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1. Inherent Atrial Fibrillation Vulnerability in the Appendages Exacerbated in Heart Failure

Author

Agrawal, Shaleka, Ashby, Joseph, Bai, Jeiyun, Feng, Fan, Cai, Xue J., Yanni, Joseph, Jones, Caroline B., Logantha, Sunil J. R. J., Vohra, Akbar, Hutcheon, Robert C., Corno, Antonio F., Dobrzynski, Halina, Stephenson, Robert S., Boyett, Mark, Hart, George, Jarvis, Jonathan, Smaill, Bruce, Zhao, Jichao, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Camara, Oscar, editor, Puyol-Antón, Esther, editor, Sermesant, Maxime, editor, Suinesiaputra, Avan, editor, Tao, Qian, editor, Wang, Chengyan, editor, and Young, Alistair, editor

Published
2024
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2. Inherent Atrial Fibrillation Vulnerability in the Appendages Exacerbated in Heart Failure

Author

Agrawal, Shaleka, primary, Ashby, Joseph, additional, Bai, Jeiyun, additional, Feng, Fan, additional, Cai, Xue J., additional, Yanni, Joseph, additional, Jones, Caroline B., additional, Logantha, Sunil J. R. J., additional, Vohra, Akbar, additional, Hutcheon, Robert C., additional, Corno, Antonio F., additional, Dobrzynski, Halina, additional, Stephenson, Robert S., additional, Boyett, Mark, additional, Hart, George, additional, Jarvis, Jonathan, additional, Smaill, Bruce, additional, and Zhao, Jichao, additional

Published
2024
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3. Regulation of sinus node pacemaking and atrioventricular node conduction by HCN channels in health and disease

Author

Boyett, Mark R., Yanni, Joseph, Tellez, James, Bucchi, Annalisa, Mesirca, Pietro, Cai, Xue, Logantha, Sunil Jit R.J., Wilson, Claire, Anderson, Cali, Ariyaratnam, Jonathan, Stuart, Luke, Nakao, Shu, Abd Allah, Eman, Jones, Sandra, Lancaster, Matthew, Stephenson, Robert, Chandler, Natalie, Smith, Matthew, Bussey, Carol, Monfredi, Oliver, Morris, Gwilym, Billeter, Rudi, Mangoni, Matteo E., Zhang, Henggui, Hart, George, and D'Souza, Alicia

Published
2021
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6. Silencing miR-370-3p rescues funny current and sinus node function in heart failure

Author

Yanni, Joseph, D’Souza, Alicia, Wang, Yanwen, Li, Ning, Hansen, Brian J., Zakharkin, Stanislav O., Smith, Matthew, Hayward, Christina, Whitson, Bryan A., Mohler, Peter J., Janssen, Paul M. L., Zeef, Leo, Choudhury, Moinuddin, Zi, Min, Cai, Xue, Logantha, Sunil Jit R. J., Nakao, Shu, Atkinson, Andrew, Petkova, Maria, Doris, Ursula, Ariyaratnam, Jonathan, Cartwright, Elizabeth J., Griffiths-Jones, Sam, Hart, George, Fedorov, Vadim V., Oceandy, Delvac, Dobrzynski, Halina, and Boyett, Mark R.

Published
2020
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7. Remodelling and dysfunction of the sinus node in pulmonary arterial hypertension

Author

Logantha, Sunil Jit R. J., primary, Yamanushi, Tomoko T., additional, Absi, Mais, additional, Temple, Ian P., additional, Kabuto, Hideaki, additional, Hirakawa, Eiichiro, additional, Quigley, Gillian, additional, Zhang, X., additional, Gurney, Alison M., additional, Hart, George, additional, Zhang, Henggui, additional, Dobrzynski, Halina, additional, Boyett, Mark R., additional, and Yanni, Joseph, additional

Published
2023
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11. Structure, function and clinical relevance of the cardiac conduction system, including the atrioventricular ring and outflow tract tissues

Author

Dobrzynski, Halina, Anderson, Robert H., Atkinson, Andrew, Borbas, Zoltan, D'Souza, Alicia, Fraser, John F., Inada, Shin, Logantha, Sunil J.R.J., Monfredi, Oliver, Morris, Gwilym M., Moorman, Anton F.M., Nikolaidou, Thodora, Schneider, Heiko, Szuts, Viktoria, Temple, Ian P., Yanni, Joseph, and Boyett, Mark R.

