Ebook Heart rate and rhythm molecular basis pharmacological modulation and clinical implications: Part 2

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Ebook Heart rate and rhythm molecular basis pharmacological modulation and clinical implications: Part 2

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(BQ) Part 2 book Heart rate and rhythm molecular basis pharmacological modulation and clinical implications presents the following contents: Mechanisms of inherited arrhythmia, role of specific channels and transporters in arrhythmia, drugs and cardiac arrhythmia.

Part V Mechanisms of Inherited Arrhythmia Chapter 21 Intracellular Calcium Handling and Inherited Arrhythmogenic Diseases Nicola Monteforte, Carlo Napolitano, Raffaella Bloise, and Silvia G Priori 21.1 Introduction Diseases caused by a single genetic defect are referred to as monogenic disorders These disorders are inherited as dominant or recessive traits with different inheritance patterns (autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, matrilineal transmission) In cardiology, there are two major clusters of monogenic disorders: (a) the cardiomyopathies due to alterations in sarcomeric and in cytoskeletal proteins, and (b) the arrhythmogenic diseases that are caused by mutations in ion channels and ion channel-controlling proteins such as the long QT syndromes (LQTS), the Brugada syndromes, the short QT syndromes (SQTS), and the catecholaminergic polymorphic ventricular tachycardia (CPVT) N Monteforte and R Bloise Molecular Cardiology, Fondazione S Maugeri IRCCS, Via Salvatore Maugeri 10/10A, 27100 Pavia, Italy C Napolitano Molecular Cardiology, Fondazione S Maugeri IRCCS, Via Salvatore Maugeri 10/10A, 27100 Pavia, Italy and Cardiovascular Genetics Program; Leon H Charney Division of Cardiology, New York University, New York, NY, USA S.G Priori (*) Molecular Cardiology, Fondazione S Maugeri IRCCS, Via Salvatore Maugeri 10/10A, 27100 Pavia, Italy and Cardiovascular Genetics Program; Leon H Charney Division of Cardiology, New York University, New York, NY, USA and Department of Cardiology, Universita` degli Studi di Pavia, Pavia, Italy e-mail: silvia.priori@fsm.it O.N Tripathi et al (eds.), Heart Rate and Rhythm, DOI 10.1007/978-3-642-17575-6_21, # Springer-Verlag Berlin Heidelberg 2011 387 388 N Monteforte et al Inherited arrhythmogenic diseases are associated with an increased risk for ventricular arrhythmias These diseases are often asymptomatic for many years and are not detected until the first clinical presentation such as syncope or sudden cardiac death In approximately 10–20% of all sudden deaths, no structural cardiac abnormalities can be identified [1] These diseases often affect young, otherwise healthy individuals, and the conventional electrocardiogram (ECG) is important for diagnosing established diseases or detecting novel entities associated with sudden cardiac death [2–4] The b-blockers are effective in some instances (e.g., LQTS, catecholaminergic ventricular tachycardia) but often an implantable cardioverter defibrillator (ICD) is the only option for high risk patients It is important to consider that the clinical manifestations of these diseases may significantly vary from one patient to the other even in the presence of the same genetic defect In technical terms, this phenomenon is attributed to the “variable expressivity” (nonuniform clinical severity of carriers of the same genetic defect) and the incomplete penetrance (i.e., the ratio between carriers of a given gene defect and the number of clinically affected individuals is lower than 1) The identification of the genes underlying the inherited arrhythmogenic syndromes has greatly contributed to the understanding of the substrate for the arrhythmia development, but more importantly, it has provided major practical information that is helpful when managing affected individuals In this chapter, we focus on the genetic basis, the clinical features, and the main therapeutic strategies of the most important channelopathies caused by a genetically determined impairment of intracellular calcium handling such as CPVT, Timothy syndrome [(TS), a variant of long QT syndrome (LQT8)], and two genetic variants of Brugada syndrome (BrS3 and BrS4) 21.2 Catecholaminergic Polymorphic Ventricular Tachycardia CPVT is a severe disorder, with a high incidence of sudden cardiac death among affected individuals The first report of a patient with this disease was published in 1975 [5], but the first systematic description came in 1978 with the work of Coumel et al [6] and was further refined by the same group in 1995 [7] In 2001, molecular genetic studies unveiled that CPVT results from inherited defects of intracellular calcium handling that cause abnormal Ca2+ release form the sarcoplasmic reticulum (SR) We reported for the first time that the autosomal dominant form of the disease was caused by mutations in the gene encoding for the cardiac ryanodine receptor (RyR2) [8] Shortly after, the gene for the autosomal recessive form of CPVT was identified as the gene encoding cardiac calsequestrin (CASQ2) [9] After identification of the underlying genetic causes, basic science studies in cell systems and animal models brought a major advancement to the understanding of arrhythmogenic mechanisms in this disease 21 Intracellular Calcium Handling and Inherited Arrhythmogenic Diseases 389 21.2.1 Calcium Handling and Arrhytmogenesis in CPVT The discovery that genetic defects in Ca2+ regulatory proteins such as the ryanodine receptor (RyR2) [10, 11] and calsequestrin (CASQ2) [12], result in CPVT, has stimulated many fundamental studies that provided new and compelling evidence to link abnormal intracellular Ca2+ signaling and arrhythmia Calcium that enters the cell during the plateau phase of the action potential (AP) triggers the release of Ca2+ from SR through ryanodine receptors [13] (Fig 21.1) This process, known as Ca2+-induced Ca2+ release (CICR), amplifies the initial Ca2+ entry signal to produce an elevation of cytosolic Ca2+ [Ca2+]i, triggering the cascade of conformational changes leading to contraction of the sarcomere During relaxation, most of the Ca2+ in the cytosol is recycled into the SR by cardiac SR calcium adenosine triphosphatase (SERCA2), the activity of which is controlled by phospholamban CaV1.2 RyR2 FKBP12.6 JCTN/TRDN T-tubule CASQ2 Plasma Membrane SR Fig 21.1 Diagram showing the localization of the proteins involved in the pathogenesis of Ca2+ handling SR sarcoplasmic reticulum, NCX sodium–calcium exchanger, JCTN junctin, TRDN triadin SERCA SR calcium adenosine triphosphatase, PLB phospholamban 390 N Monteforte et al (PLB) Additionally, some of the Ca2+ is extruded from the cell by the Na+/Ca2+ exchange (NCX) to balance the Ca2+ entry Spontaneous Ca2+ release occurs in the form of self-propagating waves of CICR that originate locally as spontaneous release events, known as Ca2+ sparks [14] During diastole, individual sparks can lead to local increase in Ca2+ current In the presence of calcium overload, the diastolic Ca2+ spark rate and SR channel sensitivity to cytosolic Ca2+ increase Spontaneous Ca2+ waves are arrhythmogenic and induce Ca2+-dependent depolarizing currents, thereby causing oscillations of the membrane potential known as delayed afterdepolarizations (DAD) [15] When sufficiently large, DADs evoke extrasystolic APs, thereby causing triggered arrhythmias Substantial evidence supports the concept that changes in luminal Ca2+ contribute to termination of CICR and facilitate RyR2 to enter in a refractory state that suppresses diastolic Ca2+ release Alterations in luminal Ca2+ control of Ca2+ release are, therefore, expected to lead to serious disruptions of the cellular Ca2+ cycling Alternative hypotheses have been advanced to explain the functional consequences of RyR2 mutations CPVT-associated mutations may lead to abnormal dissociation (reduced binding affinity) of the auxiliary protein FKBP12.6 from RyR2 [16] Less RyR2-FKBP12.6 binding in turn influences channel gating causing increased diastolic Ca2+ leak from the sarcoplasmic reticulum (SR), a phenomenon known to favor the onset of DADs and arrhythmias Alternatively, mutations may change RyR2 sensitivity to luminal Ca2+, thus reducing the Ca2+ threshold required for generation of spontaneous Ca2+ release [17] CASQ2 mutations in the autosomal recessive form of CPVT also result in deregulated SR Ca2+ release and arrhythmogenic DADs [18–22] This effect is due to reduced Ca2+ buffering properties of CASQ2 and/or by loss of CASQ2-mediated RyR2 regulation Irrespective of which of these mechanisms is involved, the final effect is the generation of arrhythmogenic spontaneous Ca2+ release from the SR and generation of DADs 21.2.2 Genetic Bases of CPVT Most familial CPVTs show autosomal dominant pattern of inheritance In 1999, Swan et al [23] identified a significant linkage between the CPVT phenotype and microsatellite markers at locus 1q42-q43 Based on this information, we performed molecular screening and identified cardiac RyR2 as the mutant CPVT gene [8] Involvement of RyR2 in the genesis of CPVT was subsequently confirmed by several other investigators (http://www.fsm.it/cardmoc) A recent analysis of published RyR2 mutations shows that they tend to cluster in 25 exons encoding discrete domains of RyR2 protein: domain I (amino acid (AA) 77–466), II (AA 2246–2534), III (AA 3778–4201), and IV (AA 4497–4959) (DI-DIV) These clusters are composed of amino acid sequences highly conserved through species and among RyR isoforms [24] and are thought to be functionally important 21 Intracellular Calcium Handling and Inherited Arrhythmogenic Diseases 391 Soon after identification of the RyR2 mutations in the autosomal dominant form of CPVT, Lahat et al [9] mapped the recessive variant on chromosome 1p23-21 and subsequently identified one mutation on the CASQ2 gene, encoding for cardiac calsequestrin CASQ2 