Catecholaminergic Polymorphic Ventricular Tachycardia from Bedside to Bench and Beyond

Current problems in cardiology (Impact Factor: 3). 02/2009; 34(1):9-43. DOI: 10.1016/j.cpcardiol.2008.09.002
Source: PubMed


Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary electrical myocardial disease characterized by exercise- and stress-related ventricular tachycardia manifested as syncope and sudden death. The disease has a heterogeneous genetic basis, with mutations in the cardiac Ryanodine Receptor channel (RyR2) gene accounting for an autosomal-dominant form (CPVT1) in approximately 50% and mutations in the cardiac calsequestrin gene (CASQ2) accounting for an autosomal-recessive form (CPVT2) in up to 2% of CPVT cases. Both RyR2 and calsequestrin are important participants in the cardiac cellular calcium homeostasis. We review the physiology of the cardiac calcium homeostasis, including the cardiac excitation contraction coupling and myocyte calcium cycling. The pathophysiology of cardiac arrhythmias related to myocyte calcium handling and the effects of different modulators are discussed. The putative derangements in myocyte calcium homeostasis responsible for CPVT, as well as the clinical manifestations and therapeutic options available, are described.

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Available from: Michael Eldar, Aug 31, 2015
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    • ", and ATP are allosteric regulators of RyR2 (Meissner and Henderson, 1987; Meissner, 1994; Laver and Honen, 2008) that play an important role in determining normal cardiac contraction and rhythmicity (Meissner, 1994; Bers, 2002), and their disruption can lead to sudden cardiac death (Blayney and Lai, 2009; Katz et al., 2009). Ca 2+ in the SR lumen and cytoplasm activates RyR2, whereas Mg 2+ (free concentration of 1 mM in cytoplasm and lumen [Meissner, 1994]) is a channel inhibitor. "
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    ABSTRACT: Regulation of the cardiac ryanodine receptor (RyR2) by intracellular Ca(2+) and Mg(2+) plays a key role in determining cardiac contraction and rhythmicity, but their role in regulating the human RyR2 remains poorly defined. The Ca(2+)- and Mg(2+)-dependent regulation of human RyR2 was recorded in artificial lipid bilayers in the presence of 2 mM ATP and compared with that in two commonly used animal models for RyR2 function (rat and sheep). Human RyR2 displayed cytoplasmic Ca(2+) activation (Ka = 4 µM) and inhibition by cytoplasmic Mg(2+) (Ki = 10 µM at 100 nM Ca(2+)) that was similar to RyR2 from rat and sheep obtained under the same experimental conditions. However, in the presence of 0.1 mM Ca(2+), RyR2s from human were 3.5-fold less sensitive to cytoplasmic Mg(2+) inhibition than those from sheep and rat. The Ka values for luminal Ca(2+) activation were similar in the three species (35 µM for human, 12 µM for sheep, and 10 µM for rat). From the relationship between open probability and luminal [Ca(2+)], the peak open probability for the human RyR2 was approximately the same as that for sheep, and both were ∼10-fold greater than that for rat RyR2. Human RyR2 also showed the same sensitivity to luminal Mg(2+) as that from sheep, whereas rat RyR2 was 10-fold more sensitive. In all species, modulation of RyR2 gating by luminal Ca(2+) and Mg(2+) only occurred when cytoplasmic [Ca(2+)] was <3 µM. The activation response of RyR2 to luminal and cytoplasmic Ca(2+) was strongly dependent on the Mg(2+) concentration. Addition of physiological levels (1 mM) of Mg(2+) raised the Ka for cytoplasmic Ca(2+) to 30 µM (human and sheep) or 90 µM (rat) and raised the Ka for luminal Ca(2+) to ∼1 mM in all species. This is the first report of the regulation by Ca(2+) and Mg(2+) of native RyR2 receptor activity from healthy human hearts.
    The Journal of General Physiology 09/2014; 144(3):263-71. DOI:10.1085/jgp.201311157 · 4.79 Impact Factor
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    • "In contrast to experimental evidence implicating a Ca 2+ clock involving RyR2 in pacemaker activity (see section on Features of Ca 2+ homeostasis in sino-atrial and atrial cells have implications for rhythm abnormalities), CPVT is associated with high incidences of SAN dysrhythmia in the form of reduced SAN automaticity resulting in basal bradycardia, sinus pauses, and impaired chronotropic responses to β-adrenergic stimulation (Leenhardt et al., 1995; Sumitomo et al., 2003; Postma et al., 2005; Katz et al., 2009). Although they do not show a basal bradycardia, RyR2-R4496C mice studied using in vivo telemetric recordings similarly showed sinus pauses overcome by atrial and junctional escapes triggered by catecholamines, and impaired SAN automaticity following isoproterenol injection. "