Published
2013
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17. Remodeling of the Purkinje Network in Congestive Heart Failure in the Rabbit

Author

Logantha, Sunil Jit R.J., primary, Cai, Xue J., additional, Yanni, Joseph, additional, Jones, Caroline B., additional, Stephenson, Robert S., additional, Stuart, Luke, additional, Quigley, Gillian, additional, Monfredi, Oliver, additional, Nakao, Shu, additional, Oh, Il-Young, additional, Starborg, Tobias, additional, Kitmitto, Ashraf, additional, Vohra, Akbar, additional, Hutcheon, Robert C., additional, Corno, Antonio F., additional, Jarvis, Jonathan C., additional, Dobrzynski, Halina, additional, Boyett, Mark R., additional, and Hart, George, additional

Published
2021
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18. Structural and Functional Properties of Subsidiary Atrial Pacemakers in a Goat Model of Sinus Node Disease

Author

Soattin, Luca, primary, Borbas, Zoltan, additional, Caldwell, Jane, additional, Prendergast, Brian, additional, Vohra, Akbar, additional, Saeed, Yawer, additional, Hoschtitzky, Andreas, additional, Yanni, Joseph, additional, Atkinson, Andrew, additional, Logantha, Sunil Jit, additional, Borbas, Balint, additional, Garratt, Clifford, additional, Morris, Gwilym Matthew, additional, and Dobrzynski, Halina, additional

Published
2021
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22. Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node

Author

Petkova, Maria, primary, Atkinson, Andrew J., additional, Yanni, Joseph, additional, Stuart, Luke, additional, Aminu, Abimbola J., additional, Ivanova, Alexandra D., additional, Pustovit, Ksenia B., additional, Geragthy, Connor, additional, Feather, Amy, additional, Li, Ning, additional, Zhang, Yu, additional, Oceandy, Delvac, additional, Perde, Filip, additional, Molenaar, Peter, additional, D’Souza, Alicia, additional, Fedorov, Vadim V., additional, and Dobrzynski, Halina, additional

Published
2020
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23. Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart

Author

Zhang, Yu, Wang, Yanwen, Yanni, Joseph, Qureshi, Mohammed Anwar, Logantha, Sunil Jit R. J., Kassab, Sarah, Boyett, Mark R., Gardiner, Natalie J., Sun, Hong, Howarth, Frank Christopher, and Dobrzynski, Halina

Subjects
calcium handling protein, Physiology, gap junction channels, cardiovascular system, cardiac conduction system, ion channels, sense organs, type I diabetes, arrhythmias, Original Research, remodeling
Abstract

Cardiovascular complications are common in type 1 diabetes mellitus (TIDM) and there is an increased risk of arrhythmias as a result of dysfunction of the cardiac conduction system (CCS). We have previously shown that, in vivo, there is a decrease in the heart rate and prolongation of the QRS complex in streptozotocin-induced type 1 diabetic rats indicating dysfunction of the CCS. The aim of this study was to investigate the function of the ex vivo CCS and key proteins that are involved in pacemaker mechanisms in TIDM. RR interval, PR interval and QRS complex duration were significantly increased in diabetic rats. The beating rate of the isolated sinoatrial node (SAN) preparation was significantly decreased in diabetic rats. The funny current density and cell capacitance were significantly decreased in diabetic nodal cells. Western blot showed that proteins involved in the function of the CCS were significantly decreased in diabetic rats, namely: HCN4, Cav1.3, Cav3.1, Cx45, and NCX1 in the SAN; RyR2 and NCX1 in the atrioventricular junction and Cx40, Cx43, Cx45, and RyR2 in the Purkinje network. We conclude that there are complex functional and cellular changes in the CCS in TIDM. The changes in the proteins involved in the function of this electrical system are expected to adversely affect action potential generation and propagation, and these changes are likely to be arrhythmogenic.

