{"title":"Gap junctions and propagation of the cardiac action potential.","authors":"Scott A Bernstein, Gregory E Morley","doi":"10.1159/000092563","DOIUrl":"https://doi.org/10.1159/000092563","url":null,"abstract":"<p><p>Pacemaker cells in the heart generate periodic electrical signals that are conducted to the working myocardium via the specialized conduction system. Effective cell-to-cell communication is critical for rapid, uniform conduction of cardiac action potentials-- a prerequisite for effective, synchronized cardiac contraction. Local circuit currents form the basis of the depolarization wave front in the working myocardium. These currents flow from cell to cell via gap junction channels. In this chapter, we trace the path of the action potential from its generation in the sinus node to propagation through the working myocardium, with a detailed discussion of the role of gap junctions. First, we review the transmembrane ionic currents and the basic principles of conduction of the action potential to the working myocardium via the specialized tissues of the heart. Next, we consider the relative contribution of cell geometry, size, and gap junction conductance. These factors are examined in terms of their source-to-sink relationships. Lastly, we will discuss new insights into the importance of gap junctions in cardiac conduction in health and disease which have been gained from high resolution optical mapping in connexin-deficient mice.</p>","PeriodicalId":50954,"journal":{"name":"Advances in Cardiology","volume":"42 ","pages":"71-85"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000092563","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26376549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cardiac ischemia and uncoupling: gap junctions in ischemia and infarction.","authors":"Stefan Dhein","doi":"10.1159/000092570","DOIUrl":"https://doi.org/10.1159/000092570","url":null,"abstract":"<p><p>Acute cardiac ischemia is often associated with ventricular arrhythmia and fibrillation. Due to the loss of ATP, the depolarization of the fibers, and the intracellular Na(+) and Ca(2+) overload with concomitant acidification as well as the accumulation of lysophosphoglyceride and arachidonic acid metabolites, propagation of action potentials will be impaired by two factors: (a) reduced sodium channel availability and (b) gap junction uncoupling. While gap junction uncoupling leads to predominant transverse uncoupling, reduced I (Na) availability results in impaired longitudinal conduction. Complete gap junction uncoupling would initiate arrhythmia, while intermediate uncoupling has been shown to enhance the safety factor (SF) of propagation, limiting the current loss to non-depolarized areas. In contrast, a reduction in I(Na) availability reduces SF, and partial gap junction uncoupling might enable effective but slow conduction which, on the other hand, could form the basis for some kind of reentrant arrhythmia, paving the way for new anti-arrhythmic approaches in gap junction coupling. In the chronic phase, remodeling processes also involve gap junctions and lead to highly heterogeneous non-uniform tissue which may serve as an arrhythmogenic trigger.</p>","PeriodicalId":50954,"journal":{"name":"Advances in Cardiology","volume":"42 ","pages":"198-212"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000092570","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26377042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Micropatterns of propagation.","authors":"Peter J Lee, Steven M Pogwizd","doi":"10.1159/000092564","DOIUrl":"https://doi.org/10.1159/000092564","url":null,"abstract":"<p><p>Alterations in microscopic conduction could contribute to microreentry and arrhythmogenesis in pathological settings. This chapter reviews microconduction in the ventricular myocardium. Gap junctions play a significant role in longitudinal and transverse propagation of the action potential wavefront in the ventricle. Studies of microscopic conduction in patterned cultures of neonatal rodent myocytes have provided novel insights into the role of gap junctions, the effects of uncoupling versus altered excitability, and the contribution of discontinuities and branching. Decreased gap junctional coupling can contribute to slowing of conduction and development of unidirectional block. However, in the setting of structural inhomogeneities and unbalanced current source and load, decreased coupling can, at times, improve conduction and be 'anti-arrhythmic,' attesting to the complexity of intercellular coupling as a therapeutic target. Genetically engineered mouse models of Cx43 depletion demonstrate slow conduction and arrhythmogenesis that appears to be reentrant in nature. Studies in these models provide novel insights into the contribution of gap junctions to impulse propagation and arrhythmogenesis in the intact heart. Overall, gap junction expression, distribution and heterogeneity are important contributors to microscopic conduction, and alterations in any of these can contribute to the development of an arrhythmogenic substrate in pathological states.