mutations represent only 1–2% of all genotyped CPVTs More recently, based on the evidence that the patients with Andersen–Tawil syndrome may develop bidirectional ventricular tachycardia [25, 26], i.e., the typical arrhythmia observed in CPVT, it has been suggested that some CPVT cases can be explained by KCNJ2 mutations (phenocopy) In 2007, a new autosomal recessive form of CPVT mapping on the chromosomal locus 7p14-22 was reported by Bhuiyan et al [27], but the responsible gene has not yet been discovered So far, more than 70 different mutations have been associated with CPVT, and these are all single-base pair substitutions causing the substitution of an amino acid As expected for autosomal recessive disorders, the number of families with CPVT linked to CASQ2 mutations is fairly small At present, only seven mutations have been discovered, and they can be inherited in homozygous or compound heterozygous form A recent analysis from our group [28] has demonstrated that genetic screening on the RyR2 gene is able to identify at least 60–65% of patients with the clinical phenotype; therefore, genetic screening should be recommended since it is able to identify most of the affected subjects and could then be extended to family members 21.2.3 Mechanisms of Arrhythmias in Autosomal Dominant CPVT The RyR2 is a tetrameric channel that regulates the release of Ca2+ from SR to the cytosol during the plateau phase of the cardiac AP When RyR2 activity is modified/altered leading to an increase or reduction of the amount of Ca2+ released, both the SR and the cytosolic Ca2+ concentration may be affected This induces compensatory phenomena that tend to restore the cellular calcium balance, such as the activation of the cardiac NCX Unfortunately, such compensatory mechanisms may be arrhythmogenic RyR2 function (SR Ca2+ release) is regulated by several accessory proteins, such as CASQ2, triadin, junctin, and FKBP12.6 (Fig 21.1) Furthermore, the adrenergic tone controls the RyR2 channel through phosphorylation, which is a crucial step determining the amount of Ca2+ released from SR Catecholamines activate protein kinase-A (PKA) and calcium-calmodulin dependent kinase II (CaMKII) that phosphorylates RyR2 at different sites and acts as a throttle on the Ca2+ release process [29] 21.2.3.1 RyR2 Mutations and CPVT The effects of RyR2 mutations have been studied in vitro and in vivo using different experimental models RyR2 mutations can affect both the activation 392 N Monteforte et al and the inactivation of the channel in several ways It is noteworthy that, when viewed independently from the subcellular mechanisms, the final common effect of CPVT mutations (both RyR2 and CASQ2) appears similar to that of digitalis intoxication, viz Ca2+ overload, activation of NCX in the forward mode, generation of transient inward NCX current (Iti), and delayed after-depolarizations (DADs) The proposed “primum movens” leading to Ca2+ overload is the uncontrolled 2+ Ca release (leakage) during diastole, which is mainly detectable upon adrenergic activation [30] (phosphorylation); but according to different authors, it may already be present in the unstimulated conditions [31, 32] Given the complexity of the SR Ca2+ release process, the leakage could in principle be due to several mechanisms [16, 30, 31] 21.2.3.2 RyR2–CPVT Mouse Models Knock-in mouse models have been pivotal to the understanding of the cellular and whole-heart pathophysiology of CPVT [33–35] Based on the assumption that by engineering RyR2–CPVT mutation in the mouse genome, it is possible to reproduce the phenotype observed in the clinical setting, the initial evidence was provided by our group in 2005 By homologous recombination, we created a conditional knock-in mouse harboring the R4496C mutation This is the first mutation that we identified in CPVT patients and it is present in several unrelated CPVT families [34] R4496C mice develop typical CPVT bidirectional VT in the absence of structural abnormalities [34] This model has been instrumental to demonstrated adrenergic-dependent DADs, increased NCX-transient inward current (Iti), and triggered activity as the cellular mechanisms for CPVT [36] (Fig 21.2) In a subsequent study [37], we observed the onset of abnormal Ca2+ waves during diastole, which paralleled the occurrence of DAD development both at baseline and during isoproterenol superfusion Increased propensity to DAD development in RyR2-R4496C mice was also demonstrated in isolated Purkinje Fig 21.2 DADs recorded from an isolated RyR2R4496C+/À myocyte stimulated at 1–5 Hz Note that DAD amplitude increases and DAD coupling interval decreases at faster pacing frequencies (modified from [36]) 21 Intracellular Calcium Handling and Inherited Arrhythmogenic Diseases 393 cells by Cerrone et al [38] Finally, additional data supporting the concept that DAD-mediated triggered activity is the arrhythmogenic mechanism for CPVT were provided by Paavola et al [39], who recorded DADs using monophasic APs in CPVT patients In an optical mapping study in collaboration with Dr Jalife and his coworkers, we showed that both polymorphic and bidirectional VT have a focal origin [38] Epicardial optical mapping was used to demonstrate that during bidirectional VT, the ventricular beats alternatively originate from the right and from the left ventricle and arise from an area coincident with the anatomic insertion of the major bundle branches of the conduction system Interestingly, administration of Lugol’s solution that ablates the Purkinje network is able to convert bidirectional VT to monomorphic left-sided VT In the same study, endocardial optical maps also showed that during polymorphic VT the site of origin of the beats mapped on the endocardial right ventricular wall correspond to free running Purkinje fibers Overall these experiments support the relevant role of Purkinje network in the pathogenesis of arrhythmias in CPVT 21.2.4 Mechanisms of Arrhythmias in Autosomal Recessive CPVT CASQ2 has been initially described as a Ca2+ buffering protein resident in the SR lumen and exists in monomeric and polymeric forms When luminal [Ca2+] is low, CASQ2 binds to junctin and triadin and inhibits SR calcium release from RyR2 Conversely, in the presence of a rise in luminal SR[Ca2+], the binding between CASQ2, triadin, and junctin is weakened and the open probability for RyR2 increases [40] Overall evidence concurs to attribute to CASQ2 the roles of a Ca2+ buffer molecule and a RyR2 modulator 21.2.4.1 CASQ2 Mutations and CPVT Mutations in CASQ2 that cause the autosomal recessive CPVT are rather uncommon, and so far no phenotypical differences have been identified between CASQ2and RyR2–CPVT The few CASQ2 mutations reported so far have been extensively studied in in-vitro and in transgenic animal MODELS In vitro studies have highlighted that the mutations may lead to major alterations in CASQ2 functions as they may impair CASQ2 polymerization, alter its buffering properties, and modify CASQ2–RyR2 interaction Terentyev et al [17] suggested that a reduction or absence of CASQ2, as it happens with the truncation mutants, leads to a decrease of the time necessary to reestablish Ca2+ storage, thus facilitating a premature activation of RyR2 and, as a consequence, diastolic Ca2+ leakage 394 N Monteforte et al 21.2.4.2 CASQ2–CPVT Mouse Models As in the case of RyR2–CPVT, mouse models reproducing the autosomal recessive CASQ2–CPVT have provided important pathophysiological information but have also been of great value for the unraveling of some molecular mechanisms of cardiac Ca2+ regulation Knollmann et al [21] created a CASQ2 knock-out mouse model, in which VT and ventricular fibrillation (VF) could be induced by b-adrenergic stimulation (isoproterenol) or even acute stressors such as auditory stimuli In isolated CASQ2 null myocytes, the authors observed increased diastolic Ca2+ leakage leading to DADs and triggered activity, thus proving that DADs are the common final arrhythmogenic mechanisms in RyR2- and CASQ2–CVPT More recently, we developed the CASQ2–R33Q/R33Q knock-in mouse model that reproduces the typical CPVT phenotype [41] At variance with the RyR2–R4496C model, arrhythmias in these mice occur in the presence of mild stressors (Fig 21.3) CASQ2–R33Q/R33Q cardiomyocytes showed DADs and triggered activity not only during b-adrenergic stimulation but also in resting conditions [41] Interestingly, we observed a prominent reduction of CASQ2 in our mice with the R33Q mutation and we were able to show that mutant calsquestrin is prone to increased trypsin degradation On the basis of these observations, it is possible to speculate that the key mechanism for autosomal recessive CPVT is the reduction in the 736R333QHO.ECG mV 2.0 5/4/2007 1:40:54 PM – 2.