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Cardiac arrhythmias, characterized by single or multiple reentrant circuits, represent a dynamic phenomenon in an excitable medium. In this review, we provide a brief overview of how cardiac action potential duration restitution, conduction velocity restitution, and intracellular calcium cycling regulate the dynamics of action potential excitation and wave propagation in relation to the genesis and maintenance of cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

In 1924, the founders of the American Heart Association (AHA) envisioned an international society focused on the heart and aimed at facilitating research, disseminating information, increasing public awareness, and developing public health policy related to heart disease. This presidential advisory provides a comprehensive review of the past century of cardiovascular and stroke science, with a focus on the AHA's contributions, as well as informed speculation about the future of cardiovascular science into the next century of the organization's history. The AHA is a leader in fundamental, translational, clinical, and population science, and it promotes the concept of the "learning health system," in which a continuous cycle of evidence-based practice leads to practice-based evidence, permitting an iterative refinement in clinical evidence and care. This advisory presents the AHA's journey over the past century from instituting professional membership to establishing extraordinary research funding programs; translating evidence to practice through clinical practice guidelines; affecting systems of care through quality programs, certification, and implementation; leading important advocacy efforts at the federal, state and local levels; and building global coalitions around cardiovascular and stroke science and public health. Recognizing an exciting potential future for science and medicine, the advisory offers a vision for even greater impact for the AHA's second century in its continued mission to be a relentless force for longer, healthier lives.

Background: Few studies have examined outcomes of catheter ablation for atrial fibrillation (AF) in patients with heart failure (HF) with preserved ejection fraction (HFpEF)., Objective: The purpose of this study was to compare outcomes of AF ablation in patients with HFpEF vs HF with reduced ejection fraction (HFrEF)., Methods: We performed a retrospective study of 230 patients with HF who underwent AF ablation, including 97 (42.2%) with HFrEF and 133 (57.8%) with HFpEF. Outcomes included adverse events, symptoms (Mayo AF Symptom Inventory [MAFSI]), New York Heart Association (NYHA) functional class, and freedom from recurrent atrial arrhythmia at 12 months., Results: Overall, 150 of 230 patients had nonparoxysmal AF (62.8% HFpEF vs 63.0% HFrEF). Patients with HFpEF had a smaller mean left atrial diameter (4.4 ± 0.8 cm vs 4.7 ± 0.7 cm; P = .013) and were less likely to be taking a beta-blocker at baseline (72.9% vs 85.6%; P = .022). Median (Q1, Q3) procedure times (233 minutes [192, 290] vs 233.5 minutes [193.0, 297.5]; P = .780) and adverse events such as acute HF (3.8% vs 6.2%; P = .395) were similar between HFpEF and HFrEF patients. Freedom from recurrent atrial arrhythmia was not significantly different in HFpEF vs HFrEF patients (33.9% vs 32.6%; adjusted hazard ratio 1.47; 95% confidence interval 0.72-3.01), with similar improvements in NYHA functional class (-0.32 vs -0.19; P = .135) and MAFSI symptom severity (-0.23 vs -0.09; P = .116) after ablation., Conclusion: Catheter ablation of AF seems to have similar effectiveness in patients with HF, regardless of presence of systolic dysfunction. There were no significant differences in procedural characteristics, arrhythmia-free recurrence, or functional improvements between patients with HFpEF and those with HFrEF., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Antiarrhythmic medications for the treatment of atrial fibrillation (AF) have limited efficacy and rare but potentially life-threatening side effects. Ranolazine is an antianginal agent that may have antiarrhythmic activity in AF., Methods and Results: Using the Duke Enterprise Data Unified Content Explorer database, we analysed a cohort of AF patients on ranolazine. Patients served as their own historic control. Electrocardiograms (ECGs) were analysed before and after ranolazine initiation to determine the effect of ranolazine on dominant frequency (DF), f-wave amplitude, and organizational index (OI). We identified 15 patients with ECGs in AF before and after ranolazine. Ranolazine was associated with lower DF by an average of 10% (5.10 ± 0.74 vs. 5.79 ± 0.96 Hz, P = 0.04) but not with changes in OI (0.47 ± 0.11 vs. 0.50 ± 0.12, P = 0.71) or amplitude (0.47 ± 0.43 vs. 0.41 ± 0.40 mV, P = 0.82). Ranolazine was also associated with lower DF in patients (n = 10) not on concomitant antiarrhythmic therapy (5.25 ± 0.78 vs. 6.03 ± 0.79 Hz, P = 0.04)., Conclusion: Ranolazine is associated with lower AF DF but no change in OI or fibrillatory wave amplitude. Prospective trials are needed to evaluate ranolazine's potential as a novel antiarrhythmic drug for AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Cholecystokinin (CCK) is produced by discrete endocrine cells in the proximal small intestine and is released following the ingestion of food. CCK is the primary hormone responsible for gallbladder contraction and has potent effects on pancreatic secretion, gastric emptying, and satiety. In addition to fats, digested proteins and aromatic amino acids are major stimulants of CCK release. However, the cellular mechanism by which amino acids affect CCK secretion is unknown. The Ca(2+)-sensing receptor (CaSR) that was originally identified on parathyroid cells is not only sensitive to extracellular Ca(2+) but is activated by extracellular aromatic amino acids. It has been postulated that this receptor may be involved in gastrointestinal hormone secretion. Using transgenic mice expressing a CCK promoter driven/enhanced green fluorescent protein (GFP) transgene, we have been able to identify and purify viable intestinal CCK cells. Intestinal mucosal CCK cells were enriched >200-fold by fluorescence-activated cell sorting. These cells were then used for real-time PCR identification of CaSR. Immunohistochemical staining with an antibody specific for CaSR confirmed colocalization of CaSR to CCK cells. In isolated CCK cells loaded with a Ca(2+)-sensitive dye, the amino acids phenylalanine and tryptophan, but not nonaromatic amino acids, caused an increase in intracellular Ca(2+) ([Ca(2+)](i)). The increase in [Ca(2+)](i) was blocked by the CaSR inhibitor Calhex 231. Phenylalanine and tryptophan stimulated CCK release from intestinal CCK cells, and this stimulation was also blocked by CaSR inhibition. Electrophysiological recordings from isolated CCK-GFP cells revealed these cells to possess a predominant outwardly rectifying potassium current. Administration of phenylalanine inhibited basal K(+) channel activity and caused CCK cell depolarization, consistent with changes necessary for hormone secretion. These findings indicate that amino acids have a direct effect on CCK cells to stimulate CCK release by activating CaSR and suggest that CaSR is the physiological mechanism through which amino acids regulate CCK secretion.

