Catecholaminergic polymorphic ventricular tachycardia: A paradigm to understand mechanisms of arrhythmias associated to impaired Ca2+ regulation
ABSTRACT In the 8 years since the discovery of the genetic bases of catecholaminergic polymorphic ventricular tachycardia (CPVT), we have witnessed a remarkable improvement of knowledge on arrhythmogenic mechanisms involving disruption of cardiac Ca(2+) homeostasis. Studies on the consequences of RyR2 and CASQ2 mutations in cellular systems and mouse models have shed new light on pathways that are also implicated in arrhythmias occurring in highly prevalent diseases, such as heart failure. This research track has also led to the identification of therapeutic targets of potential clinical impact to abate the burden of sudden death in CPVT. Here, we review the current knowledge on the pathophysiology of CPVT also highlighting the existing controversies and possible future development.
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- "Up to 50 % of mortality in heart failure does not result from pump failure but from ventricular tachyarrhythmias (Grimm and Maisch 2002) that are the consequence of dysfunctions in cardiac Ca2+ homeostasis: Resting (diastolic) Ca2+ which is increased in heart failure(Gwathmey et al. 1990) as well as SR Ca2+ leak in a rare genetic disease called CPVT (Lehnart et al. 2008) can result in transient inward currents mediated by the sarcolemmal Na+/Ca2+ exchanger that, in turn, can lead to DADs and triggered activity. Both HF and CPVT have been linked to aberrant Ca2+ release through ‘leaky’ RyR2 channels (see Lehnart et al. 2009; Cerrone et al. 2009; Kushnir and Marks 2010 for recent reviews). "
ABSTRACT: ADP-ribosyl cyclases (ADPRCs) catalyse the conversion of nicotinamide adenine dinucleotide to cyclic adenosine diphosphoribose (cADPR) which is a second messenger involved in Ca(2+) mobilisation from intracellular stores. Via its interaction with the ryanodine receptor Ca(2+) channel in the heart, cADPR may exert arrhythmogenic activity. To test this hypothesis, we have studied the effect of novel cardiac ADPRC inhibitors in vitro and in vivo in models of ventricular arrhythmias. Using a high-throughput screening approach on cardiac sarcoplasmic reticulum membranes isolated from pig and rat and nicotinamide hypoxanthine dinuleotide as a surrogate substrate, we have identified potent and selective inhibitors of an intracellular, membrane-bound cardiac ADPRC that are different from the two known mammalian ADPRCs, CD38 and CD157/Bst1. We show that two structurally distinct cardiac ADPRC inhibitors, SAN2589 and SAN4825, prevent the formation of spontaneous action potentials in guinea pig papillary muscle in vitro and that compound SAN4825 is active in vivo in delaying ventricular fibrillation and cardiac arrest in a guinea pig model of Ca(2+) overload-induced arrhythmia. Inhibition of cardiac ADPRC prevents Ca(2+) overload-induced spontaneous depolarizations and ventricular fibrillation and may thus provide a novel therapeutic principle for the treatment of cardiac arrhythmias.Archiv für Experimentelle Pathologie und Pharmakologie 04/2012; 385(7):717-27. DOI:10.1007/s00210-012-0750-2 · 2.36 Impact Factor
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ABSTRACT: In this contribution we present experimental results of optically controlled mm-wave array antennas which may be used in broadband mobile communication systems. Two operation principles have been investigated: downlink beam forming for transmission and uplink beam steering for optimization of the reception. In both cases the field distributions of the antennas were formed by a silica based photonic beam forming network.
Conference Paper: Fully differential CMOS current feedback operational amplifier[Show abstract] [Hide abstract]
ABSTRACT: This paper presents a new CMOS Fully differential current feedback operational amplifier (FDCFOA). The proposed CMOS realization of the FDCFOA is based on a novel class AB fully differential buffer circuit. Besides the proposed FDCFOA circuit is operating at supply voltages of +/- 1.5 V, it has a total standby current of 400 muA. The applications of the FDCFOA to realize variable gain amplifier, fully differential integrator, and fourth order fully differential maximally flat low pass filter are given. The fourth order filter provides 8 dB gain and a bandwidth of 4.3 MHz to accommodate the wideband COMA standard. The proposed FDCFOA and its applications are simulated using CMOS 0.35 mum technology.Electrical, Electronic and Computer Engineering, 2004. ICEEC '04. 2004 International Conference on; 10/2004