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 736R333QHO.ECG mV 2.0 5/4/2007 1:40:56 PM – 2.0 0.2 736R333QHO.ECG mV 2.0 5/4/2007 1:40:58 PM – 2.0 0.2 736R333QHO.ECG 5/4/2007 1:41:00 PM mV 2.0 – 2.0 0.2 736R333QHO.ECG 5/4/2007 1:41:02 PM mV 2.0 – 2.0 0.2 Fig 21.3 ECG recording showing the onset of bidirectional ventricular tachycardia in a mouse model (modified from [41]) 664 N Strutz-Seebohm and G Seebohm retigabine RL-3 H N H N O F N O N H O NH2 N F N CH3 F F F retigabine analogue MaxiPost H N H N S O F N Br O Cl O O CN 2-arylthiazol O S O N F F F F F N H benzo (d)isoxazole N O N O O HO HO salicylat analogue CF3 OCF3 N H CF3 N H N S O 3-aminoquinazolin-one Fig 37.3 Structure and putative discrete binding sites of two classes of KCNQ channel agonists The binding sites of R-L3 and retigabine have been shown experimentally binding sites suggest very strict molecular requirements for the compounds to be ligands for the specific agonist binding pocket These molecular constraints determine size (volume), geometry, and chemical nature (hydrophobicity, aromaticity) of the compound Meanwhile, several additional KCNQ channel agonists have been reported Based on the knowledge on R-L3 and retigabine binding sites, the binding sites of these new compounds can be predicted The size and chemical nature of the agonists suggest a scheme, in which MaxiPost and benzo(d)isoxazole may bind to the R-L3 site and retigabine analogs, 2-arythiazole, and 3-aminoquinazoline-one may target the retigabine binding site (Fig 37.3) However, these predictions have not yet been experimentally tested 37.8 The Quest for Potassium Channel Activators Often agonists are found by accident when screening for compounds intended for other targets Possibly there is a technical problem unaddressed by modern screening techniques: Pharmaceutical companies screen for lead structures Then they modify these leads to explore the structure in detail to find the molecule with the best combination of EC50, bioavailability, selectivity, and drug stability This concept works well for binding sites on the surface or in relatively large cavities An example is the search for small molecule K channel blockers, for which the 37 K Channel Openers as New Anti-arrhythmic Agents 665 Fig 37.4 Structure and putative binding site in the central cavity of IKs (KCNQ1/KCNE1) channel inhibitors The binding sites of 293B and L7 have been shown experimentally preferential binding site is the large central cavity of K channels (Fig 37.4) Thus, in the conventional screen, lead structures and analogs binding to surface-accessible binding sites are preferentially identified Therefore, it is not surprising that agonists are often found randomly when working with compounds intended for distinct targets but not by systematic screens for channel activators For example, an IKs antagonist with a lead benzodiazepine scaffold was found to lengthen the QT interval by MSD Testing this compound discovered that it was a potent IKs blocker Screens for further IKs antagonists with the benzodiazepine scaffold were performed By accident the IKs agonist R-L3 was identified The classical screening methods of the last years used to identify channel blockers are possibly not well suited for the identification of activators Most commonly voltage-dependent fluorescence in cell-based assays is used to identify channel blockers These assays might identify blockers of K+ permeation relatively well However, it is questionable whether they are sensitive enough to identify the effects of agonists Thus, the classical fluorescence-based screening methods might not be very effective for the discovery of activators Alternative screening methods such as automated patch clamp or automated two electrode voltage clamp (TEVC) helped to overcome the insensitivity of fluorescence-based screens These electrophysiological methods used to be relatively slow [36], but very recent technical advances in automated patch clamp in 386-well format increased the throughput considerably The analysis of functional data and 3D-modeling of channel activator interactions could allow us to use computer-aided approaches to design putative K channel activators Such in silico approaches could be combined with the electrophysiological screening methods to aid the identification and development of K channel agonists 666 37.9 N Strutz-Seebohm and G Seebohm Conclusions Activators of K channels are promising candidates to restore channel function in acquired or inherited cardiac channelopathies However, 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Drug Discov Today 2001;6:1278–87 37 Grunnet M Repolarization of the cardiac action potential Does an increase in repolarization capacity constitute a new anti-arrhythmic principle? Acta Physiol (Oxf) 2010;198:1–48 Index A AAP10, 507, 512, 513, 517–519 Acetylcholine (ACh), 15, 16, 73, 95, 101, 127, 128, 165, 203, 220, 226, 431, 533, 599, 604, 605 Acidosis, 18, 358, 507, 512, 513, 517, 519, 547, 548, 552–554, 568, 570, 642 Aconitine, 512 Actin, 463 Action potential (AP), 3, 5–8, 10, 12, 14, 18, 22, 474– 477 AN cells, 215, 226 clamp technique, 434, 437, 442 diastolic depolarisation, 5, 16, 215 model, 435–437 morphology, 439 N cells, 215 NH cells, 215, 226 optical AP, 217 pacemaker potential, 5, 10, 33, 215 plateau, 5, 9, 12, 147, 161, 178, 274, 389, 392, 400, 416, 432, 434, 435, 455, 475, 546, 600, 616, 641 prolongation, 409 propagation, 440 Purkinje fibres, 211, 215–219, 221, 222, 224–227 repolarisation, see Repolarization resting potential, 5, 6, 11, 14, 18, 109, 176, 226, 569, 611 shape, 271, 276 shoretning, 435–437, 439 space–time plot, 440 upstroke velocity, 177, 181, 222, 226, 227, 511, 526 ventricular, 211, 215, 216, 219, 221, 222, 224–226 waveforms, 176–178, 180, 434, 442 Action potential-clamp, 105–107 Activation curve, 38, 53, 60–63, 65–67, 74 Adrenergic cascade, 50, 51 signaling, 50, 51 stimulation, 48, 50–55, 57 b-adrenergic receptor (b-AR), 94–95 b-adrenergic stimulation, 260–262, 339, 340, 342, 355, 357, 358 a2 adrenoceptor, 126, 128 b adrenoceptor, 126 Afterdepolarization, 358 Agonist binding site, 663 effects, 659 examples, 659 Akap10, 128 A-kinase anchoring proteins (AKAPs), 353 Aldosterone, 479 Alinidine, 69 Andersen syndrome, 14, 15 Angina, 70, 129, 339 Angiotensin-II, 508, 515 Anisotropy, 510–511, 514 AnkB, 128 ANK2 variant, 127 Ankyrin-B syndrome, 461–468 Ankyrin-G, 461, 462, 467–468 Ankyrin-R, 461 Ankyrins, 461–469 Antiarrhythmic, 8, 20, 22, 71, 144, 299, 319, 416, 512, 517, 533–535, 555, 602–606, 616, 617, 639, 641–649, 652 APD, 180–182 APD, QT and ERP prolongation, 639–653 shortening, 641, 644, 647, 648, 652 O.N Tripathi et al (eds.), Heart Rate and Rhythm, DOI 10.1007/978-3-642-17575-6, # Springer-Verlag Berlin Heidelberg 2011 669 670 Apoptosis, 368, 369, 375, 376 Aquaporins, 581–589 Arrhythmia, 9–12, 18, 61, 125–127, 139–146, 176, 183–185, 224, 245–247, 263, 270, 294–296, 307–319, 324, 325, 339–341, 344, 345, 356–359, 369–373, 388–403, 431–435, 451–456, 463–468, 477–481, 485–496, 511, 526–537, 544–556, 569–575, 601, 616, 646, 658–661 DAD, 18, 19, 181, 294–295, 309, 390–394, 549–556, 570, 601–605 EAD, 18, 181–186, 287, 294, 549, 552, 556, 600–602, 642 reentry, See Reentry Arrhythmogenesis, 9, 18, 21, 141, 181, 246, 288, 368, 438, 503–519, 527–529, 532, 533, 546, 548, 605 mechanisms, 432, 434, 438–439, 443 treatment, 432, 434 Arrhythmogenesis predilection sites, 245 arrhythmia substrates, 246 atrial arrhythmias, 245 embryonic AVC, 240, 242, 247 genetic labeling, 246 internodal tracts, 247 pulmonary vein myocardium, 245, 246 ATP, 504, 507, 513, 518 ATP-dependent potassium channel (KATP), 15, 21, 143, 146, 166, 203, 294, 328, 439, 526, 599, 659, 663 AT1-receptor, 515 Atrial fibrillation (AF), 11–16, 19–21, 183, 241–246, 358, 421, 432, 434, 456, 464, 467, 468, 485–496, 504, 514–515, 599–606 familial (FAF), 451, 456 Atrioventricular (AV) junction atrial myocardium, 213, 215 branching AV bundle, 214 bundle development, 242–243 central fibrous body (CFB), 213–215 compact atrioventricular (AV) node, 211, 213–216, 218–220, 226, 227 conduction axis, 212, 214–216, 218–221, 226, 227 coronary sinus (CS), 213, 214, 217 crista terminalis, 217 Eustachian valve, 213 fossa ovalis, 217 inferior nodal extensions (INE), 211, 213–215, 218–220, 226, 227 inferior vena cava, 217 Index node, 233 penetrating (AV)/ His bundle, 213–215, 226, 227 tendon of Todaro, 213, 217 Thebesian valves, 213 transitional cells/zone, 211, 213–215, 226, 227 triangle of Koch, 211–213 tricuspid valve, 212, 213, 217 ventricular myocardium, 211 Automated planar patch clamp (APC), 630–631 Automaticity, 231, 232, 234, 246, 368, 370 Autoregulation, 257–258 AVC myocardium, 231, 236, 240, 247 AVN development, 241 AV nodal re-entrant tachycardia (AVNRT) dual pathway, 215–216 fast-slow, 217 slow-fast, 216, 217 slow-slow, 217 AV node, 155, 156, 169, 233 B Bainbridge response, 134 B56 alpha, 463 b2a subunit, 353 Binding assays, 631, 632 Bio-pacemaker, 109, 111 Bmp2, 240, 241 Border zone, 283, 287, 296, 313, 315–317, 514, 527 Bradycardia, 68, 72–73 Bradykinin, 528 Brugada syndrome (BrS), 8, 14, 183, 387, 388, 401–403, 467–468 Bundle of His, 242–243 C Ca ATPase, 255, 260 Cable theory, 508, 509 Ca2+/calmodulin, 351, 352, 358, 359 Ca-calmodulin dependent protein kinase II, 260, 261 Ca channels, 8–10 activators, CCA, 9–10 blockers, CCB, 9–10 L-type, R-type, 10, 21 T-type, 10 Ca2+ clock, 83, 93 CACNA1C, 9, 400–403, 432, 437, 444, 481, 616 Index Ca2+ handling proteins, 337, 338, 345 NCX1, 220–221 RYR2, 220, 221 SERCA2A, 220 Calcineurin, 357 Calcium, 313–315, 319, 387–403 dynamics, 160, 164, 186–187 NCX, 159–161, 164 Calmodulin kinase II (CAMKII), 92–96, 351–359 cAMP, 60–63, 65, 72, 74, 84, 92, 95, 188 Carbenoxolone, 530, 533 Cardiac action potential, 158, 176–189, 355, 358, 455, 599, 620, 641, 651 Cardiac conduction system, 474 AV node, 211, 215, 221, 225 branching AV bundle, 214 development, 244–245 left bundle branch, 215, 221 penetrating (AV)/ His bundle, 211, 213–215, 226, 227 Purkinje fibres, 211, 215, 221, 225 right bundle branch, 222 sinus/sinoatrial (SA) node, 215 Cardiac cycle, 3, 4, 19, 22 Cardiac glycosides, 260, 262, 432 Cardiac hypertrophy, See Hypertrophy Cardiac ion channel, 3–21, 175–183, 285, 462, 463, 481, 628–636 Cardiac T-tubules, 256–257 Cardiac wave length, 639–641 Cardiomyocyte differentiation, 245 Cardiomyocytes, 323–326, 328–331 Cardiomyopathy, 12, 15, 19, 20 hypertrophic obstructive (HOCM), 516 PKC a, 504, 517 Ca release channels, 20 InsP3 receptor, 20, 21, 323, 326–330 Ryanodine receptor, 20–21, 324 Catecholaminergic polymorphic ventricular tachycardia (CPVT), 20, 21, 325, 331, 387–399, 549 Catecholamines, 50–56, 527–529, 533 Ca transient, 255, 257, 258, 260–263 Ca2+ transient, 46, 48, 53–55, 57 CaV1.2, 9, 20, 198, 201, 204, 205, 219, 225, 226, 354, 399, 437, 633 Cav1.3, 9, 10, 201, 219, 221, 467 CaV3.2, 10, 198, 201, 202, 205, 633 Caveolae, 5, 62, 65–66, 481, 547, 586, 589 Caveolin 3, 65–66, 481 CAVIN, 481 671 Cell cycle, 365, 368, 376 Cell signaling pathway, 187–189 Channel-blocking effects, 431 Channelopathies, 7, 22, 388, 403, 414, 432, 455, 473, 