Talk:Detailed Cardiac - Sinus Node
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Cite this page: Hill, M.A. (2020, August 7) Embryology Detailed Cardiac - Sinus Node. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Detailed_Cardiac_-_Sinus_Node
Computational analysis of the human sinus node action potential: model development and effects of mutations
J Physiol. 2017 Feb 9. doi: 10.1113/JP273259.
Fabbri A1, Fantini M1, Wilders R2, Severi S1.
The sinoatrial node (SAN) is the normal pacemaker of the mammalian heart. Over several decades, a large amount of data on the ionic mechanisms underlying the spontaneous electrical activity of SAN pacemaker cells has been obtained, mostly in experiments on single cells isolated from rabbit SAN. This wealth of data has allowed the development of mathematical models of the electrical activity of rabbit SAN pacemaker cells. Our aim was to construct a more comprehensive model of the electrical activity of a human SAN pacemaker cell, using recently obtained electrophysiological data from human SAN pacemaker cells. We based our model on the recent Severi-DiFrancesco model of a rabbit SAN pacemaker cell. The action potential and calcium transient of the resulting model are close to the experimentally recorded values: the model has a much smaller 'funny current' (If ) than do rabbit cells, but its modulatory role is highly similar. Changes in pacing rate upon the implementation of mutations associated with sinus node dysfunction agree with the clinical observations. This agreement holds for both loss-of-function and gain-of-function mutations in the HCN4, SCN5A, and KCNQ1 genes, underlying ion channelopathies in If , fast sodium current, and slow delayed rectifier potassium current, respectively. We conclude that our human SAN cell model can be a useful tool in the design of experiments and the development of drugs that aim to modulate heart rate. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
PMID 28185290 DOI: 10.1113/JP273259
Development of the cardiac pacemaker
Cell Mol Life Sci. 2016 Oct 21.
Liang X1, Evans SM2,3,4, Sun Y5.
The sinoatrial node (SAN) is the dominant pacemaker of the heart. Abnormalities in SAN formation and function can cause sinus arrhythmia, including sick sinus syndrome and sudden death. A better understanding of genes and signaling pathways that regulate SAN development and function is essential to develop more effective treatment to sinus arrhythmia, including biological pacemakers. In this review, we briefly summarize the key processes of SAN morphogenesis during development, and focus on the transcriptional network that drives SAN development. KEYWORDS: Cardiac progenitors; Heart field; Pacemaker; Sinus node development; Sinus node dysfunction; Transcriptional regulation
PMID 27770149 DOI: 10.1007/s00018-016-2400-1
New Approaches to Biological Pacemakers: Links to Sinoatrial Node Development
Trends Mol Med. 2015 Dec;21(12):749-61. doi: 10.1016/j.molmed.2015.10.002. Epub 2015 Nov 20.
Irreversible degeneration of the cardiac conduction system is a common disease that can cause activity intolerance, fainting, and death. While electronic pacemakers provide effective treatment, alternative approaches are needed when long-term indwelling hardware is undesirable. Biological pacemakers comprise electrically active cells that functionally integrate with the heart. Recent findings on cardiac pacemaker cells (PCs) within the sinoatrial node (SAN), along with developments in stem cell technology, have opened a new era in biological pacing. Recent experiments that have derived PC-like cells from non-PCs have brought the field closer than ever before to biological pacemakers that can faithfully recapitulate SAN activity. In this review, I discuss these approaches in the context of SAN biology and address the potential for clinical translation. Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 26611337 PMCID: PMC4679473 DOI: 10.1016/j.molmed.2015.10.002
Genetic Regulation of Sinoatrial Node Development and Pacemaker Program in the Venous Pole
J Cardiovasc Dev Dis. 2015 Dec;2(4):282-298. Epub 2015 Nov 30.
Ye W1, Song Y2, Huang Z2, Zhang Y3, Chen Y4.
The definitive sinoatrial node (SAN), the primary pacemaker of the mammalian heart, develops from part of pro-pacemaking embryonic venous pole that expresses both Hcn4 and the transcriptional factor Shox2. It is noted that ectopic pacemaking activities originated from the myocardial sleeves of the pulmonary vein and systemic venous return, both derived from the Shox2+ pro-pacemaking cells in the venous pole, cause atrial fibrillation. However, the developmental link between the pacemaker properties in the embryonic venous pole cells and the SAN remains largely uncharacterized. Furthermore, the genetic program for the development of heterogeneous populations of the SAN is also under-appreciated. Here, we review the literature for a better understanding of the heterogeneous development of the SAN in relation to that of the sinus venosus myocardium and pulmonary vein myocardium. We also attempt to revisit genetic models pertinent to the development of pacemaker activities in the perspective of a Shox2-Nkx2-5 epistatic antagonism. Finally, we describe recent efforts in deciphering the regulatory networks for pacemaker development by genome-wide approaches. KEYWORDS: SAN; atrial fibrillation; pacemaker development; pulmonary vein; venous pole
Transcription factor ISL1 is essential for pacemaker development and function
J Clin Invest. 2015 Aug 3;125(8):3256-68. doi: 10.1172/JCI68257. Epub 2015 Jul 20.
Liang X, Zhang Q, Cattaneo P, Zhuang S, Gong X, Spann NJ, Jiang C, Cao X, Zhao X, Zhang X, Bu L, Wang G, Chen HS, Zhuang T, Yan J, Geng P, Luo L, Banerjee I, Chen Y, Glass CK, Zambon AC, Chen J, Sun Y, Evans SM.
The sinoatrial node (SAN) maintains a rhythmic heartbeat; therefore, a better understanding of factors that drive SAN development and function is crucial to generation of potential therapies, such as biological pacemakers, for sinus arrhythmias. Here, we determined that the LIM homeodomain transcription factor ISL1 plays a key role in survival, proliferation, and function of pacemaker cells throughout development. Analysis of several Isl1 mutant mouse lines, including animals harboring an SAN-specific Isl1 deletion, revealed that ISL1 within SAN is a requirement for early embryonic viability. RNA-sequencing (RNA-seq) analyses of FACS-purified cells from ISL1-deficient SANs revealed that a number of genes critical for SAN function, including those encoding transcription factors and ion channels, were downstream of ISL1. Chromatin immunoprecipitation assays performed with anti-ISL1 antibodies and chromatin extracts from FACS-purified SAN cells demonstrated that ISL1 directly binds genomic regions within several genes required for normal pacemaker function, including subunits of the L-type calcium channel, Ank2, and Tbx3. Other genes implicated in abnormal heart rhythm in humans were also direct ISL1 targets. Together, our results demonstrate that ISL1 regulates approximately one-third of SAN-specific genes, indicate that a combination of ISL1 and other SAN transcription factors could be utilized to generate pacemaker cells, and suggest ISL1 mutations may underlie sick sinus syndrome.
PMID 26193633 PMCID: PMC4563735 DOI: 10.1172/JCI68257