Published
2019

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

Author

Doris, Ursula, Kharche, Sanjay, Petkova, Maria, Borbas, Balint, Logantha, Sunil Jit R.J., Fedorenko, Olga, Maczewski, MIchal, Mackiewicz, Urszula, Zhang, Yu, Chahal, Anwar, D’Souza, Alicia, Atkinson, Andrew J., Dobrzynski, Halina, and Yanni, Joseph

Subjects
Electrophysiology, Pacemaker of the heart, Ion channels, Computer modelling, 6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología [CDU], Gender, Sinoatrial, Arrhythmias
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 Ca v1.3, Kir3.1, and Nkx2-5, as well as expression of the L-Type Ca 2+ 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 Ca v 1.3, K ir 3.1 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 Ca v 1.3. The differences identified in this study advance our understanding of sex differences in cardiac electrophysiology and arrhythmias.

Published
2019
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25. Identification of key small non-coding micrornas controlling pacemaker mechanisms in the human sinus node

Author

Petkova, Maria, Atkinson, Andrew J., Yanni, Joseph, Stuart, Luke, Aminu, Abimbola J., Ivanova, Alexandra D., Pustovit, Ksenia B., Geragthy, Connor, Feather, Amy, Li, Ning, Zhang, Yu, Oceandy, Delvac, Perde, Filip, Molenaar, Peter, D’souza, Alicia, Fedorov, Vadim V., Dobrzynski, Halina, Petkova, Maria, Atkinson, Andrew J., Yanni, Joseph, Stuart, Luke, Aminu, Abimbola J., Ivanova, Alexandra D., Pustovit, Ksenia B., Geragthy, Connor, Feather, Amy, Li, Ning, Zhang, Yu, Oceandy, Delvac, Perde, Filip, Molenaar, Peter, D’souza, Alicia, Fedorov, Vadim V., and Dobrzynski, Halina

Abstract

BACKGROUND: The sinus node (SN) is the primary pacemaker of the heart. SN myocytes possess distinctive action potential morphology with spontaneous diastolic depolarization because of a unique expression of ion channels and Ca2+-handling proteins. MicroRNAs (miRs) inhibit gene expression. The role of miRs in controlling the expression of genes responsible for human SN pacemaking and conduction has not been explored. The aim of this study was to determine miR expression profile of the human SN as compared with that of non-pacemaker atrial muscle. METHODS AND RESULTS: SN and atrial muscle biopsies were obtained from donor or post-mortem hearts (n=10), histology/ immunolabeling were used to characterize the tissues, TaqMan Human MicroRNA Arrays were used to measure 754 miRs, Ingenuity Pathway Analysis was used to identify miRs controlling SN pacemaker gene expression. Eighteen miRs were significantly more and 48 significantly less abundant in the SN than atrial muscle. The most interesting miR was miR-486-3p predicted to inhibit expression of pacemaking channels: HCN1 (hyperpolarization-activated cyclic nucleotide-gated 1), HCN4, voltage-gated calcium channel (Cav )1.3, and Cav 3.1. A luciferase reporter gene assay confirmed that miR-486-3p can control HCN4 expression via its 3′ untranslated region. In ex vivo SN preparations, transfection with miR-486-3p reduced the beating rate by ≈35±5% (P<0.05) and HCN4 expression (P<0.05). CONCLUSIONS: The human SN possesses a unique pattern of expression of miRs predicted to target functionally important genes. miR-486-3p has an important role in SN pacemaker activity by targeting HCN4, making it a potential target for therapeutic treatment of SN disease such as sinus tachycardia.