656, 658 CICR, 86, 93, 187 Cilobradine, 69, 71 Cl channels, 17, 18 C-linker, 62, 65 Clonidine, 69 Closed state, 415, 416 Closed-state inactivation, 416 Collateralization, 532 Commotio cordis (CC), 139–141, 143, 145 Conduction, 368–373 failure, 511 system cells, 234 velocity, 504, 506, 512 Conduction system cardiomyocytes cardiac neural crest, 237–238 cellular origin, 237–238 Purkinje network, 238 Congestive heart failure (CHF), 12, 20, 140, 323, 344, 345, 358, 548–551, 588 Connexin (Cx), 19, 20, 233, 287–288, 296, 368, 371, 372, 505–507, 513–517, 519 half-life time, 19, 507 Constant field approximation, 40 Contraction, 337, 338, 340 Control, defibrillation, 279–280 Coronary artery disease (CAD), 71 Coupled system, 96 Coupling, 103, 107, 108, 113–115 capacitive, 509, 510 ephaptic, 509–510 gap junction, 504, 510–512 Coupling-clamp, 107–109, 114 Current-clamp, 102–105, 107, 108, 111, 112 Current decay, 411, 412, 418, 421, 422 Cx37, 505, 508 Cx40, 19, 371, 505, 507, 508, 510, 514–517 Cx40, 233, 234, 237, 238, 240, 242–244, 247 Cx43, 19, 233, 288, 371, 372, 503–506, 508, 510, 512–517, 532–533 phosphorylation, 531–533 Cx45, 19, 233, 371, 505, 507, 513, 516, 517 Cyclic nucleotide binding domain (CNBD), 16, 62, 72–73 Cyclopiazonic acid (CPA), 88, 90, 91, 93 672 Index D Delayed afterdepolarization (DAD), 18, 19, 37, 181, 295, 308, 390–394, 400, 549–552, 570, 601, 605 Delayed rectifier current, 634 K+ current, 202, 372, 373 Delayed repolarization, 627, 634, 635 Development, 230–247 Diastolic depolarization (DD), 5, 16, 34–38, 44, 45, 47, 49, 54, 55, 59, 61, 62, 68–70, 73, 84–87, 101, 105–107, 110–113, 115, 136, 138, 140, 200, 215, 232, 557 Diffusion, 270, 271, 274, 277, 278 Digitalis, 511, 513 Dilated cardiomyopathy (DCM), 183 Dispersion, 504, 512, 517, 518, 639, 641, 644 Disturbances of repolarization, 639, 643–645, 647 Drug potency, 617, 629, 630 Dynamic AP-clamp, 107, 108, 111, 112, 115 Dynamic-clamp, 101–115 Excitation-transcription coupling, 7, 21, 329–330 Exploratory safety pharmacology, 634 E Early afterdepolarization (EAD), 18, 181, 185, 186, 294, 372, 549, 552, 600, 604, 642 Early, first and second-generation model, 177 E-cadherin, 463, 468 Electrical cycle, 3, Electrical inhomogeneity, 532 Electrocardiogram (ECG), 3, 4, 19, 22, 72, 120, 134, 184–185, 217, 220, 235, 295, 388, 402, 416, 432, 435–437, 455, 464, 467, 474–475, 477, 589, 611–612, 627, 632, 639, 652, 656 Embryonic cardiomyocytes, 197–205, 234 Embryonic heart, 231, 233, 235, 237, 238, 242–244 Embryonic stem cell (ESC), 68, 69, 74 Em oscillations, 199, 200, 203 Entrainment, 83–92, 96 Epicardial border zone (EBZ), 313–316, 319, 320 Exchangers Na-Ca, 159, 161, 162 Na-k, 159 Excitation contraction coupling (ECC), 3, 8, 9, 20, 133, 146, 186, 187, 255, 256, 262, 264, 324–327, 351, 354 Excitation-metabolism coupling, 7, 327–328 G Gain-of-function, 413, 414, 417, 419–423 Gap junction (GJ), 233, 503–519, 525–538 remodelling, 515, 516 Gap junction channels, 5, 19–20, 114, 503–506 connexins, 19–20, see also Cx Gating, 410, 414–418, 420–423 Gene mutations, 431, 432, 438, 439, 443 Genetically modified mice, 473–481 Genetic mutation, 485 Genetic polymorphisms, 124, 126, 486 Genetics, 71, 231–247, 344, 374, 387–403, 414, 415, 431–443, 455, 473, 485–496, 550, 601, 655 GIRK1/GIRK4, 15, 127, 659 GJ uncoupling, 529, 531, 532, 534, 537 Glycoside-related arrhythmogenesis, 432 Goldman-Hodgkin-Katz (GHK) current equation, 40–41 G protein-coupled receptor (GPCR), 94–96 F Falipamil, 69 Fendiline, Fiber rotation, 277–279 Fibrillation atrial (AF), 11, 12, 14, 16, 19, 20, 72, 140, 183, 241, 245, 339, 358, 414, 421, 432–451, 456–464, 467, 485–496, 504, 514–515, 543, 599–606 ventricular (VF), 140, 215, 224, 270, 394, 464, 512, 519, 525, 532, 555, 557, 611, 616, 641 Fibroblast, 138, 141 Fibroblast growth factor (FGF), 514 Force-frequency relation, 258, 259, 262 Frontloading, 634 Funny current (If), 16, 38, 53, 59–74, 80, 87, 101–113, 158, 163-165, 168–170, 198, 200, 203–205, 225, 232, 293, 370, 552, 633 H HCN4, 16, 63–75, 103–107, 112, 113, 115, 200, 204, 218–219, 232, 238–240, 370, 481 HCN channels, 15, 16, 62–75, 109–111, 200, 222, 232, 293, 370 Index cyclic nucleotide binding domain (CNBD), 16, 62, 72, 73 ivabradine, 16, 68–71 HDAC5, 353, 357 Heart development, 72, 201, 236, 367, 372 disease, 182, 323, 355–359, 374, 399–401, 480, 514, 548, 588 Heart failure (HF), 10–12, 15, 16, 18, 21, 262–263, 355–358, 510, 512, 514–517, 519 AV node, 220, 221, 226, 227 Ca2+ handling proteins, 220–221 ion channels, 220, 221, 226 PR interval, 220, 221 Purkinje fibres, 220, 221, 226, 227 Heart rate (HR), 4, 16, 19, 56, 61, 69, 71, 127, 133–147, 232, 262, 299, 355, 398, 432, 443, 474–476, 549, 589–590, 601, 643 Heart rate variability (HRV), 119–129 hERG, 12, 66, 204, 373, 433–444, 476, 606, 611–621, 627–635, 644–645, 650–651, 656, 667 activator, 629 blocker, 629 current, 434, 441 Hodgkin-Huxley, 158, 177, 270, 272, 273 Holt-Oram syndrome, 241 HRV effect of ambient temperature, 123 circadian autonomic rhythm, 124 physical training, 124 postprandial hypotension, 123 posture, 123, 124 frequency domain methods, 121 frequency domain parameters, 122, 124 nonlinear methods, 120, 121 nonlinear parameters (Poincare’ plot), 123 parameters, 122, 127 time domain methods, 119, 120 time domain parameters, 122, 124 Human embryonic stem cells, 374 Human ESc-derived cardiomyocytes, 204 Hyperpolarization-activated Cyclic Nucleotide-gated (HCN), See HCN channels Hypertrophy, 10, 11, 14, 17, 18, 21, 61, 136, 263, 284–300, 323, 325–330, 341, 343, 357–358, 368, 369, 480, 495, 510, 515–516, 546–547, 550, 565, 587–588 673 I ICaL, 9, 10, 34, 37, 45–46, 52, 86–88, 101, 109, 163–165, 185, 198, 200–201, 203–205, 219, 225, 256–263, 272, 290, 307–309, 313, 375, 400, 433, 452, 633 ICaT, 10, 38, 46, 163–168, 190, 198, 201–202, 204, 205, 218, 225, 290, 295, 299, 308, 633 ICH S7A, 634 ICH S7B, 633 If, See Funny current IFM motif, 410, 415 Ignition, 86, 87 IK components, 159, 161, 163–166, 169 sinus, 158, 159, 170 IKACh/IK,ACh, 15, 95, 101, 127, 128, 164–166, 203, 220, 225, 599–605 Inactivation gate, 410, 415, 416, 418, 422 INCX, 198, 202, 205 Induced pluripotent stem cells, 374 Inhibitor, 657, 658, 665 Inhomogeneities conduction, 275–277 ionic, 275–277 Inositol 1,4,5 trisphosphate (InsP3/IP3) receptor, 20, 21, 312, 316, 324, 326–327, 329–330, 462–463, 466, 467 Instability, 639, 641, 642, 644–646, 651 Intercalated disc, 8, 19, 353, 462, 467, 468 Intracellular Ca2+ handling, 323–331 Inward rectifier K+ current, IK1, 14–15, 41, 111, 158, 181, 220, 272, 353, 355, 368, 436, 488, 599, 602 Ion channels, 5–22, 36, 40, 67, 84, 105, 144, 166, 177, 181–183, 186, 189, 205, 218, 220–221, 226, 232, 263, 270, 285, 307, 316, 325, 331, 357, 370, 387, 430, 438, 455, 462, 464, 475–476, 480–481, 485, 487, 488, 492, 543, 571, 589, 599–606, 628–636, 655–660 density heterogeneity, 182 gene mutations, 431, 438 ICaL, See ICaL ICaT, See ICaT If, See Funny current INa, 7–8, 158, 176, 184, 204, 219, 225, 258, 287, 288, 290–292, 410–412, 468, 549, 552, 604, 650 KATP, See ATP-dependent K channel (KATP) 674 Ion channels (cont.) Kv, 10–12, 74, 176, 218–221, 292–293, 476, 564, 613, 618 mislocation, 480–481 mutation, 487, 490 Ion channels/Ionic currents Cav1.2 , Cav1.3 (ICaL), 9–10, 218, 219, 221, 225 Cav3.1, Cav3.2, Cav3.3 (ICaT), 10, 219 ERG (IKr), 12, 218, 220, 221, 225, 226 HCN1, HCN2, HNC4 (If), 16, 219 Kir2.1 (IK1), 14, 41, 111, 218, 220, 225, 226 Kir3.1, Kir3.4 (IKACh), 15, 203, 220, 601 Kv1.5 (IKur), 11, 218, 220, 221, 225, 226, 292, 480, 488, 602 Kv1.4, Kv4.2, Kv4.3 (Ito), 11–12, 104, 218, 219, 225 KvLQT (IKs), 12, 204, 218, 220, 225, 226, 287, 435, 455 Nav1.1, Nav1.5 (INa), 7–8, 218, 225, 355, 409–422, 462, 467–468, 589 Ischemia, 507, 511–515, 517–519, 525–538 acute, 511–513, 518 chronic, 512–514 Ischemia-reperfusion, 15, 20–21, 328, 339, 340, 343, 344, 517, 552–555 Ischemic heart disease (IHD), 69, 323, 343, 552–555 Ischemic preconditioning, 344, 529, 531 Isoprenaline (ISO), 50–52, 55, 56, 256–263 Ivabradine, 16, 68–71 K K (potassium) channels, 10–15, 143, 294, 455, 488, 657 Ca-activated (KCa), 10, 12–13, 21, 495, 606 inwardly rectifying (Kir), 10, 14–15, 176, 203–205, 218, 221, 225–226, 351, 368, 436–438, 488, 569, 583, 586, 601, 602, 613, 633, 656, 663 Kv channels, See under Ion channels Na-activated (KNa), 10, 12–13 two pore (K2P), 13–14, 19, 605 KCNE1, 452–456, 476–477, 480 KCNE2, 480 See also MiRP1 KCNH2, 464 KCNQ1, 12, 51, 188, 414, 422, 435–436, 452–457, 464, 476, 478, 480, 487–489, 616, 656, 661, 663 KCR1, 65–67 Knockout conditional, 72 inducible, 72 Index DKPQ, 183–185 KV1.5, 11, 476, 478, 480 KV4.2, 12, 476, 480 L Late diastolic Ca2+ elevation (LDCAE), 85, 86, 88, 92, 95 Lateralization, 510, 514–516 Lead potential (VL), 33–57 Leptin receptor, 128 Lipid rafts, 65 Local Ca2+ releases (LCR), 85–88, 91–95 Long QT syndrome (LQT), 4, 8, 9, 12, 14, 183, 186, 188, 315, 355, 388, 399, 409–423, 434–435, 455, 464, 465, 656–658, 619–621, 661–662 variant, 452 Looping, heart tube, 235–241 L-type Ca channels (LTCC), 9, 30, 86, 91, 92, 127, 165, 185–188, 200–201, 255–257, 261–263, 285, 307, 329, 337–340, 345, 353–354, 358, 399–400, 437, 544, 570, 601, 616, 633, 663 L-type Ca current (ICaL/ICa,L), 9, 34, 52–54, 86–87, 109, 163, 165–166, 176, 200–201, 207, 218, 224–225, 256, 263, 289–290, 307–308, 313, 370, 375, 400, 433, 451, 601, 633 Luo–Rudy models, 180–181 Luo-Rudy phase I, LRI, 271, 273, 274, 277, 279–281 M Magnesium, 298 Manual patch clamp (MPC), 628–631 MAP kinase, 341, 343 Mathematical modelling, 211, 226–227 Mechano-electric feedback (MEF), 17, 133–147 MEF2-dependent gene transcription, 357 Membrane clock (M clock), 83, 94 Mesenchymal stem cell (MSC), 74 Microdomains, 62, 65, 67 MicroRNA, 365–377 miR–1, 367–368, 371–373, 375–377 miR–133, 367–370, 372, 373, 376 miR–499, 376–377 MiRP1, 65–67 Mitochondria, 323, 324, 326–328, 331 Mitochondrial channels, 7, 18, 21, 22 Mode gating, 358 Model AV node, 155, 156, 169 Index cardiac rhythm, 155, 170 