</p>","PeriodicalId":50954,"journal":{"name":"Advances in Cardiology","volume":"42 ","pages":"86-106"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000092564","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26376550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structural and functional coupling of cardiac myocytes and fibroblasts.","authors":"Patrizia Camelliti, Colin R Green, Peter Kohl","doi":"10.1159/000092566","DOIUrl":"https://doi.org/10.1159/000092566","url":null,"abstract":"<p><p>Cardiac myocytes and fibroblasts form extensive networks in the heart, with numerous anatomical contacts between cells. Fibroblasts, obligatory components of the extracellular matrix, represent the majority of cells in the normal heart, and their number increases with aging and during disease. The myocyte network, coupled by gap junctions, is generally believed to be electrically isolated from fibroblasts in vivo. In culture, however, the heterogeneous cell types form functional gap junctions, which can provide a substrate for electrical coupling of distant myocytes, interconnected by fibroblasts only. Whether similar behavior occurs in vivo has been the subject of considerable debate. Recent electrophysiological, immunohistochemical, and dye-coupling data confirmed the presence of direct electrical coupling between the two cell types in normal cardiac tissue (sinoatrial node), and it has been suggested that similar interactions may occur in post-infarct scar tissue. Such heterogeneous cell coupling could have major implications on in vivo electrical impulse conduction and the transport of small molecules or ions in both the normal and pathological myocardium. This review illustrates that it would be wrong to adhere to a scenario of functional integration of the heart that does not allow for a potential active contribution of non-myocytes to cardiac electrophysiology, and proposes to focus further research on the relevance of non-myocytes for cardiac structure and function.</p>","PeriodicalId":50954,"journal":{"name":"Advances in Cardiology","volume":"42 ","pages":"132-149"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000092566","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26377038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Role of connexins in atrial fibrillation.","authors":"Stefan Dhein","doi":"10.1159/000092568","DOIUrl":"10.1159/000092568","url":null,"abstract":"<p><p>Atrial fibrillation (AF) is the most common arrhythmia in humans. AF is accompanied by a remodeling process which changes the electrophysiology of the cells and the gap junctional communication within the tissue. Gap junctions, forming communicating channels between neighboring cells, and their specific geometric arrangement seem to contribute to the initiation of AF within the pulmonary veins as well as to the stabilization of AF providing a heterogeneous biophysical network of cells enabling multiple wavelets. These tissue changes are accompanied by fibrosis and changes in the expression levels of Cx43 and Cx40, probably depending on the underlying diseases or the animal model used. New studies point to a modulating role of angiotensin II in this process and a possible therapeutic role for ACE inhibitors or AT(1) antagonists.</p>","PeriodicalId":50954,"journal":{"name":"Advances in Cardiology","volume":"42 ","pages":"161-174"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000092568","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26377040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cardiac connexins: genes to nexus.","authors":"Heather S Duffy, Alfredo G Fort, David C Spray","doi":"10.1159/000092550","DOIUrl":"10.1159/000092550","url":null,"abstract":"<p><p>Gap junctions are formed of at least 20 connexin proteins in mammals and possibly pannexins as well. Of the connexins, at least 5 (Cx30.2, Cx37, Cx40, Cx43 and Cx45) are prominently expressed in the heart and each shows regional and cell type specific expression. Contributions of each of these connexins to heart function has been in many cases illuminated by connexin null mice. The cardiac connexin genes whose genomic organization and transcriptional controls have been studied most thoroughly indicate more complex possibilities for alternate promoter usage than originally thought as well a multiple transcription factor binding sites; presumably, such complexity governs developmental timing and regional connexin expression patterns. The structure of cardiac connexin proteins indicate four primarily alpha-helical transmembrane domains, cytoplasmic amino and carboxyl termini and a cytoplasmic loop, all of which contain some regions of alpha-helix, and extracellular loops that are primarily Beta-structure. A number of proteins that bind to cardiac connexins are known, and more are certain to be discovered, linking the connexin into an intercellular signaling complex, the nexus. Binding sites may either correspond to structured regions within the connexin molecules or be unstructured, leading to presumably low-affinity and dynamic interactions.</p>","PeriodicalId":50954,"journal":{"name":"Advances in Cardiology","volume":"42 ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000092550","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26434947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"If current inhibition: cellular basis and physiology.","authors":"M E Mangoni, L Marger, J Nargeot","doi":"10.1159/000095403","DOIUrl":"https://doi.org/10.1159/000095403","url":null,"abstract":"<p><p>The slow diastolic depolarization phase in cardiac pacemaker cells is the electrical basis of cardiac automaticity. The hyperpolarization-activated current (I(f)) is one of the key mechanisms underlying diastolic depolarization. Particularly, I(f) is unique in being activated on membrane hyperpolarization following the repolarization phase of the action potential. I(f) has adapted biophysical properties and voltage-dependent gating to initiate pacemaker activity. I(f) possibly constitutes the first voltage-dependent trigger of the diastolic depolarization. For these reasons, I(f) is a natural pharmacological target for controlling heart rate in cardiovascular disease. In this view, I(f) inhibitors have been developed in the past, yet the only molecule