Published
2020

26. Mechanistic insights from targeted molecular profiling of repolarization alternans in the intact human heart

Author

Orini, Michele, primary, Yanni, Joseph, additional, Taggart, Peter, additional, Hanson, Ben, additional, Hayward, Martin, additional, Smith, Andrew, additional, Zhang, Henggui, additional, Colman, Michael, additional, Jones, Gareth, additional, Jie, Xiao, additional, Dobrzynski, Halina, additional, Boyett, Mark R, additional, and Lambiase, Pier D, additional

Published
2019
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27. Congestive Heart Failure Leads to Prolongation of the PR Interval and Atrioventricular Junction Enlargement and Ion Channel Remodelling in the Rabbit

Author

Nikolaidou, Theodora, Cai, Xue J., Stephenson, Robert S., Yanni, Joseph, Lowe, Tristan, Atkinson, Andrew J., Jones, Caroline B., Sardar, Rida, Corno, Antonio F., Dobrzynski, Halina, Withers, Philip J., Jarvis, Jonathan C., Hart, George, and Boyett, Mark R.

Subjects
Heart Failure, Male, Ventricular Remodeling, Myocardium, lcsh:R, B110, lcsh:Medicine, Cardiomegaly, Atrial Remodeling, X-Ray Microtomography, Ion Channels, RC1200, Disease Models, Animal, Electrocardiography, Echocardiography, Connexin 43, cardiovascular system, Animals, lcsh:Q, RNA, Messenger, Rabbits, lcsh:Science, Research Article
Abstract

Heart failure is a major killer worldwide. Atrioventricular conduction block is common in heart failure; it is associated with worse outcomes and can lead to syncope and bradycardic death. We examine the effect of heart failure on anatomical and ion channel remodelling in the rabbit atrioventricular junction (AVJ). Heart failure was induced in New Zealand rabbits by disruption of the aortic valve and banding of the abdominal aorta resulting in volume and pressure overload. Laser micro-dissection and real-time polymerase chain reaction (RTPCR) were employed to investigate the effects of heart failure on ion channel remodelling in four regions of the rabbit AVJ and in septal tissues. Investigation of the AVJ anatomy was performed using micro-computed tomography (micro-CT). Heart failure animals developed first degree heart block. Heart failure caused ventricular myocardial volume increase with a 35% elongation of the AVJ. There was downregulation of HCN1 and Cx43 mRNA transcripts across all regions and downregulation of Cav1.3 in the transitional tissue. Cx40 mRNA was significantly downregulated in the atrial septum and AVJ tissues but not in the ventricular septum. mRNA abundance for ANP, CLCN2 and Navβ1 was increased with heart failure; Nav1.1 was increased in the inferior nodal extension/compact node area. Heart failure in the rabbit leads to prolongation of the PR interval and this is accompanied\ud by downregulation of HCN1, Cav1.3, Cx40 and Cx43 mRNAs and anatomical enlargement of the entire heart and AVJ.

Published
2015

28. A Sexy Approach to Pacemaking

Author

Doris, Ursula, primary, Logantha, Sunil, additional, Petkova, Maria, additional, Zhang, Yu, additional, Kharche, Sanjay, additional, Dobrzynski, Halina, additional, and Yanni, Joseph, additional

Published
2017
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29. Atrioventricular Node Dysfunction and Ion Channel Transcriptome in Pulmonary Hypertension

Author

Temple, Ian P., primary, Logantha, Sunil Jit R.J., additional, Absi, Mais, additional, Zhang, Yu, additional, Pervolaraki, Eleftheria, additional, Yanni, Joseph, additional, Atkinson, Andrew, additional, Petkova, Maria, additional, Quigley, Gillian M., additional, Castro, Simon, additional, Drinkhill, Mark, additional, Schneider, Heiko, additional, Monfredi, Oliver, additional, Cartwright, Elizabeth, additional, Zi, Min, additional, Yamanushi, Tomoko T., additional, Mahadevan, Vaikom S., additional, Gurney, Alison M., additional, White, Ed, additional, Zhang, Henggui, additional, Hart, George, additional, Boyett, Mark R., additional, and Dobrzynski, Halina, additional