experiment, 155, 158, 161, 162, 164–166, 168, 170 historical development, 156 NCX, 159–161, 164 relaxation oscillator, 155, 158 Model-clamp, 107–111, 114 M2R, 15, 94, 95 Multichannel block, 635 Murine ESc-derived cardiomyocytes, 203–204 Mutant ion channel, 183 Mutation, 485–490, 492, 494–496 missense, 72, 73 point, 73 Myocardial infarction (MI), 11, 18, 119, 125, 126, 314–317 Myocardial ischemia and infraction, 355, 357, 358 N Na-Ca exchange (NCX), 86–89, 93, 159–161, 164, 255–258, 260–263, 432 Na+/Ca2+ exchanger, 337–340, 354, 462, 463, 466, 467 Na channels, 7–8, 135, 176, 182, 409–423, 462, 468, 487–489, 508, 604, 642, 657 Na+-H+ exchanger (NHE), 337, 338, 342–343 Na+/K +-ATPase, 159, 337, 338, 340, 341, 343–345, 462, 463, 466, 467 Nav1.5, 8, 219, 225, 353, 355, 358, 409–423, 467–468, 589, 634 N-cadherin, 468 NCX1, 198, 202, 205 Nernst equation, 35 Network, 156, 163 Nifedipine, 9, 570 Nitric oxide, 528, 533 N588K amino-acid mutation, 433, 434, 438, 439, 441 hERG mutation, 434, 435, 438–442 Nkx2–5 NMDA receptor, NR2B subunit, 354 Nonequilibrium gating, 186 Non-ion channel, 485, 487, 488, 490 Non-uniformity, 510–511 Nuclear ion channels, 21, 331 Nucleus, 323, 324, 329–331 Numerical modeling, 83, 86, 96 O Obscurin, 462, 463 Occlusion, coronary artery, 307, 525–537 675 Ohm’s law, 40 Open-state inactivation, 418, 420, 423 Oscillations, calcium, 158, 159 P Pacemaker biological, 73–74 cells, 3, 6, 17, 33, 48, 50, 87, 114, 134–136, 165, 176, 202, 232–234, 369, 546, 573 electronic, 73 gene program, 240 myocardium, 234, 246, 247 potential, 5, 9, 33, 158, 215, 238, 246 system cells, 234 Pacemaker activity, 7, 16, 19, 20, 33–56, 67–71, 101–115, 159–166, 197–205, 219, 221, 227, 375, 552, 573 adrenergic, 165 cholinergic effects, 165 PDE, 92, 94, 95 Peptide, antiarrhythmic, 507, 512, 517–519 Peripheral ventricular conduction system, 236, 243 development, 243–244 endothelin, 244 neuregulin signaling, 244 Purkinje network, 243 signaling, 244 trabecular myocardium, 243–244 Persistent current, 413, 417–421, 423 Phase 1A arrhythmias, 525–528 Phase 1B arrhythmias, 527–534, 536, 537 Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), 65 Phospholamban (PLB), 255, 261, 262, 353–355 Phosphorylation, 84, 91–96, 261, 262 Pitx2c, 239, 240 PKC, 504, 507, 508, 517 Plasma membrane Ca2+ ATPase, 341 Pluripotent stem cell derived cardiomyocytes, 375 Polymorphisms, 486, 491–493 Population patch clamp (PPC), 630 Positive chronotropy, 50–56 PR interval, 3, 4, 217, 219–221, 373, 474, 495, 633 Precordial thump (PT), 144–146 Primary ventricular cardiomyocytes, 475 Primitive myocardium, 234, 244, 247 Proarrhythmia, 639–653 676 Progressive cardiac conduction defect (PCCD), 183 Propagation, 3, 73, 182, 232–235, 242, 274, 278, 287, 353, 371, 375, 409, 474–477, 503–519, 528, 550 SA to AV nodes, 169–170 Protein kinase, 260–261 Protein kinase A (PKA), 50–53, 55, 57, 91–96, 339 Protein kinase C (PKC), 340 Protein phosphatase 2A (PP2A), 358, 462, 463 Purkinje, 155, 156, 158, 161, 168, 169 human, 156, 168 Markov, 168 ventricle junction, canine, 169 Purkinje cells, 176, 244, 287, 306–312, 320, 392, 570, 613 Purkinje fibres, 3, 6, 8, 10–12, 14, 16–18, 20–21, 60, 69, 109, 140, 155, 168, 178–211, 221–227, 232, 238, 242, 287, 327, 370, 373, 439, 451–452, 474, 503, 549, 556, 589 Cx40, 222, 224 left bundle branch, 215, 221, 222 network, 234, 238, 307, 393 right bundle branch, 222 terminal, 211, 213, 221 Q QRS, 3, 184, 217, 235, 373, 397, 475, 633, 646 QT interval, 4, 186, 294, 396, 399, 403, 410, 416, 421, 431–443, 455, 464–465, 474, 611, 616, 633, 639, 646, 656–658, 663 QT variability (QTV), 125–127 R Reactive oxygen species, 358, 359 Receptors b-adrenergic (b-AR), 61, 73 muscarinic, 61, 65 Reduced Priebe-Beuckelmann (RBP) model, 271, 277 Reentry (re-entry), 143, 216, 270, 288, 403, 488, 526–528, 543, 641–643, 646 Relative contribution (rc), 43, 45 Remodeling, 357, 358 Respiratory sinus arrhythmia (RSA), 119, 134, 135, 138 Reverse use dependence, 643, 644, 646 R1135H mutation, 435 Rotigaptide, 507, 513, 517, 530, 533 Index R-type Ca channels, 10, 21 Rubidium flux, 632 Ryanodine, 20, 88–91, 95, 306, 328 Ryanodine receptors (RyRs), 20, 21, 46, 84–86, 88, 90, 92–95, 186–188, 220, 255, 257, 261–263, 305–307, 312, 324–325, 353–355, 357, 370, 388, 389, 391–394, 399, 544, 546, 551–554 S Safety factor, 511 Safety index, 648–649 SAP97, 65–67 Sarcolemma (SL), 5, 7, 8, 13–16, 18–22, 337–345 Sarcoplasmic reticulum (SR), 5, 7, 20–22, 46, 48, 51, 55, 255, 257, 258, 260–263, 323–331, 337–340, 345 Ca2+ ATPase, 337 InsP3/IP3 receptor, 20, 21, 316, 323–324, 326–327, 462–463, 466, 467 Ryanodine receptor, See Ryanodine receptor (RyRs) SCN5A, 8, 176, 183, 204, 355, 402, 409, 414–417, 420, 421, 464, 468, 478, 481, 488–489, 495, 616, 656, 657 SERCA, 84, 86, 91–93, 323–327, 330, 331 See SR Ca ATPase Short QT syndrome (SQTS), 12, 451, 456 long, 431, 432, 434, 435, 443 shortened interval, 431, 432, 435, 437, 439, 443 treatment, 439–442 Shox2, 240 Sick sinus syndrome (SSS), 8, 16, 95, 183, 414, 465, 468, 496 Signaling calcineurin, 299–300 JAK-STAT, 300 MAP kinases, 286 PKC isoforms, 287 Ras, 300 Simulations, 46, 88–91, 93–95, 107, 112, 170, 175–189, 216, 273–280, 314, 439, 457, 510 Sinoatrial node (SAN), 3, 6–12, 15–17, 19, 20, 57, 59, 64, 83, 104, 109–115, 127, 134–139, 146, 155, 159, 163–166, 168, 176, 232–234, 240, 354, 355, 465–467, 474, 494 Index cell (SANC), 33–36, 38, 42, 46, 48, 50, 55, 57, 83–96 central, 19, 69, 159, 165, 167, 168 contraction model, 51, 166 development, 232, 240 formation, 239, 240 heterogeneity, 165, 168, 169 If, See Funny Current IK, 159, 163–166 Ikr, 165–170 Ist, 165, 166, 168, 170 Isus, 165–169 model, 33, 38, 45, 50, 51 pacemaker activity, 16, 19–21, 35–56, 67–69, 71, 101–115, 159, 238–239, 552 peripheral, 19, 159, 165, 167, 168 potential, 33, 34, 36, 38 primordium, 239, 240 rhythm, 20, 70, 170, 216, 222, 600, 602, 604–605, 611, 646 Sinus node, 232–233, 236–240 node development, 238–240 pauses, 72, 616 venosus, 67, 85, 235, 238–240, 244, 246 Sinus node dysfunction (SND), 72, 128, 465, 467 Sodium channel (Na+ channel/NaV), 7–8, 157, 183, 218–219, 225, 353–355, 409–423, 462, 468, 487–490, 580, 633, 642, 651 Source-sink-problem, 511 Spectrin, 463 SQT1 and KCNH2, 433–435 SQT3 and KCNJ2, 436–438 SQT2 and KCNQ1, 435–436, 438, 442 SQT4 and SQT5, 437–438 SQTS, treatment, 439–442 SR Ca ATPase, 255, 256, 261–263 SR Ca2+ATPase (SERCA2a), 353, 354 SR Ca2+ release channels, 323–325 Sterol regulatory element binding protein–1 (SREBP–1), 127 Store operated Ca2+ channel (SOCC), 17, 337, 338, 340–341, 344, 345 Stretch-activated channels (SAC), 18–19, 133, 136–147, 569 cation non-selective (SACNS), 136–138, 142, 143, 146 potassium-selective (SACK), 142, 143 Strophanthidin, 260 677 Structure agonist, 660, 664 Structure inhibitor, 658, 665 Subsarcolemmal cisterna, 46 space, 46 Sudden cardiac death (SCD), 12, 465 Sympathovagal drive, 120 Synchronization, 102, 103, 107, 109, 113–115 Syncope, 72, 183, 339, 388, 395–398, 402, 432, 435, 455, 465, 656, 657 T Tail current, 103, 202, 439, 454, 615, 629 Tbx2, 240–244 Tbx3, 68, 237, 239–244, 246, 247 knock-out embryos, 243 Tbx5, 241–243 Tbx18/Tbx18+, 68, 238–240 Tbx20, 241 TdP, See Torsades de pointes Thallium flux assay, 632 Three-dimensional (3D) slab, 269, 277 Timothy syndrome, 9, 388, 399–401, 403 TNNP, 271–281 Torsades de pointes (TdP), 12, 400, 416, 431, 455, 616, 619, 639, 640, 642, 644–647, 652 Transcriptional regulation, 238–245 Transcriptional repressors, 244, 245, 247 Transient outward K+ current (Ito), 11–12, 163–170, 176, 202, 204, 219, 225, 272, 287–288, 319, 355, 373, 377, 476, 480, 552, 599, 602, 611–612, 633, 658, 662 Ito,fast/Ito,f, 12, 292, 355, 476, 480 Transverse (t-) tubules, 8, 9, 12, 18, 20, 46, 234, 255–264, 305, 316, 353, 375, 389, 462, 467, 589 TRIaD, 639, 643–653 Triangulation, 635, 639, 642–645, 651 Triggered activity, 181, 183 TRP channels, 17, 19, 86, 340, 564–575, 605–606 store operated Ca channel (SOCC), 17 T-tubule membranes, 467 T-wave, 4, 18, 140, 143, 184, 432, 436–439, 464, 467, 474, 644 morphology, 432, 437, 439 over-sensing, 439 Two-dimensional (2D) sheet, 269, 274 Type long QT syndrome (type LQTS), 464 678 U Uncoupling, 526, 528, 529, 531, 532, 534, 536, 537 Upstroke, 5–9, 37, 86, 137, 164, 177, 181, 222, 226, 227, 287, 355, 409, 511, 527, 599, 651 V Veins, pulmonary, 515 Ventricular arrhythmias, 10, 12, 14, 19, 61, 126, 176, 224, 298, 307, 327, 357, 388, 397, 432, 433, 438, 439, 464, 465, 467, 468, 513, 525–538, 543–557, 611 Ventricular conduction system, 234–236, 242, 243 Ventricular fibrillation (VF), 18, 140–146, 215, 224, 270, 394, 397, 435, 443, 464, 512, 517, 525, 532, 555, 611, 616, 639–642, 644–648 Ventricular premature beats (VPB), 532, 536 Ventricular refractory period, 432, 434, 438 Ventricular repolarisation, 432–436, 438 Index Ventricular tachycardia (VT), 16, 20, 72, 127, 140, 144–146, 188, 270, 296–297, 325, 387–398, 431, 437, 439, 516, 549, 555, 640, 641, 644–647, 662 Verapamil, 9, 635 Voltage-clamp, 103–108, 111, 112 Voltage-Gated K+ (potassium/KV) channels, 10–12, 74, 176, 204, 218–219, 225, 292, 353, 373, 435, 476–477, 488, 564, 601, 613–618, 633, 656 Voltage-gated Na+ (NaV) channels, See Sodium channel W Wenckebach, 181 Window current, 38, 411–413, 420–422 Y Yotiao (AKAP9), 453, 455 Z Zatebradine, 68–70 ZD7288, 68, 71, 74 ZP123, 513 ... 0.8 1.0 1 .2 1.4 1.6 1.8 2. 0 736R333QHO.ECG mV 2. 0 5/4 /20 07 1:40:56 PM – 2. 0 0 .2 736R333QHO.ECG mV 2. 0 5/4 /20 07 1:40:58 PM – 2. 0 0 .2 736R333QHO.ECG 5/4 /20 07 1:41:00 PM mV 2. 0 – 2. 0 0 .2 736R333QHO.ECG... 736R333QHO.ECG mV 2. 0 5/4 /20 07 1:40:54 PM – 2. 0 0 .2 0.4 0.6 0.8 1.0 1 .2 1.4 1.6 1.8 2. 0 0.4 0.6 0.8 1.0 1 .2 1.4 1.6 1.8 2. 0 0.4 0.6 0.8 1.0 1 .2 1.4 1.6 1.8 2. 0 0.4 0.6 0.8 1.0 1 .2 1.4 1.6 1.8 2. 0 0.4 0.6... Tripathi et al (eds.), Heart Rate and Rhythm, DOI 10.1007/978-3-6 42- 17575-6 _22 , # Springer-Verlag Berlin Heidelberg 20 11 409 410 T Zimmer and K Benndorf Fig 22 .1 Structure and function of the cardiac