Available evidence suggests that the ion channels that generate the normal action potential are also the basis for the arrhythmias that occur in disease states. Therefore, a thorough understanding of the function of the ion channels that generate the action potential is an important foundation for understanding the bases of arrhythmias and their treatment. This need is made all the more pressing by the discoveries in molecular genetics and membrane biophysics that have elucidated the fundamental mechanisms of a broad range of cardiac arrhythmias., (Copyright © 2010. Published by Elsevier Inc.)

Background: Medical errors have been increasingly identified as a major source of morbidity and mortality in both outpatient and acute care settings. Central to the evaluation of many medical problems, the 12-lead electrocardiogram (ECG) is susceptible to both technical and interpretative errors. Proper interpretation, however, is dependent on the quality and accuracy of the acquired ECG., Methods: We evaluated the impact of both a newly designed electrocardiograph and a newly developed automated computer algorithm on the incidence and detection of electrode cable reversals (lead reversals). The study tested the association of the incidence of electrode cable reversals and the design of the connection terminal. The study was performed during a 7-month period preceding (53,875 ECGs) and after (53,344 ECGs) the implementation of the new system. Electrode cable reversals occurring in various sites of the medical center were tabulated and compared. We then sought to determine if computer detection algorithms could increase point-of-care detection of electrode cable reversals and, thereby, offset the influence of cardiograph design changes. Two commercially available automated detection algorithms were compared for their abilities to identify electrode cable reversals in our study population., Results: During the 7-month postimplementation period, there was a significant increase in the incidence in electrode cable reversals (0.5% vs 0.1%, P < .001). The incidence of reversals for ECGs obtained in the emergency department was twice that of those obtained within the hospital (0.79% vs 0.38%, P < .01). Automated detection of electrode cable reversals from the 7-month study period increased from 38% to 71% (P < or = .0001), using a recently released automated algorithm supplied by the manufacturer., Conclusions: Electrode cable reversals are a prevalent source of medical errors that receives very little attention by the clinical community. The association of an increase in electrode cable reversals with an altered electrode cable connection terminal, coupled with an increased ability to detect electrode cable reversals using the manufacturer's recently developed algorithms, emphasizes the importance of ongoing research efforts to identify technical errors in electrocardiography.

