potential recording was used to determine differences in beating rate between sexes. RESULTS: mRNAs for Cav1.3, Kir3.1, and Nkx2-5, as well as expression of the L-Type Ca²⁺ channel protein, were higher in the female SAN. Females had significantly higher intrinsic heart rates and the effect of nifedipine on isolated SAN preparations was significantly greater in male SAN. Computer modelling using a SAN cell model demonstrated a higher propensity of pacemaker-related arrhythmias in females. CONCLUSION: This study has identified key differences in the expression of Cav1.3, Kir3.1 and Nkx2-5 at mRNA and/or protein levels between male and female SAN. Cav1.3 plays an important role in the pacemaker function of the SAN, therefore the higher intrinsic heart rate of the female SAN could be caused by the higher expression of Cav1.3. The differences identified in this study advance our understanding of sex differences in cardiac electrophysiology and arrhythmias.
BACKGROUND: Functional properties of the sinoatrial node (SAN) are known to differ between sexes. Women have higher resting and intrinsic heart rates. Sex determines the risk of developing certain arrhythmias such as sick sinus syndrome, which occur more often in women. We believe that a major contributor to these differences is in gender specific ion channel expression. METHODS: qPCR was used to compare ion channel gene expression in the SAN and right atrium (RA) between male and female rats. Histology, immunohistochemistry and signal intensity analysis were used to locate the SAN and determine abundance of ion channels. The effect of nifedipine on extracellular potential recording was used to determine differences in beating rate between sexes. RESULTS: mRNAs for Cav1.3, Kir3.1, and Nkx2-5, as well as expression of the L-Type Ca²⁺ channel protein, were higher in the female SAN. Females had significantly higher intrinsic heart rates and the effect of nifedipine on isolated SAN preparations was significantly greater in male SAN. Computer modelling using a SAN cell model demonstrated a higher propensity of pacemaker-related arrhythmias in females. CONCLUSION: This study has identified key differences in the expression of Cav1.3, Kir3.1 and Nkx2-5 at mRNA and/or protein levels between male and female SAN. Cav1.3 plays an important role in the pacemaker function of the SAN, therefore the higher intrinsic heart rate of the female SAN could be caused by the higher expression of Cav1.3. The differences identified in this study advance our understanding of sex differences in cardiac electrophysiology and arrhythmias.
Authors: Matthew R Stoyek; Eilidh A MacDonald; Melissa Mantifel; Jonathan S Baillie; Bailey M Selig; Roger P Croll; Frank M Smith; T Alexander Quinn Journal: Front Physiol Date: 2022-02-28 Impact factor: 4.566