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  • Cover

  • Heart Rate and Rhythm

  • ISBN 9783642175749

  • Preface

  • Contents

    • Contributors

  • Part I: Normal Cardiac Rhythm and Pacemaker Activity

    • Chapter 1: Cardiac Ion Channels and Heart Rate and Rhythm

      • 1.1 Introduction

      • 1.2 Molecular Basis of Cardiac Electrical Activity

      • 1.3 Sarcolemmal Ion Channels

        • 1.3.1 Voltage-Gated Na Channels

        • 1.3.2 Voltage-Gated Ca Channels

        • 1.3.3 Voltage-Gated K Channels (KV)

        • 1.3.4 Ca- and Na-Activated K Channels (KCa/KNa)

        • 1.3.5 Leak K Channels (K2P/4 TM)

        • 1.3.6 Inwardly Rectifying K Channels (2 TM)

        • 1.3.7 Cyclic Nucleotide-Regulated Channels

        • 1.3.8 Transient Receptor Potential Channels

        • 1.3.9 Chloride Channels

        • 1.3.10 Stretch-Activated Channels

        • 1.3.11 Gap Junction Channels

      • 1.4 Sarcoplasmic Reticulum Membrane Ion Channels

        • 1.4.1 Ryanodine Receptor Channels

        • 1.4.2 SR Inositol Triphosphate Receptor Channels

      • 1.5 Mitochondrial and Nuclear Channels

      • 1.6 Conclusions

      • References

    • Chapter 2: Ionic Basis of the Pacemaker Activity of SA Node Revealed by the Lead Potential Analysis

      • 2.1 Introduction

      • 2.2 The Lead Potential (VL) Analysis

        • 2.2.1 The Primary Concept of VL

        • 2.2.2 Contribution of Each Ionic Current Estimated Using the Primary VL Analysis

      • 2.3 Sophistication of the VL Analysis

        • 2.3.1 Derivation of the Refined VL

        • 2.3.2 Estimation of Contributions of Each Ionic Component

        • 2.3.3 Contribution of Each Ionic Component to the Pacemaker Potential Quantified by the VL Analysis

      • 2.4 Variations in the Ionic Mechanisms Hypothesized by Different Mathematical Pacemaker Cell Models

        • 2.4.1 Contribution of INaCa Intensified by the Localized Ca2+ in Kurata Model

        • 2.4.2 Intracellular Ca2+ Clock in Maltsev and Lakatta Model

      • 2.5 Ionic Mechanisms Underlying the Positive Chronotropy Induced by Catecholamine Stimulation

        • 2.5.1 Revision of the Kyoto Model: From Sarai et al. Model to Himeno et al. Model

        • 2.5.2 Modeling the Catecholamine Effects on Individual Current Systems

          • 2.5.2.1 IKs; ISRU and IPMCA

          • 2.5.2.2 ICaL

          • 2.5.2.3 Ist

          • 2.5.2.4 Ih; Iha or If

          • 2.5.2.5 INaK

        • 2.5.3 Modification of Membrane Potential, Ionic Currents and Ca2+ Transient During the Catecholamine Stimulation

        • 2.5.4 Contribution of Each Ionic Component to the Pacemaker Depolarization During Catecholamine Stimulation

      • 2.6 Conclusions

      • References

    • Chapter 3: The ``Funny´´ Pacemaker Current

      • 3.1 Introduction: The Mechanism of Cardiac Pacemaking

        • 3.1.1 Historical Background and Basic Biophysical Properties of If

        • 3.1.2 Voltage Dependence of f-Channel Activation

        • 3.1.3 If-Mediated Autonomic Modulation of Cardiac Rate

      • 3.2 Molecular Structure of Pacemaker Channels

        • 3.2.1 HCN Composition of Native Pacemaker Channels

        • 3.2.2 Regulation of HCN Channels

          • 3.2.2.1 Src-Kinases

          • 3.2.2.2 Cholesterol and Membrane Phospholipids

          • 3.2.2.3 Protein-Protein Interactions

            • Caveolin 3

            • MiRP1

            • KCR1

            • SAP97

      • 3.3 Pacemaker Channels in Cardiac Development

        • 3.3.1 f/HCN Channels During Embryonic Cardiac Development

        • 3.3.2 f/HCN Channels in Embryonic Stem Cell Differentiation

      • 3.4 f-Channels Blockers

        • 3.4.1 Effects of Heart Rate Reducing Agents on HCN Isoforms

      • 3.5 Genetics of HCN Channels

        • 3.5.1 Transgenic Animal Models

        • 3.5.2 Pathologies Associated with HCN Dysfunctions

      • 3.6 Biological Pacemaker

        • 3.6.1 HCN-Gene Strategies

        • 3.6.2 Stem Cell-Based Biological Pacemakers

      • 3.7 Conclusions

      • References

    • Chapter 4: Novel Perspectives on Cardiac Pacemaker Regulation: Role of the Coupled Function of Sarcolemmal and Intracellular Pr

      • 4.1 Introduction

      • 4.2 Interactions and Entrainment of SL Electrogenic Function and [Ca2+]i Cycling During the SANC Spontaneous Cycle

        • 4.2.1 Interactions During Late Diastolic Depolarization

        • 4.2.2 Interactions During the AP

        • 4.2.3 Interactions During Early and Mid Diastolic Depolarization

      • 4.3 Importance of Entrainment of SL and SR Function in SANC Basal AP Firing

      • 4.4 Phosphorylation of Ca2+ Cycling and Membrane Proteins Is Required for Basal SAN Automaticity

      • 4.5 Coupled-Clock System Robustness: LCR Period Regulation by Ca2+, PKA, and CaMKII Signaling

      • 4.6 System Flexibility: Pacemaker Rate Modulation via G Protein-Coupled receptor (GPCR) Signaling

      • 4.7 Clinical Implications

      • 4.8 Conclusions

      • References

    • Chapter 5: Pacemaker Activity of the SA Node: Insights from Dynamic-Clamp Experiments

      • 5.1 Introduction

      • 5.2 Dynamic-Clamp Methodology

        • 5.2.1 Current-Clamp and Voltage-Clamp

        • 5.2.2 Action Potential-Clamp Technique

        • 5.2.3 Dynamic-Clamp

          • 5.2.3.1 Coupling-Clamp

          • 5.2.3.2 Model-Clamp

          • 5.2.3.3 Dynamic AP-Clamp

      • 5.3 Role of If in SAN Pacemaker Activity Studied with Dynamic-Clamp Methodology

      • 5.4 SAN Cell Synchronization Studied with Dynamic-Clamp Methodology

      • 5.5 Conclusion

      • References

    • Chapter 6: Heart Rate Variability: Molecular Mechanisms and Clinical Implications

      • 6.1 Introduction

      • 6.2 Heart Rate Variability as Indicator of Cardiac Autonomic Tone

      • 6.3 The Quantification of Autonomic Drive to Myocardium

      • 6.4 Physiologic Factors Influencing HRV

      • 6.5 HRV Alteration in Various Diseases

      • 6.6 The Relationship of HRV and QT Variability

      • 6.7 Molecular Basis of the Physiological and Pathophysiological Aspects of HRV

      • 6.8 Conclusions

      • References

    • Chapter 7: Mechano-Electric Feedback in the Heart: Effects on Heart Rate and Rhythm

      • 7.1 Introduction

      • 7.2 Mechanical Modulation of Heart Rate

        • 7.2.1 Background

        • 7.2.2 Clinical Observations

        • 7.2.3 Experimental Studies

        • 7.2.4 Underlying Mechanisms

        • 7.2.5 Summary

      • 7.3 Proarrhythmic Effects of Mechanical Stimulation

        • 7.3.1 Background

        • 7.3.2 Clinical Observations

        • 7.3.3 Experimental Studies

        • 7.3.4 Underlying Mechanisms

        • 7.3.5 Summary

      • 7.4 Antiarrhythmic Effects of Mechanical Stimulation

        • 7.4.1 Background

        • 7.4.2 Clinical Observations

        • 7.4.3 Experimental Studies

        • 7.4.4 Underlying Mechanisms

        • 7.4.5 Summary

      • 7.5 Conclusion

      • References

  • Part II: Modeling

    • Chapter 8: A Historical Perspective on the Development of Models of Rhythm in the Heart

      • 8.1 Introduction

      • 8.2 The Models and Their Key Features

        • 8.2.1 Noble [10, 11]

        • 8.2.2 McAllister-Noble-Tsien (MNT) [14]

        • 8.2.3 Yanagihara-Noma-Irisawa [16]

        • 8.2.4 Bristow-Clark [17]

        • 8.2.5 Noble-Noble [18]

          • 8.2.5.1 Multicellular (100 Cells)

        • 8.2.6 DiFrancesco-Noble (DFN) [22]

          • 8.2.6.1 Multicellular (100 Cells)

        • 8.2.7 Reiner-Antzelevitch [29]

          • 8.2.7.1 SA Node

        • 8.2.8 Noble et al. [30]

          • 8.2.8.1 SA Node

        • 8.2.9 Wilders [31]

          • 8.2.9.1 SA Node

        • 8.2.10 Winslow et al. [32]

        • 8.2.11 Demir et al. [2]

        • 8.2.12 Dokos et al. [3]

          • 8.2.12.1 Rabbit SA Node

        • 8.2.13 Endresen [4]

          • 8.2.13.1 SA Node

        • 8.2.14 Demir et al. [5]

          • 8.2.14.1 Rabbit SA Node

        • 8.2.15 Zhang et al. [6]

          • 8.2.15.1 SA Node

        • 8.2.16 Kurata et al. [35]

          • 8.2.16.1 Rabbit SA Node

        • 8.2.17 Sarai et al. [7, 36]

          • 8.2.17.1 SA Node and Ventricular Cell

        • 8.2.18 Garny et al. [8]

        • 8.2.19 Lovell et al. [9]

        • 8.2.20 Mangoni et al. [38]

          • 8.2.20.1 Mouse SA Node

        • 8.2.21 Stewart et al. [39]

        • 8.2.22 Aslanidi et al. [40]

        • 8.2.23 Inada et al. [41]

      • 8.3 Conclusions

      • References

    • Chapter 9: Simulation of Cardiac Action Potentials

      • 9.1 Introduction

      • 9.2 Brief Review of the Cardiac Action Potential Waveform

      • 9.3 First-Generation Models

      • 9.4 Second Generation Models

      • 9.5 The Noble Model of the Purkinje Fiber

      • 9.6 The Beeler Reuter Model of the Ventricular Myocardial Cell

      • 9.7 The Luo-Rudy Models of the Ventricular Myocyte

      • 9.8 Heterogeneity of Channel Expression: Cell-Type-Specific Modeling

      • 9.9 Simulation of Human Cardiac Action Potentials

      • 9.10 Mutations in the Cardiac Sodium Channel: The Use of Simulations to Elucidate Mechanism

      • 9.11 In Silico Cardiac Dynamics: From DNA to Electrocardiogram

      • 9.12 Modeling Calcium Dynamics and the Excitation Contraction (EC) Phenomenon

      • 9.13 Modeling Cell Signaling Pathways and Neurohumoral Regulation

      • 9.14 Conclusions

      • References

  • Part III: Cardiac Development and Anatomy

    • Chapter 10: Development of Pacemaker Activity in Embryonic and Embryonic Stem Cell-Derived Cardiomyocytes

      • 10.1 Introduction

      • 10.2 Development of Pacemaker Activity in Embryonic Cardiomyocytes

        • 10.2.1 Electrophysiological Activity at Early Developmental Stage

        • 10.2.2 Hyperpolarization-Activated and Cyclic Nucleotide-Gated (HCN) Channel Current (If)

        • 10.2.3 Long Lasting (L)-Type Ca2+ Channel Current (ICaL)

        • 10.2.4 T-Type Ca2+ Channel Current (ICaT)

        • 10.2.5 Sodium Calcium Exchanger Current (INCX)

        • 10.2.6 Delayed Rectifier K+ Current

        • 10.2.7 Other Pacemaker Currents

      • 10.3 Pacemaker Activity in Murine ESc-Derived Cardiomyocytes

      • 10.4 Pacemaker Activity in Human ESc-Derived Cardiomyocytes

      • 10.5 Conclusions

      • References

    • Chapter 11: Molecular Basis of the Electrical Activity of the Atrioventricular Junction and Purkinje Fibres