Published
2016
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31. Exercise training reduces resting heart rate via downregulation of the funny channel HCN4

Author

D’Souza, Alicia, primary, Bucchi, Annalisa, additional, Johnsen, Anne Berit, additional, Logantha, Sunil Jit R.J., additional, Monfredi, Oliver, additional, Yanni, Joseph, additional, Prehar, Sukhpal, additional, Hart, George, additional, Cartwright, Elizabeth, additional, Wisloff, Ulrik, additional, Dobryznski, Halina, additional, DiFrancesco, Dario, additional, Morris, Gwilym M., additional, and Boyett, Mark R., additional

Published
2014
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33. Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat

Author

D'Souza, Alicia, Howarth, Frank C., Yanni, Joseph, Dobryznski, Halina, Boyett, Mark R., Adeghate, Ernest, Bidasee, Keshore R, Singh, Jaipaul, D'Souza, Alicia, Howarth, Frank C., Yanni, Joseph, Dobryznski, Halina, Boyett, Mark R., Adeghate, Ernest, Bidasee, Keshore R, and Singh, Jaipaul

Published
2011

34. Molecular basis of the electrical activity of the atrioventricular junction and Purkinje fibres

Author

Ravens, U, Tripathi, O N, Sanguinetti, M C, Dobrzynski, Halina, Monfredi, Oliver, Greener, Ian, Atkinson, Andrew, Inada, Shin, Taube, Mary-Anne, Yanni, Joseph, Fedorenko, Olga, Molenaar, Peter, Anderson, Robert, Efimov, Igor, Boyett, Mark, Ravens, U, Tripathi, O N, Sanguinetti, M C, Dobrzynski, Halina, Monfredi, Oliver, Greener, Ian, Atkinson, Andrew, Inada, Shin, Taube, Mary-Anne, Yanni, Joseph, Fedorenko, Olga, Molenaar, Peter, Anderson, Robert, Efimov, Igor, and Boyett, Mark

Published
2011

35. Functional, Anatomical, and Molecular Investigation of the Cardiac Conduction System and Arrhythmogenic Atrioventricular Ring Tissue in the Rat Heart

Author

Atkinson, Andrew J., primary, Logantha, Sunil Jit R. J., additional, Hao, Guoliang, additional, Yanni, Joseph, additional, Fedorenko, Olga, additional, Sinha, Aditi, additional, Gilbert, Stephen H., additional, Benson, Alan P., additional, Buckley, David L., additional, Anderson, Robert H., additional, Boyett, Mark R., additional, and Dobrzynski, Halina, additional

Published
2013
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38. Epistatic Rescue of Nkx2.5 Adult Cardiac Conduction Disease Phenotypes by Prospero-Related Homeobox Protein 1 and HDAC3

Author

Risebro, Catherine A., primary, Petchey, Louisa K., additional, Smart, Nicola, additional, Gomes, John, additional, Clark, James, additional, Vieira, Joaquim M., additional, Yanni, Joseph, additional, Dobrzynski, Halina, additional, Davidson, Sean, additional, Zuberi, Zia, additional, Tinker, Andrew, additional, Shui, Bo, additional, Tallini, Yvonne I., additional, Kotlikoff, Michael I., additional, Miquerol, Lucile, additional, Schwartz, Robert J., additional, and Riley, Paul R., additional

Published
2012
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45. Computer simulation of Purkinje fibres from a rabbit model of congestive heart failure.

