Cardiac fibroblasts express various ion channels in particul

Cardiac fibroblasts express various ion channels, in particular voltage-gated K channels and nonselective cation channels of the transient receptor potential (TRP) family . Both K and TRP channels are important determinants of fibroblast function, with TRP channels acting as Ca entry pathways that stimulate fibroblast differentiation into secretory myofibroblast phenotypes that produce ECM proteins. A study investigated the activity of voltage-gated sodium channels in human atrial fibroblasts and myofibroblasts and found that the TRP melastatin-related 7 (TRPM7) channel, a Ca/Mg-permeable channel, is strongly expressed in human atrial fibroblasts and likely plays an essential role in TGF-β-elicited fibrogenesis in human AF . Recently, Harada et al. showed that the Ca-permeable TRP canonical-3 (TRPC3) channels regulate cardiac fibroblast proliferation and differentiation, perhaps by controlling the Ca influx that activates extracellular signal-regulated kinase signaling. They showed that TRPC3 expression was upregulated in atria of AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. Interestingly, the expression and function of TRPC3 channels disappeared after differentiation of fibroblasts to myofibroblasts under culture conditions, which suggests that TRPC3 controls proliferation and differentiation of fibroblasts but is downregulated in the end-cell myofibroblast. This negative feedback system may prevent excessive ECM remodeling. In contrast, TRPM7 expression remained high in myofibroblasts, implicating that TRPM7 is likely the dominant TRP channel in differentiated myofibroblasts . TRPC3 channels act as a platform for protein kinase C associated with ERK-1/2 activation, which contributes to fibroblast function. Because angiotensin II increases the cellular production of diacylglycerol, which activates TRPC3 channels, angiotensin-induced increases in intracellular Ca and protein kinase C activation synergistically contribute to fibroblast proliferation via the TRPC3 channel. Harada et al. showed that a selective TPRC3 channel blocker, pyrazole-3, suppressed angiotensin II-induced Ca influx, proliferation, and α-SMA protein expression in fibroblasts in addition to extracellular signal-regulated kinase phosphorylation and ECM gene expression. Knocking down TRPC3 by small hairpin RNA decreased canine atrial fibroblast proliferation. Harada et al. also showed that microRNA-26 was downregulated in canine AF atria, and experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has nuclear factor of activated T cells (NFAT) meclofenoxate in the 5′ promoter region, and microRNA-26 transcription was negatively regulated by NFAT. Because NFAT activation is increased in AF fibroblasts, AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, pyrazole-3 suppressed AF while decreasing fibroblast proliferation and ECM gene expression. Harada et al. introduces the possibility of a novel potential therapeutic target that prevents fibroblast activation for the treatment of AF. The authors importantly showed that TRPC3 plays an important role in AF by promoting fibroblast pathophysiology as well as the mechanism of TRPC upregulation in AF via microRNA-26. The present findings point to TRPC3 as a candidate target for AF prevention.
Introduction Pacemakers are equipped with a memory function for intracardiac electrograms (EGMs), which facilitates analysis of the pacing and sensing status of the pacemaker while also providing an automated diagnosis function for arrhythmia episodes [1–3]. Furthermore, it is important to correctly set the post-ventricular atrial blanking (PVAB) period to avoid far-field R wave (FFRW) over-sensing and to maintain an adequate mode switching function. However, too large a PVAB value prevents proper sensing of the atrial wave and leads to an incorrect automated diagnosis of tachyarrhythmia because of under-sensing of the atrial potentials.[4–6].
Methods The study population comprised 150 patients who underwent implantations of Medtronic dual chamber pacemakers and who had maintained both atrial and ventricular sensing (either in DDD, DDI, or VDD modes) from March 2008 to October 2010. The implanted pacemaker generators were either Kappa series (n=80), EnPulse series (n=17), or ADAPTA series (n=53). At the subjects\' first visit to the pacemaker clinic after enrollment in this study, the settings of the parameters for storing intracardiac EGMs were chosen; the detection rates for atrial high-rate (AHR) episodes and ventricular high-rate (VHR) episodes were set at 170bpm and 180bpm, respectively. The supraventricular tachycardia filter was set to the “on” position so that fulfillment of both AHR and VHR excluded the diagnosis of a VHR episode. AHR and VHR episodes were selected as the types of high-rate types of episodes to be saved. “Include” was chosen for refractory senses so that atrial sensing was included in tachyarrhythmia diagnosis even if that sensing was within the refractory period. “Summed” was chosen as the EGM type to be saved; this meant that the SEGM, which is the merged AEGM and VEGM, was selected as the intracardiac EGM to be saved. The time out was set at 12 weeks (that is, EGMs were saved for 12 weeks after being recorded, and after that period, the EGMs would be deleted and only the tachycardia log would be preserved). The EGM allocation was set at 4 for 4/4s; thus EGMs of 4 episodes were saved including 4-s recordings of the EGMs before and after detection of each high-rate episode.