HISTOLOGY AND HISTOPATHOLOGY

From Cell Biology to Tissue Engineering

 

A sexy approach to pacemaking: differences in function and molecular make up of the sinoatrial node

Ursula Doris1, Sanjay Kharche1,2, Maria Petkova1, Balint Borbas1, Sunil Jit R.J. Logantha1, Olga Fedorenko3,4, Michal Maczewski5, Urszula Mackiewicz4, Yu Zhang1, Anwar Chahal6,7, Alicia D'Souza1, Andrew J. Atkinson1, Halina Dobrzynski1# and Joseph Yanni1#

1Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, England, 2Department of Biophysics and Lawson Health Research Institute, University of Western Ontario, London, Canada, 3Mental Health Research Institute, Tomsk National Research Medical Centre, 4School of Non-Destructive Testing and Security, National Tomsk Polytechnic University, Tomsk, Russian Federation, 5Medical Centre of Postgraduate Education, Warsaw, Poland, 6Mayo Clinic, Rochester, Minnesota, USA and 7Papworth Hospital NHS Trust, Cambridge, UK
#Contributed equally

Offprint requests to: Halina Dobrzynski, CTF Building, 46 Grafton Street, Manchester, M13 9NT, England, UK. e-mail: halina.dobrzynski@manchester.ac.uk


Summary. 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. Histol Histopathol 34, 1255-1268 (2019)

Key words: Ion channels, Arrhythmias, Pacemaker of the heart, Sinoatrial node, Gender, Electrophysiology, Computer modelling

DOI: 10.14670/HH-18-115