Author

Li, Jue, Logantha, Sunil Jit, Yanni, Joseph, Cai, Xue, Zhang, Henggui, Dobrzynski, Halina, Hart, George, and Boyett, Mark

Abstract

This study used computer simulation to investigate the influence of heart failure (HF) on the Purkinje fibre. The study was based on a rabbit model of HF caused by volume and pressure overload. In the left ventricular free running Purkinje fibres, the expression level of the key cardiac ion channels was measured at the mRNA (messenger RNA) level using qPCR (quantitative polymerase chain reaction). Major changes were observed. To simulate the effect of these changes, we began with a model of the healthy rabbit Purkinje fibre action potential. In the absence of ionic current measurements from failing rabbit Purkinje fibres, we assumed that changes in ionic currents mirrored changes in ion channel expression: ionic conductances were adjusted based on changes in expression of the relevant ion channels. In the simulations, if all changes observed were incorporated, the Purkinje fibre is predicted to become inexcitable. Such an outcome would result in left bundle branch block (as observed in HF patients). The simulations predict that HF-dependent changes in INaL, Ito, IKr and IK1 and will have the most influence on the Purkinje fibre action potential. The predicted changes in the Purkinje fibre action potential were compared to actual changes measured using sharp microelectrodes. [ABSTRACT FROM PUBLISHER]

Published
2013

46. Chronic effects of mild hyperglycaemia on left ventricle transcriptional profile and structural remodelling in the spontaneously type 2 diabetic Goto-Kakizaki rat.

Author

D'Souza, Alicia, Howarth, Frank, Yanni, Joseph, Dobrzynski, Halina, Boyett, Mark, Adeghate, Ernest, Bidasee, Keshore, and Singh, Jaipaul

Abstract

Heart failure in chronic type 2 diabetes mellitus is partly attributable to adverse structural remodelling of the left ventricle (LV), but the contribution of hyperglycaemia (HG) per se in remodelling processes is debated. In this study, we examined the molecular signature of LV remodelling in 18-month-old spontaneously diabetic male Goto-Kakizaki (GK) rats that represent a long-term mildly diabetic phenotype, using histological, immunoblotting and quantitative gene expression approaches. Relative to age-matched Wistar controls, mildly diabetic GK rats presented with LV hypertrophy, increased expression of natriuretic peptides and phosphorylation of pro-hypertrophic Akt. Fibrosis proliferation in the GK LV paralleled increased transcriptional and biologically active pro-fibrogenic transforming growth factor-β1 (TGFβ1) in the LV with upregulated mRNA abundance for key extracellular matrix (ECM) components such as fibronectin, collagen type(s) 1 and 3α and regulators including matrix metalloproteinases 2 and 9, and their tissue inhibitor (TIMP) 4, connexin 43 and α5-integrin. GK rats also presented with altered mRNA expression for cardiac sarcoplasmic reticulum CaATPase, Na/Ca exchanger and the L-type Ca channels which may contribute to the altered Ca transient kinetics previously observed in this model at 18 months of age ( t test, p < 0.05 vs. age-matched Wistar control for all parameters). The results indicate that chronic mild HG can produce the molecular and structural correlates of a hypertrophic myopathy. Diffuse ECM proliferation in this model is possibly a product of HG-induced TGFβ1 upregulation and altered transcriptional profile of the ECM. [ABSTRACT FROM AUTHOR]

Published
2014
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47. Ageing-dependent remodelling of ion channel and Ca2+ clock genes underlying sino-atrial node pacemaking.

Author

Tellez, James O., Mączewski, Michal, Yanni, Joseph, Sutyagin, Pavel, Mackiewicz, Urszula, Atkinson, Andrew, Inada, Shin, Beresewicz, Andrzej, Billeter, Rudi, Dobrzynski, Halina, and Boyett, M. R.

