{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T13:09:28Z","timestamp":1788008968798,"version":"build-2784847793"},"reference-count":36,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2012,11,21]],"date-time":"2012-11-21T00:00:00Z","timestamp":1353456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Spatial dispersion of action potential duration is a substrate for the maintenance of cardiac fibrillation, but the mechanisms are poorly understood.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The rapid delayed rectifying K<jats:sup>+<\/jats:sup> current (<jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub>) that flows through sarcolemmal <jats:italic>ether\u2010\u00e0\u2010go\u2010go<\/jats:italic>\u2010related (hERG) channels plays a fundamental role in the control of rotor frequency and localization during atrial and ventricular fibrillation, although <jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub> is heterogeneously distributed throughout the heart chambers.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Using a novel magnetofection technique to induce regional overexpression of hERG, we have investigated the mechanisms by which regional gradients in <jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub> control rotor localization, frequency and wavebreak during fibrillation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our study establishes a mechanistic link between regional <jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub> heterogeneity, action potential duration and patterns of wavebreak in fibrillation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Knowledge that ion channel gradients are important in the mechanism of cardiac fibrillation should lead to improved therapy.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><jats:p><jats:bold>Abstract\u2002<\/jats:bold> Spatial dispersion of action potential duration (APD) is a substrate for the maintenance of cardiac fibrillation, but the mechanisms are poorly understood. We investigated the role played by spatial APD dispersion in fibrillatory dynamics. We used an <jats:italic>in vitro<\/jats:italic> model in which spatial gradients in the expression of <jats:italic>ether\u2010\u00e0\u2010go\u2010go<\/jats:italic>\u2010related (hERG) protein, and thus rapid delayed rectifying K<jats:sup>+<\/jats:sup> current (<jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub>) density, served to generate APD dispersion, high\u2010frequency rotor formation, wavebreak and fibrillatory conduction. A unique adenovirus\u2010mediated magnetofection technique generated well\u2010controlled gradients in hERG and green fluorescent protein (GFP) expression in neonatal rat ventricular myocyte monolayers. Computer simulations using a realistic neonatal rat ventricular myocyte monolayer model provided crucial insight into the underlying mechanisms. Regional hERG overexpression shortened APD and increased rotor incidence in the hERG overexpressing region. An APD profile at 75 percent repolarization with a 16.6\u00a0\u00b1\u00a00.72\u00a0ms gradient followed the spatial profile of hERG\u2010GFP expression; conduction velocity was not altered. Rotors in the infected region whose maximal dominant frequency was \u226512.9\u00a0Hz resulted in wavebreak at the interface (border zone) between infected and non\u2010infected regions; dominant frequency distribution was uniform when the maximal dominant frequency was &lt;12.9\u00a0Hz or the rotors resided in the uninfected region. Regularity at the border zone was lowest when rotors resided in the infected region. In simulations, a fivefold regional increase in <jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub> abbreviated the APD and hyperpolarized the resting potential. However, the steep APD gradient at the border zone proved to be the primary mechanism of wavebreak and fibrillatory conduction. This study provides insight at the molecular level into the mechanisms by which spatial APD dispersion contributes to wavebreak, rotor stabilization and fibrillatory conduction.<\/jats:p>","DOI":"10.1113\/jphysiol.2012.238758","type":"journal-article","created":{"date-parts":[[2012,10,23]],"date-time":"2012-10-23T04:56:22Z","timestamp":1350968182000},"page":"6363-6379","source":"Crossref","is-referenced-by-count":32,"title":["Spatial gradients in action potential duration created by regional magnetofection of hERG are a substrate for wavebreak and turbulent propagation in cardiomyocyte monolayers"],"prefix":"10.1113","volume":"590","author":[{"given":"Katherine","family":"Campbell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conrado 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