to have reached the clinical development is ivabradine. At the cellular level, the remarkable success of ivabradine is to be ascribed to its relatively high affinity for f-channels. Furthermore, ivabradine is the most I(f)-specific inhibitor known to date, since moderate inhibition of other voltage-dependent ionic currents involved in automaticity can be observed only at very high concentrations of ivabradine, more than one order of magnitude from that inhibiting I(f). Finally, the mechanism of block of f-channels by ivabradine has particularly favorable properties in light of controlling heart rate under variable physiological conditions. In this article, we will discuss how I(f) inhibition by ivabradine can lead to reduction of heart rate. To this aim, we will comment on the role of I(f) in cardiac automaticity and on the mechanism of action of ivabradine on f-channels. Some aspects of the cardiac pacemaker mechanism that improve the degree of security of ivabradine will also be highlighted.</p>","PeriodicalId":50954,"journal":{"name":"Advances in Cardiology","volume":"43 ","pages":"17-30"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000095403","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26224068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Connexin43 and ischemic preconditioning.","authors":"Rainer Schulz, Gerd Heusch","doi":"10.1159/000092571","DOIUrl":"https://doi.org/10.1159/000092571","url":null,"abstract":"<p><p>Connexin43 (Cx43) is the essential protein to form hemichannels and gap junctions in the myocardium. The phosphorylation status of Cx43 which is regulated by a variety of protein kinases and phosphatases determines hemichannel and/or gap junction conductance and permeability. Gap junctions are involved in cell-cell coupling while hemichannels contribute to cardiomyocyte volume regulation. Cx43-formed channels are involved in ischemia/reperfusion injury, since blockade of a large portion of Cx43-formed channels attenuates ischemic hypercontracture, infarct development and post myocardial infarction remodeling. Ischemic preconditioning's protection also depends on functional Cx43-formed channels, since uncoupling of channels or genetic Cx43 deficiency abolishes infarct size reduction by ischemic preconditioning. The exact underlying mechanism(s) how Cx43 mediates protection remain to be established.</p>","PeriodicalId":50954,"journal":{"name":"Advances in Cardiology","volume":"42 ","pages":"213-227"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000092571","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26376459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hai Lin, Koichi Ogawa, Issei Imanaga, Narcis Tribulova
{"title":"Alterations of connexin 43 in the diabetic rat heart.","authors":"Hai Lin, Koichi Ogawa, Issei Imanaga, Narcis Tribulova","doi":"10.1159/000092573","DOIUrl":"https://doi.org/10.1159/000092573","url":null,"abstract":"<p><p>In the streptozotocin-induced diabetic rat heart, a decrease in the conductivity and suppression of electrical cell-to-cell coupling has been observed. To clarify this mechanism, the present study was performed to investigate the gap junction connexin 43 (Cx43) using immunohistochemistry, immunoblot, electron-microscopic analyses. Enhanced activation of PKCepsilon, augmentation of PKCepsilon-mediated phosphorylation of Cx43, a decrease in the total amount of Cx43, a reduction in the number of immunoreactive particles for Cx43 at the intercalated disk and internalization, annular profiles of the gap junction were all recognized in the diabetic heart. Such a deterioration in the expression of Cx43 was alleviated by treatment with either lysosomal (leupeptin) or proteasomal inhibitor (ALLN). These results suggest that the PKCepsilon-mediated hyperphosphorylation of Cx43 makes Cx43 vulnerable to proteolytic degradation, while a decrease in the conductivity in the diabetic heart is also caused by a decrease in the number of gap junction channels due to an acceleration of the proteolytic degradation of Cx43. The remodeling of Cx43 induced by the activation of PKC may therefore contribute to the formation of the arrhythmogenic substrate.</p>","PeriodicalId":50954,"journal":{"name":"Advances in Cardiology","volume":"42 ","pages":"243-254"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000092573","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26376461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Future directions: what data do we need?","authors":"Michal Tendera","doi":"10.1159/000095432","DOIUrl":"https://doi.org/10.1159/000095432","url":null,"abstract":"<p><p>Pure heart rate reduction by ivabradine during exercise results in the decrease in oxygen demand and the increase in oxygen supply through the prolongation of diastole. These properties are crucial for its beneficial effect in patients with chronic stable angina. The ability of ivabradine to reduce the heart rate at rest can also have a potential use in clinical practice. In fact, the new directions for future clinical research are focused on this property. Chronic coronary artery disease, acute coronary syndromes and heart failure represent the areas in which resting heart rate reduction may improve cardiovascular prognosis. Application of ivabradine in these conditions deserves full attention, with dedicated and properly powered outcome trials.</p>","PeriodicalId":50954,"journal":{"name":"Advances in Cardiology","volume":"43 ","pages":"106-111"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000095432","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26281539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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