Subjects
AGING, ION channels, CALCIUM channels, CARDIAC pacemakers, GENE expression, ELECTROPHYSIOLOGY, LABORATORY rats
Abstract

The function of the sino-atrial node (SAN), the pacemaker of the heart, is known to decline with age, resulting in pacemaker disease in the elderly. The aim of the study was to investigate the effects of ageing on the SAN by characterizing electrophysiological changes and determining whether changes in gene expression are involved. In young and old rats, SAN function was characterized in the anaesthetized animal, isolated heart and isolated right atrium using ECG and action potential recordings; gene expression was characterized using quantitative PCR. The SAN function declined with age as follows: the intrinsic heart rate declined by 18 ± 3%; the corrected SAN recovery time increased by 43 ± 13%; and the SAN action potential duration increased by 11 ± 3% (at 75% repolarization). Gene expression in the SAN changed considerably with age, e.g. there was an age-dependent decrease in the Ca2+ clock gene, RYR2, and changes in many ion channels (e.g. increases in Nav1.5, Navβ1 and Cav1.2 and decreases in Kv1.5 and HCN1). In conclusion, with age, there are changes in the expression of ion channel and Ca2+ clock genes in the SAN, and the changes may provide a partial explanation for the age-dependent decline in pacemaker function. [ABSTRACT FROM AUTHOR]

Published
2011
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49. Abstract 14572: Mir-486 Regulates Pacemaker Activity in the Human Heart via the Funny, HCN4, Channel.

Author

Petkova, Maria, Yanni, Joseph, D'Souza, Alicia, Zhang, Yu, Atkinson, Andrew, Geraghty, Connor, Borbas, Balint, Li, Ning, Oceandy, Delvac, Perde, Filip, Molenaar, Peter, Fedorov, Vadim, and Dobrzynski, Halina

Subjects
*CARDIAC pacemakers, *SINOATRIAL node, *ION channels, *CONNECTIVE tissues, *BEAT generation
Abstract

Background: The sinus node (SN) performs its function as the primary pacemaker of the heart partially via HCN4, Cav1.3 and Cav3.1 channels responsible for funny, L-Type and T-Type Ca2+ currents (If, ICaL and ICaT) respectively that generate the early and late phase of diastolic depolarisation. The aim of this study was to identify, and functionally validate, small non-coding microRNAs that can target these channels expression hence regulate the pacemaker activity. Methods and Results: Using qPCR we investigated 700 microRNAs in the human SN vs. right atrium (RA). The location of the SN in specimens was confirmed with histology for the presence of small nodal cells surround the nodal artery and embedded in a network of connective tissue. Immunohistochemistry and western blot confirmed significantly higher expression of HCN4, Cav1.3 and Cav3.1 in the human SN vs RA (n=4; p≤0.05). Using bioinformatics, we selected miR-486-3p for further investigation as it was predicted to inhibit the expression of all these three ion channels. miR-486-3p (conserved between human and rat) was injected into the rat SN preparations and compared to a control group (injected with a non-targeting scrambled microRNA). All preparations were kept in culture and spontaneous beating rate was recorded. All preparations were then collected for either immunohistochemistry or qPCR analysis. QPCR data show that miR-486-3p together with miR-1-3p, miR-30, miR-133a, miR-371-3p (predicted to inhibit HCN4, Cav1.3 and Cav3.1) are significantly more abundant in the human RA vs. SN (n=6, p≤0.05), which may explain non-pacemaking properties of atrial myocardium. Rat ex-vivo experiments revealed that miR-486-3p at 15hr incubation significantly reduces the SN beating rate (n=9) vs. control group (n=9; p≤0.05). QPCR and/or immunohistochemistry on the miR-486-3p treated rat SN (n=8) vs. control (n=8) show that miR-486-3p is significantly upregulated (p≤0.05), HCN4 is significantly downregulated (p≤0.05), whereas Cav1.3 and Cav3.1 are not altered. Finally, luciferase experiments in H9C2 cells revealed interaction between human miR-486-3p and human HCN4 gene at the 3'UTR. Conclusion: miR-486-3p is an important upstream regulator of the pacemaker function via targeting HCN4 channel and needs further attention as a potential target for treatment of SN dysfunctions. [ABSTRACT FROM AUTHOR]

Published
2018

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