The National Heart, Lung, and Blood Institute and Office of Rare Diseases at the National Institutes of Health organized a workshop (September 14 to 15, 2006, in Bethesda, Md) to advise on new research directions needed for improved identification and treatment of rare inherited arrhythmias. These included the following: (1) Na+ channelopathies; (2) arrhythmias due to K+ channel mutations; and (3) arrhythmias due to other inherited arrhythmogenic mechanisms. Another major goal was to provide recommendations to support, enable, or facilitate research to improve future diagnosis and management of inherited arrhythmias. Classifications of electric heart diseases have proved to be exceedingly complex and in many respects contradictory. A new contemporary and rigorous classification of arrhythmogenic cardiomyopathies is proposed. This consensus report provides an important framework and overview to this increasingly heterogeneous group of primary cardiac membrane channel diseases. Of particular note, the present classification scheme recognizes the rapid evolution of molecular biology and novel therapeutic approaches in cardiology, as well as the introduction of many recently described diseases, and is unique in that it incorporates ion channelopathies as a primary cardiomyopathy in consensus with a recent American Heart Association Scientific Statement.

Some mutations of the sodium channel gene Na(V1.5) are multifunctional, causing combinations of LQTS, Brugada syndrome and progressive cardiac conduction system disease (PCCD). The combination of Brugada syndrome and PCCD is uncommon, although they both result from a reduction in the sodium current. We hypothesize that slow conduction is sufficient to cause S-T segment elevation and undertook a combined experimental and theoretical study to determine whether conduction slowing alone can produce the Brugada phenotype. Deletion of lysine 1479 in one of two positively charged clusters in the III/IV inter-domain linker causes both syndromes. We have examined the functional effects of this mutation using heterologous expression of the wild-type and mutant sodium channel in HEK-293-EBNA cells. We show that DeltaK1479 shifts the potential of half-activation, V(1/2m), to more positive potentials (V(1/2m) = -36.8 +/- 0.8 and -24.5 +/- 1.3 mV for the wild-type and DeltaK1479 mutant respectively, n = 11, 10). The depolarizing shift increases the extent of depolarization required for activation. The potential of half-inactivation, V(1/2h), is also shifted to more positive potentials (V(1/2h) = -85 +/- 1.1 and -79.4 +/- 1.2 mV for wild-type and DeltaK1479 mutant respectively), increasing the fraction of channels available for activation. These shifts are quantitatively the same as a mutation that produces PCCD only, G514C. We incorporated experimentally derived parameters into a model of the cardiac action potential and its propagation in a one dimensional cable (simulating endo-, mid-myocardial and epicardial regions). The simulations show that action potential and ECG changes consistent with Brugada syndrome may result from conduction slowing alone; marked repolarization heterogeneity is not required. The findings also suggest how Brugada syndrome and PCCD which both result from loss of sodium channel function are sometimes present alone and at other times in combination.