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    ABSTRACT: Ryanodine receptor type 2 (RyR2) mutations are implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT) thought to result from altered myocyte Ca(2+) homeostasis reflecting inappropriate "leakiness" of RyR2-Ca(2+) release channels arising from increases in their basal activity, alterations in their phosphorylation, or defective interactions with other molecules or ions. The latter include calstabin, calsequestrin-2, Mg(2+), and extraluminal or intraluminal Ca(2+). Recent clinical studies additionally associate RyR2 abnormalities with atrial arrhythmias including atrial tachycardia (AT), fibrillation (AF), and standstill, and sinus node dysfunction (SND). Some RyR2 mutations associated with CPVT in mouse models also show such arrhythmias that similarly correlate with altered Ca(2+) homeostasis. Some examples show evidence for increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2. A homozygotic RyR2-P2328S variant demonstrates potential arrhythmic substrate resulting from reduced conduction velocity (CV) in addition to delayed afterdepolarizations (DADs) and ectopic action potential (AP) firing. Finally, one model with an increased RyR2 activity in the sino-atrial node (SAN) shows decreased automaticity in the presence of Ca(2+)-dependent decreases in I Ca, L and diastolic sarcoplasmic reticular (SR) Ca(2+) depletion.
    Frontiers in Physiology 06/2013; 4:150. DOI:10.3389/fphys.2013.00150 · 3.53 Impact Factor
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    • "It is therefore interesting to note that mutation of only 1 out of 4,497 amino acid residues is sufficient to perturb the gating of the channel, and almost all arrhythmogenic mutations regardless of their loci induce a gain-of-function phenotype. The mechanism by which CPVT mutations in RyR2 give rise to altered channel function is a topic of very active debate and investigation (Katz et al., 2009; Priori, 2010; Thomas et al., 2010). An important approach to resolve this issue is to understand the effect of regulatory proteins and cellular processes as well as the direct consequences of CPVT1 mutations on the gating mechanisms of RyR2, but before this can be done, it is essential to have an accurate description of the gating kinetics of the wild-type (WT) channel. "
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    ABSTRACT: Cardiac muscle contraction, triggered by the action potential, is mediated by the release of Ca(2+) from the sarcoplasmic reticulum through ryanodine receptor (RyR)2 channels. In situ, RyR2 gating is modulated by numerous physiological and pharmacological agents, and altered RyR2 function underlies the occurrence of arrhythmias in both inherited and acquired diseases. To understand fully the mechanisms underpinning the regulation of RyR2 in the normal heart and how these systems are altered in pathological conditions, we must first gain a detailed knowledge of the fundamental processes of RyR2 gating. In this investigation, we provide key novel mechanistic insights into the physical reality of RyR2 gating revealed by new experimental and analytical approaches. We have examined in detail the single-channel gating kinetics of the purified human RyR2 when activated by cytosolic Ca(2+) in a stringently regulated environment where the modulatory influence of factors external to the channel were minimized. The resulting gating schemes are based on an accurate description of single-channel kinetics using hidden Markov model analysis and reveal several novel aspects of RyR2 gating behavior: (a) constitutive gating is observed as unliganded opening events; (b) binding of Ca(2+) to the channel stabilizes it in different open states; (c) RyR2 exists in two preopening closed conformations in equilibrium, one of which binds Ca(2+) more readily than the other; (d) the gating of RyR2 when bound to Ca(2+) can be described by a kinetic scheme incorporating bursts; and (e) analysis of flicker closing events within bursts reveals gating activity that is not influenced by ligand binding. The gating schemes generated in this investigation provide a framework for future studies in which the mechanisms of action of key physiological regulatory factors, disease-linked mutations, and potential therapeutic compounds can be described precisely.
    The Journal of General Physiology 07/2012; 140(2):139-58. DOI:10.1085/jgp.201110706 · 4.79 Impact Factor
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