      • 11.1 Introduction

      • 11.2 Atrioventricular Node

        • 11.2.1 Anatomical Location

        • 11.2.2 Histology

        • 11.2.3 Function

          • 11.2.3.1 Dual Pathway Electrophysiology

          • 11.2.3.2 AV Nodal Reentrant Tachycardia

        • 11.2.4 Molecular Basis of Electrical Activity of the AV Node

          • 11.2.4.1 Pacemaker Channel

          • 11.2.4.2 Na+ Channel

          • 11.2.4.3 Ca2+ Channels

          • 11.2.4.4 K+ Channels

          • 11.2.4.5 Ca2+-Handling Proteins

          • 11.2.4.6 Changes in Ion Channels and Ca2+-Handling Proteins in the AV Conduction Axis of the Failing Heart

      • 11.3 The Purkinje Network

        • 11.3.1 Anatomy

        • 11.3.2 Functional Properties

        • 11.3.3 Molecular Basis of the Electrical Activity of the Purkinje Network

      • 11.4 Mathematical Modelling of AV Node

      • 11.5 Conclusions

      • References

    • Chapter 12: Molecular Basis and Genetic Aspects of the Development of the Cardiac Chambers and Conduction System: Relevance to Heart Rhythm

      • 12.1 Introduction

      • 12.2 The Cardiac Pacemaker and Conduction System

        • 12.2.1 The Sinus Node

        • 12.2.2 The Atrioventricular Node

        • 12.2.3 The Ventricular Conduction System

        • 12.2.4 General Characteristics of Pacemaker Cells and Conduction System Cells

      • 12.3 Development of the Heart

      • 12.4 Cellular Origin of Conduction System Cardiomyocytes

      • 12.5 Transcriptional Regulation of Pacemaker and Conduction System Development

        • 12.5.1 Development of the Sinus Node

        • 12.5.2 Development of the Atrioventricular Node

        • 12.5.3 Development of the Atrioventricular Bundle (Bundle of His)

        • 12.5.4 Development of the Peripheral Ventricular Conduction System

        • 12.5.5 Model for Cardiac Conduction System Development

      • 12.6 Predilection Sites of Arrhythmogenesis

      • 12.7 Conclusions

      • References

    • Chapter 13: Role of the T-Tubules in the Response of Cardiac Ventricular Myocytes to Inotropic Interventions

      • 13.1 Introduction

      • 13.2 Cardiac T-Tubules

      • 13.3 Autoregulation

      • 13.4 Stimulation Frequency

      • 13.5 Cardiac Glycosides

      • 13.6 beta-Adrenergic Stimulation

      • 13.7 Heart Failure

      • 13.8 Conclusions

      • References

  • Part IV: Mechanisms of Acquired Arrhythmia

    • Chapter 14: An Overview of Spiral- and Scroll-Wave Dynamics in Mathematical Models for Cardiac Tissue

      • 14.1 Introduction

      • 14.2 Experimental Background and Mathematical Models

        • 14.2.1 Mathematical Models of Cardiac Tissue

      • 14.3 Numerical Studies and Representative Results

        • 14.3.1 Single Cell

        • 14.3.2 Homogeneous Two-Dimensional Sheet of Cells

        • 14.3.3 Two-Dimensional Sheet of Cells with Inhomogeneities

        • 14.3.4 Homogeneous Three-Dimensional Slab of Tissue

      • 14.4 The Control of Spiral-Wave Turbulence

      • 14.5 Conclusions

      • References

    • Chapter 15: Post-infarction Remodeling and Arrhythmogenesis: Molecular, Ionic, and Electrophysiological Substrates

      • 15.1 Introduction

      • 15.2 Signal Transduction Pathways for Post-MI Remodeling

      • 15.3 Remodeling of the Peri-Infarction Border Zone

        • 15.3.1 Electrophysiological Changes

        • 15.3.2 Changes in Connexin Function in the Post-infarction Border Zone

      • 15.4 Remodeling of the Remote Noninfarcted Myocardium

        • 15.4.1 LTCC Current (ICaL)

        • 15.4.2 T-type Ca2+ Channel Current (ICaT)

        • 15.4.3 Na+ Channel Current (INa)

        • 15.4.4 Voltage-Gated Potassium Currents (Kv)

        • 15.4.5 Pacemaker (Funny) Current (If)

        • 15.4.6 ATP-Dependent Potassium (KATP) Channels

      • 15.5 Electrophysiological Mechanisms of Arrhythmia Generation in the Post-MI Remodeled Ventricular Myocardium

        • 15.5.1 EAD-Triggered Activity

        • 15.5.2 DAD-Triggered Activity

        • 15.5.3 Reentrant Excitation

      • 15.6 Pharmacological Agents That May Impact Arrhythmogenic Substrates of Post-MI Remodeling

        • 15.6.1 Drugs That Modify Post-MI Downregulated K+ Currents

        • 15.6.2 Magnesium

        • 15.6.3 Aldosterone-Receptor Antagonists

        • 15.6.4 Thyroid Hormone Analogs

        • 15.6.5 Calcium Channel Blockers

      • 15.7 Drugs That Modulate Post-MI Signaling Pathways

        • 15.7.1 The Calcineurin Pathway

        • 15.7.2 The JAK-STAT Pathway

        • 15.7.3 The Ras Pathway

      • 15.8 Conclusions

      • References

    • Chapter 16: The Role of Intracellular Ca2+ in Arrhythmias in the Postmyocardial Infarction Heart

      • 16.1 Introduction

        • 16.1.1 Excitation-Contraction Coupling

        • 16.1.2 ECC Coupling in Purkinje Cells from Normal Hearts

        • 16.1.3 Reversal of Excitation-Contraction Coupling

      • 16.2 Ca2+ Homeostasis in Subendocardial Purkinje Cells During the Subacute Healing Phase Postmyocardial Infarction

        • 16.2.1 Purkinje Cell Ca2+ Currents

        • 16.2.2 Intracellular Ca2+ Cycling

        • 16.2.3 Structural Remodeling in Purkinje Cells That Survive in the Infarcted Heart

      • 16.3 Ca2+ Homeostasis in Epicardial Border Zone Cells of Healing Phase Post-MI (4-5 Days)

        • 16.3.1 EBZ Ca2+ Currents

        • 16.3.2 Remodeling of Ankyrin-B-Associated Proteins Following Myocardial Infarction

        • 16.3.3 Intracellular Ca2+ Cycling

        • 16.3.4 Na-Ca Exchanger Currents

      • 16.4 Conclusions

      • References

    • Chapter 17: Molecular and Biochemical Characteristics of the Intracellular Ca2+ Handling Proteins in the Heart

      • 17.1 Introduction

      • 17.2 Excitation-Contraction Coupling

        • 17.2.1 SR Ca2+ Release Channels

        • 17.2.2 SR Ca2+-ATPase

        • 17.2.3 SR Inositol Trisphosphate Receptors

      • 17.3 Excitation-Metabolism Coupling

      • 17.4 Excitation-Transcription Coupling

      • 17.5 Conclusion

      • References

    • Chapter 18: Pharmacological Modulation and Clinical Implications of Sarcolemmal Ca2+-Handling Proteins in Heart Function

      • 18.1 Introduction

      • 18.2 Sarcolemmal L-type Ca2+ Channel

      • 18.3 Sarcolemmal Na+-Ca2+ Exchanger

      • 18.4 Sarcolemmal Store-Operated Ca2+ Channel

      • 18.5 Sarcolemmal Ca2+-Pump ATPase

      • 18.6 Sarcolemmal Na+-H+ Exchanger

      • 18.7 Sarcolemmal Na+-K+ ATPase

      • 18.8 Conclusions

      • References

    • Chapter 19: Calmodulin Kinase II Regulation of Heart Rhythm and Disease

      • 19.1 Introduction

      • 19.2 CaMKII Subcellular Localization

      • 19.3 CaMKII Regulation of Excitation-Contraction Coupling

      • 19.4 CaMKII Regulation of Cardiac Pacemaking and Conduction

      • 19.5 CaMKII Role in Disease and Arrhythmias

        • 19.5.1 Pathways for Increased Calmodulin Kinase Activation in Disease

      • 19.6 Conclusions

      • References

    • Chapter 20: MicroRNA and Pluripotent Stem Cell-Based Heart Therapies: The Electrophysiological Perspective

      • 20.1 Introduction

      • 20.2 MicroRNAs as Negative Transcriptional Regulators

      • 20.3 Role of miR in Heart Development

        • 20.3.1 MiR-1

        • 20.3.2 MiR-133

        • 20.3.3 Other miRs

      • 20.4 MiR and Arrhythmias

        • 20.4.1 Automaticity

        • 20.4.2 Excitation-Contraction Coupling

        • 20.4.3 Conduction and Gap Junctions

        • 20.4.4 Membrane Repolarization

          • 20.4.4.1 IKs

          • 20.4.4.2 IKr

          • 20.4.4.3 Ito

      • 20.5 MiR and Human Cardiovascular Biology

      • 20.6 Pluripotent hESCs and iPSCs as a Potential Source of CMs

        • 20.6.1 MiR Profile of hiPSC and hESC

        • 20.6.2 Pluripotent Stem Cell-Derived CMs

        • 20.6.3 miR-1 and miR-499 Play Differential Roles in Cardiac Differentiation of hESC

      • 20.7 Conclusions

      • References

  • Part V: Mechanisms of Inherited Arrhythmia

    • Chapter 21: Intracellular Calcium Handling and Inherited Arrhythmogenic Diseases

      • 21.1 Introduction

      • 21.2 Catecholaminergic Polymorphic Ventricular Tachycardia

        • 21.2.1 Calcium Handling and Arrhytmogenesis in CPVT

        • 21.2.2 Genetic Bases of CPVT

        • 21.2.3 Mechanisms of Arrhythmias in Autosomal Dominant CPVT

          • 21.2.3.1 RyR2 Mutations and CPVT

          • 21.2.3.2 RyR2-CPVT Mouse Models

        • 21.2.4 Mechanisms of Arrhythmias in Autosomal Recessive CPVT

          • 21.2.4.1 CASQ2 Mutations and CPVT

          • 21.2.4.2 CASQ2-CPVT Mouse Models

        • 21.2.5 Clinical Presentation and Diagnosis

        • 21.2.6 Current Therapy and Future Directions

          • 21.2.6.1 CPVT Therapy in the Clinical Setting

          • 21.2.6.2 Experimental Therapies for CPVT

      • 21.3 Timothy Syndrome

        • 21.3.1 L-Type Calcium Channel

        • 21.3.2 Genetic Basis of Timothy Syndrome

        • 21.3.3 Clinical Presentation and Diagnosis

      • 21.4 Brugada Syndrome

      • 21.5 Conclusions

      • References

    • Chapter 22: Molecular Mechanisms of Voltage-Gated Na+ Channel Dysfunction in LQT3 Syndrome

      • 22.1 Introduction

      • 22.2 Gating Mechanism

      • 22.3 LQT3 Mutations

      • 22.4 Persistent Na+ Current: A Characteristic Feature of Most LQT3 Mutant Channels

      • 22.5 Alternative Gain-of-Function Defects in Nav1.5 Mutant Channels

      • 22.6 Conclusions

      • References

    • Chapter 23: The Short QT Syndrome

      • 23.1 Introduction: The Genetic Short QT Syndrome as a Distinct Clinical Entity

      • 23.2 SQT1 and KCNH2

      • 23.3 SQT2 and KCNQ1

      • 23.4 SQT3 and KCNJ2

      • 23.5 SQT4 and SQT5

      • 23.6 Mechanisms of Arrhythmogenesis

      • 23.7 Treatment

      • 23.8 Conclusions

      • References

    • Chapter 24: Adrenergic Regulation and Heritable Arrhythmias: Key Roles of the Slowly Activating Heart IKs Potassium

      • 24.1 Introduction

      • 24.2 Early Studies

      • 24.3 Molecular Identity of the IKs Channel

      • 24.4 IKs and Heritable Arrhythmia

      • 24.5 Conclusions

      • References

    • Chapter 25: Defects in Ankyrin-Based Protein Targeting Pathways in Human Arrhythmia

      • 25.1 Introduction

      • 25.2 Ankyrin Dysfunction in Human Arrhythmia

        • 25.2.1 Ankyrin-B Dysfunction in Human Ventricular Arrhythmia

        • 25.2.2 Ankyrin-B Dysfunction in Human Sinus Node Disease

        • 25.2.3 Physiological and Cellular Roles of Ankyrin-B in the Ventricle

        • 25.2.4 Physiological and Cellular Roles of Ankyrin-B in the Sinus Node

        • 25.2.5 Ankyrin-G Dysfunction and Human Brugada Syndrome

      • 25.3 Conclusion

      • References

    • Chapter 26: Genetically Modified Mice: Useful Models to Study Cause and Effect of Cardiac Arrhythmias?