Context: Peer review should evaluate the merit and quality of abstracts but may be biased by geographic location or institutional prestige. The effectiveness of blinded peer review at reducing bias is unknown., Objective: To evaluate the effect of blinded review on the association between abstract characteristics and likelihood of abstract acceptance at a national research meeting., Design and Setting: All abstracts submitted to the American Heart Association's annual Scientific Sessions research meeting from 2000-2004. Abstract review included the author's name and institution (open review) from 2000-2001, and this information was concealed (blinded review) from 2002-2004. Abstracts were categorized by country, primary language, institution prestige, author sex, and government and industry status., Main Outcome Measure: Likelihood of abstract acceptance during open and blinded review, by abstract characteristics., Results: The mean number of abstracts submitted each year for evaluation was 13,455 and 28.5% were accepted. During open review, 40.8% of US and 22.6% of non-US abstracts were accepted (relative risk [RR], 1.81; 95% confidence interval [CI], 1.75-1.88), whereas during blinded review, 33.4% of US and 23.7% of non-US abstracts were accepted (RR, 1.41; 95% CI, 1.37-1.45; P<.001 for comparison between peer review periods). Among non-US abstracts, during open review, 31.1% from English- speaking countries and 20.9% from non-English-speaking countries were accepted (RR, 1.49; 95% CI, 1.39-1.59), whereas during blinded review, 28.8% and 22.8% of abstracts were accepted, respectively (RR, 1.26; 95% CI, 1.19-1.34; P<.001). Among abstracts from US academic institutions, during open review, 51.3% from highly prestigious and 32.6% from nonprestigious institutions were accepted (RR, 1.57; 95% CI, 1.48-1.67), whereas during blinded review, 38.8% and 29.0% of abstracts were accepted, respectively (RR, 1.34; 95% CI, 1.26-1.41; P<.001)., Conclusions: This study provides evidence of bias in the open review of abstracts, favoring authors from the United States, English-speaking countries outside the United States, and prestigious academic institutions. Moreover, blinded review at least partially reduced reviewer bias.

Brugada syndrome is a primary arrhythmic syndrome arising in the structurally normal heart. Any proposed mechanism should account for the major features of the syndrome: localization of the ST segment and T-wave changes to the right precordial leads, association of conduction slowing at several levels, precipitation or aggravation of the major ECG changes by sodium channel-blocking drugs and the occurrence of ventricular fibrillation. Heterogeneity of repolarization across the ventricle wall plays a major role. Any agency that shifts the net current gradient during phase I outward would exaggerate the normal heterogeneity of repolarization and result in the ST segment and T-wave changes characteristic of the syndrome. When the outward current shift is marked, premature repolarization may occur in epicardial zone and the resulting gradient may precipitate reentry. The syndrome is inherited as an autosomal dominant. However, 75% of clinically affected individuals are males. In 20% of cases, the syndrome is associated with mutations of the cardiac sodium channel gene SCN5A. The mutations result in a loss-of-function as a result of the synthesis of a non-functional protein, altered protein trafficking, or change in gating. Agencies that reduce the sodium current may precipitate the characteristic ECG changes, for example, sodium channel blockers and membrane depolarization by hyperkalemia. Sympathetic stimulation may reverse the ECG changes and reduce arrhythmia recurrence. By its nonspecific potassium channel blocking action, quinidine may also reduce arrhythmia recurrence. We still do not know the basis for defect in the majority of patients with Brugada syndrome.

Voltage- and/or conformation-dependent association and dissociation of local anesthetic-class drugs from a putative receptor site in domain IV S6 of the sodium channel and slow conformation transitions of the drug-associated channel have been proposed as mechanisms of use- and frequency-dependent reduction in sodium current. To distinguish these possibilities, we have explored the reactivity to covalent modification by thiols and block of the mutations F1760C and F1760A at the putative receptor site of the cardiac sodium channel expressed as stable cell lines in HEK-293 cells. Both mutations decreased steady-state fast inactivation, shifting V1/2h from -86 +/- 1.3 mV (WT) to -72.3 +/- 1.4 mV (F1760C) and -67.7 +/- 1 mV (F1760A). In the absence of drug, the F1760C mutant channel displayed use-dependent current reduction during pulse-train stimulation, and faster onset of slow inactivation. This mutant also retained some sensitivity to lidocaine. In contrast, the F1760A mutant showed no use-dependent current reduction or sensitivity to lidocaine. The covalent-modifying agent MTS-ET enhanced use-dependent current reduction of the F1760C mutant channel only. The use-dependent reduction in current of the covalently modified channel completely recovered with rest. Lidocaine produced no additional block during exposure to MTS-ET-treated cells (MTS-ET 43 +/- 2.7%: MTS-ET lidocaine 47 +/- 4.5%), implying interaction at a common binding site. The data suggest that use-dependent binding at the F1760 site results in enhanced slow inactivation rather than alteration of drug association and dissociation from that site and may be a general mechanism of action of sodium-channel blocking agents.

Advances in endocardial mapping techniques and ablation have greatly increased the indications for catheter-ablation of supraventricular arrhythmias. Rate or rhythm control is a valid treatment option for patients with atrial fibrillation; however, all patients with one or more risk factors should be treated with oral anticoagulants. The early success rate and long-term cure of atrial fibrillation by radiofrequency catheter ablation continues to increase. The number of centers offering this treatment option has increased substantially. Implantable defibrillator-cardioverters are the primary treatment modality for patients with ventricular tachycardia and their role in primary prevention is also being defined. Future advances in arrhythmia management will include improvements in catheter design and energy sources for ablation, and greater monitoring capacity of implantable devices.

Objective: The fate of an impulse arising from stimulation is determined by the ability of the wave front to recruit sufficient Na channels from adjacent cells. Previous numerical studies of mutant Na channels revealed both the velocity of a conditioning wave and the recruiting capacity of the front as determinants of the vulnerable period (VP), an interval within which excitation results in unidirectional conduction. Drugs that block excitatory Na channels in a voltage dependent manner, such as antiarrhythmics, abused substances and antidepressants, slow the restoration of Na conductance trailing an action potential and are associated with proarrhythmia and sudden cardiac death. We hypothesized that drug-induced slowing of Na conductance recovery would flatten the Na conductance restoration gradient thereby reducing the recruiting capacity of a front, extending the VP and increasing the probability of unidirectional propagation., Methods: In a cable of ventricular cells, we explored the sensitivity of the VP to voltage-dependent blockade. While varying the unbinding time constant from 100 ms to 5 s, we measured the Na conductance restoration gradient, the liminal length, the refractory period (RP) and the VP., Results: Reducing the rate of drug unbinding flattened the restoration gradient, diminished the recruiting capacity of a premature impulse and extended the liminal length, RP and the VP. The VP was linearly dependent on the drug unbinding time constant. Rapidly unbinding drugs (time constant <1 s) reduced the liminal length below that of a quiescent cable., Conclusions: Slowing the unbinding rate of voltage-dependent drug block of Na channels extended the RP and the VP. Drugs with unbinding time constants greater than 1 s dramatically increased the probability of unidirectional propagation, reflecting increases in both the RP and the VP. This study provides a new mechanism linking Na channel function, compromised by voltage-dependent Na channel drug block, with proarrhythmic conditions that can lead to sudden cardiac death following premature stimulation.

Objective: The vulnerable period (VP) defines an interval during which premature impulses can trigger reentrant arrhythmias leading to ventricular fibrillation and sudden death. The mechanistic basis of the success or failure of impulse propagation during the VP remains unclear. Recent clinical reports of gene mutations, drugs and cardiac disease link a variety of often lethal conditions with loss of cardiac Na channel function (NaLOF) and reentrant proarrhythmia. We hypothesized that during the VP, the Na conductance at the stimulus site is graded and that NaLOF would favor reentry specifically by flattening this gradient, which would destabilize antegrade front formation., Methods: Using numerical studies of propagation in a one-dimensional cable of ventricular cells, we identified the boundaries of the VP using paired (s1-s2) stimulation. We explored VP alterations associated with different NaLOF scenarios including reduced channel density, accelerated rate of inactivation, and prolonged recovery from inactivation., Results: Following the passage of a wave over the s2 site, a gradient in the restoration of Na channel conductance was demonstrated to exist during the VP. The VP boundaries coincided with different thresholds for stable retrograde and antegrade impulse propagation. Reducing channel density, accelerating inactivation and slowing the recovery from inactivation flattened the restoration gradient and extended the VP. VP extension was directly proportional to the time constant of Na channel recovery., Conclusions: Mutations that accelerate inactivation, slow recovery from inactivation, or reduce Na channel density flatten the restoration gradient within the VP which prolongs the VP and increases the probability that a premature impulse will initiate reentry. These studies define a new mechanism that links alterations in Na channel function with conditions that enable premature excitation to generate proarrhythmia and sudden death.