      • 26.1 Introduction

      • 26.2 Comparison of Human and Mouse Heart Rate

      • 26.3 Different Expression Patterns of Voltage-Gated K+ Channels in Human and Mouse Ventricular Myocytes

      • 26.4 What Is Wrong with My Mouse?

        • 26.4.1 Methodologies to Genetically Modified Mice

        • 26.4.2 Influence of Genetic Background on Phenotype

        • 26.4.3 Influence of Flanking Genes on Phenotypic Outcome

        • 26.4.4 Complications in Phenotypic Analysis

        • 26.4.5 Effects of Ion Channel Mislocation on Cardiac Phenotype

      • 26.5 Conclusions

      • References

    • Chapter 27: Genetics of Atrial Fibrillation

      • 27.1 Introduction

      • 27.2 Heritability of AF

      • 27.3 Monogenic Forms of AF

        • 27.3.1 Linkage Analysis

        • 27.3.2 Candidate Gene Studies

      • 27.4 AF in the General Population (Community-Based AF)

        • 27.4.1 Association Studies

        • 27.4.2 Candidate Gene Association Studies in AF

        • 27.4.3 Genome Wide Association Studies in AF

        • 27.4.4 PR Interval as Intermediate Phenotype for AF

      • 27.5 Conclusion and Future Perspectives

      • References

  • Part VI: Role of Specific Channels and Transporters in Arrhythmia

    • Chapter 28: The Role of Gap Junctions in Impulse Propagation in the Heart: New Aspects of Arrhythmogenesis and New Antiarrhythmic Agents Targeting Gap Junctions

      • 28.1 Introduction

      • 28.2 Structure, Function and Regulation of Cardiac Gap Junctions

      • 28.3 Propagation of the Cardiac Impulse

        • 28.3.1 Cable Theory

        • 28.3.2 Ephaptic Coupling

        • 28.3.3 Gap Junction Coupling

        • 28.3.4 Anisotropy and Non-uniformity (Inhomogeneity)

        • 28.3.5 Source-Sink Problem

      • 28.4 Role of Gap Junctions in Arrhythmogenesis

        • 28.4.1 Acute Ischemia

        • 28.4.2 Intoxications (Digitalis)

        • 28.4.3 Acidosis

        • 28.4.4 Chronic Infarction

        • 28.4.5 Atrial Fibrillation

      • 28.5 Heart Failure and Cardiac Hypertrophy

      • 28.6 Antiarrhythmic Peptides Targeting Gap Junctions

      • 28.7 Conclusions

      • References

    • Chapter 29: Possible Mechanisms of the Acute Ischemia-Induced Ventricular Arrhythmias: The Involvement of Gap Junctions

      • 29.1 Introduction

      • 29.2 Early Metabolic, Ionic, and Electrophysiological Alterations Occurring After Coronary Artery Occlusion and Their Role in t

      • 29.3 Mechanisms of Generation of Phase 1B Arrhythmias: Role of Gap Junctions

      • 29.4 Pharmacological Modification of Gap Junction Function and Arrhythmias

      • 29.5 Conclusions

      • References

    • Chapter 30: Role of NCX1 and NHE1 in Ventricular Arrhythmia

      • 30.1 Introduction: The Origin and Diversity of Cardiac Arrhythmias

      • 30.2 NCX1: A Major Regulator of [Ca2+]i Balance in Cardiac Cells

        • 30.2.1 The Significance of NCX1 in Maintaining Intracellular Ca2+ Balance

        • 30.2.2 Physiological Regulation of NCX1 Activity: [Ca2+]i, [Na+]i, and pHi Dependence

        • 30.2.3 The Contribution of NCX1 Currents to AP and the Iti

      • 30.3 NHE1: The Major Regulator of Hi+ (pHi) and Nai+ in Cardiomyocytes and an Important Promoter of Cardiac Hypertrophy

        • 30.3.1 The Essential Role of NHE1 in pHi and Nai+ Regulation and Cellular Growth

        • 30.3.2 Physiological Regulation of NHE1

      • 30.4 Role of Altered Exchanger Activities in Cardiac Arrhythmia and Heart Disease

        • 30.4.1 NCX1-Induced [Ca2+]i Overload and Its Role in Triggered Arrhythmia

        • 30.4.2 NHE1-Induced [Na+]i Overload, a Generator of Ischemia-Induced [Ca2+]i Overload, and Cardiac Hypertrophy

        • 30.4.3 NCX1 and Ventricular Arrhythmias in Congestive Heart Failure

        • 30.4.4 NHE1-NCX1 Interaction and Ventricular Arrhythmia Generation During Acute Ischemia-Reperfusion Injury and Chronic IHD

      • 30.5 Inhibition of the NCX1 and NHE1 as Possible Pharmacological Strategy in Ventricular Arrhythmias

        • 30.5.1 The Effects of Acute NCX1 Inhibition in Ventricular Arrhythmia Models

        • 30.5.2 The Effects of Acute NHE1 Inhibition in Ventricular Arrhythmia Models

      • 30.6 Conclusions

      • References

    • Chapter 31: TRP Channels in Cardiac Arrhythmia: Their Role During Purinergic Activation Induced by Ischemia

      • 31.1 Introduction

      • 31.2 General Properties of TRP Channels

        • 31.2.1 Canonical TRP, TRPC

      • 31.3 Vanilloid Channels, TRPV

      • 31.4 Melastatin Channels, TRPM

      • 31.5 Mucolipin Channels, TRPML

      • 31.6 Polycystin Channels, TRPP

      • 31.7 Ankyrin Channels, TRPA

      • 31.8 NO-Mechano-Potential Sensitive Channels, TRPN

      • 31.9 TRP Channels and Arrhythmia

        • 31.9.1 Mechanosensitive TRP Channels

          • 31.9.1.1 The Ca2+-Activated Nonselective Cation Channel, TRPM4

        • 31.9.2 Purinergic Receptor-Mediated Activation of TRPC Channels

      • 31.10 Conclusions

      • References

    • Chapter 32: Cardiac Aquaporins: Significance in Health and Disease

      • 32.1 Introduction

        • 32.1.1 Water and Non-water Transporting Roles

        • 32.1.2 Signalling and Regulation

        • 32.1.3 Protein Partners

        • 32.1.4 Involvement in Health and Disease

      • 32.2 Aquaporins in the Heart

        • 32.2.1 Physiological and Pathological Conditions

        • 32.2.2 Heart Rate and Rhythm

      • 32.3 Conclusion

      • References

  • Part VII: Drugs and Cardiac Arrhythmia

    • Chapter 33: Ion Channels as New Drug Targets in Atrial Fibrillation

      • 33.1 Introduction

      • 33.2 The Atrial Action Potential

      • 33.3 Electrophysiological Background of AF

      • 33.4 Electrical and Structural Remodelling in AF

      • 33.5 Current Drug Treatment of AF

      • 33.6 Novel Approaches

        • 33.6.1 Atrial-Selective Drugs

        • 33.6.2 Ion Channels with Unknown Potential as Drug Targets

        • 33.6.3 Other Mechanisms

      • 33.7 Conclusions

      • References

    • Chapter 34: hERG1 Channel Blockers and Cardiac Arrhythmia

      • 34.1 Introduction

      • 34.2 Molecular and Biophysical Properties of ERG1 Channels

      • 34.3 Physiological Roles of ERG Channels

      • 34.4 Drug-Induced QT Prolongation and Torsades de Pointes Arrhythmia

      • 34.5 Structural Basis for Sensitivity of hERG1 Channels to Block by Structurally Diverse Drugs

      • 34.6 Drug-Induced Alteration of hERG1 Trafficking

      • 34.7 hERG1 Channel Activators as Therapy for Long QT Syndrome?

      • 34.8 Conclusions

      • References

    • Chapter 35: Preclinical Drug Safety and Cardiac Ion Channel Screening

      • 35.1 Introduction

      • 35.2 In Vitro Cardiac Ion Channel Screening Techniques

        • 35.2.1 Electrophysiological Screens for Drug Effects on hERG/IKr Channels

          • 35.2.1.1 Traditional Approaches to Measuring Drug Effects on hERG

          • 35.2.1.2 Automated Planar Patch-Clamp Methods

        • 35.2.2 Non-electrophysiological Approaches for Determining hERG Channel-Drug Interactions

      • 35.3 Safety Screenings of Non-hERG Cardiac Ion Channel Currents

      • 35.4 Timing of Cardiac Ion Channel Screening in Drug Discovery: hERG and Non-hERG Channels

      • 35.5 Conclusion and Future Directions

      • References

    • Chapter 36: QT Prolongation Is a Poor Predictor of Proarrhythmia Liability: Beyond QT Prolongation!

      • 36.1 Introduction: QT Paradox

      • 36.2 Proarrhythmia

        • 36.2.1 Cardiac Wavelength

        • 36.2.2 Reentry

          • 36.2.2.1 Ectopics and Ventricular Tachycardia

          • 36.2.2.2 Ventricular Fibrillation

          • 36.2.2.3 Torsade de Pointes

        • 36.2.3 Disturbances of Depolarization

        • 36.2.4 Disturbances of Repolarization: TRIaD

          • 36.2.4.1 Reverse Use Dependence

          • 36.2.4.2 Instability

          • 36.2.4.3 Triangulation

          • 36.2.4.4 TRIaD

      • 36.3 VT, VF and TdP

        • 36.3.1 Two Proarrhythmic Axes

        • 36.3.2 QT Prolongation: A TdP Surrogate?

        • 36.3.3 TdP: Only the Tip of the Iceberg

      • 36.4 Cardiac Safety Evaluation

        • 36.4.1 Proarrhythmic Safety Index

        • 36.4.2 Overt Proarrhythmia (PSI 10)

        • 36.4.3 Absence of Proarrhythmia (PSI 100)

        • 36.4.4 Gray Zone (10 PSI 100)

      • 36.5 Preclinical Detection of Disturbances of lambda-TRIaD

        • 36.5.1 Cellular

        • 36.5.2 Isolated Cardiac Tissues

        • 36.5.3 Perfused Isolated Heart

        • 36.5.4 Animal

      • 36.6 Conclusions

      • References

    • Chapter 37: K Channel Openers as New Anti-arrhythmic Agents

      • 37.1 Introduction

      • 37.2 Acquired and Inherited Alterations of the ECG Morphology

      • 37.3 Pharmacological Inhibition of Cardiac Potassium Channels

      • 37.4 Impaired Channel Function Can Cause Cardiac Arrhythmia

      • 37.5 Activation of Potassium Channels

      • 37.6 In Vitro and In Vivo Effects of Potassium Channel Activators

      • 37.7 The Structural Basis of Channel Activation

      • 37.8 The Quest for Potassium Channel Activators

      • 37.9 Conclusions

      • References

  • Index

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