The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na(+) channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted V(1/2)h( infinity ) to more negative membrane potentials and increased k(h) consistent with a reduction of inactivation valence of 1. The shift in h( infinity ) was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). V(1/2)m was shifted to more positive potentials, and k(m) was doubled in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (change in charge, -1 and -2, respectively). For both mutations, V(1/2)h was shifted back toward control; however, V(1/2)m shifted progressively to more positive potentials. The late component of Na(+) current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.

The sodium channel is an integral membrane protein that plays a central role in conduction of the cardiac impulse in working cardiac myocytes and cells of the His-Purkinje system. The channel has two fundamental properties, ion conduction and gating. Specific domains of the channel protein control each of these functions. Ion conduction describes the mechanisms of the selective movement of sodium ion across the pore in the cell membrane. The selectivity of the channel for sodium ions is at least 10 times greater than that for other monovalent cations; the channel does not normally conduct divalent cations. Gating describes the opening and closing of the sodium channel pore. Sodium channels open transiently during membrane depolarization and close by a process termed inactivation. The cardiac sodium channel protein is a multimeric complex consisting of an alpha and an auxiliary beta-subunit. The genes encoding the sodium channel have been cloned and sequenced. The alpha subunit gene, SCN5A is sufficient to express a functional channel. However, beta subunit co-expression increases the level of channel expression and alters the voltage dependence of inactivation. Mutations of the sodium channel may result in incomplete inactivation during maintained depolarization, a decrease in the level of channel expression or acceleration of inactivation. The resulting clinical phenotypes include long QT syndrome, type III (LQT III), Brugada syndrome, and heart block. LQT III and Brugada syndromes have a high case fatality rate and are best treated with an implantable defibrillator.

The role of inactivation as a central mechanism in blockade of the cardiac Na(+) channel by antiarrhythmic drugs remains uncertain. We have used whole-cell and single channel recordings to examine the block of wild-type and inactivation-deficient mutant cardiac Na(+) channels, IFM/QQQ, stably expressed in HEK-293 cells. We studied the open-channel blockers disopyramide and flecainide, and the lidocaine derivative RAD-243. All three drugs blocked the wild-type Na(+) channel in a use-dependent manner. There was no use-dependent block of IFM/QQQ mutant channels with trains of 20 40-ms pulses at 150-ms interpulse intervals during disopyramide exposure. Flecainide and RAD-243 retained their use-dependent blocking action and accelerated macroscopic current relaxation. All three drugs reduced the mean open time of single channels and increased the probability of their failure to open. From the abbreviation of the mean open times, we estimated association rates of approximately 10(6)/M/s for the three drugs. Reducing the burst duration contributed to the acceleration of macroscopic current relaxation during exposure to flecainide and RAD-243. The qualitative differences in use-dependent block appear to be the result of differences in drug dissociation rate. The inactivation gate may play a trapping role during exposure to some sodium channel blocking drugs.

The cytoskeleton of the cardiomyocyte has been shown to modulate ion channel function. Cytoskeletal disruption in vitro alters Na(+) channel kinetics, producing a late Na(+) current that can prolong repolarization. This study describes the properties of the cardiac Na(+) channel and cardiac repolarization in neonatal mice lacking ankyrin(B), a cytoskeletal "adaptor" protein. Using whole-cell voltage clamp techniques, I(Na) density was lower in ankyrin(B)(-/-) ventricular myocytes than in wild-type (WT) myocytes (-307+/-26 versus -444+/-39 pA/pF, P<0.01). Ankyrin(B)(-/-) myocytes exhibited a hyperpolarizing shift in activation and inactivation kinetics compared with WT. Slower recovery from inactivation contributed to the negative shift in steady-state inactivation in ankyrin(B)(-/-). Single Na(+) channel mean open time was longer in ankyrin(B)(-/-) versus WT at test potentials (V(t)) of -40 mV (1.0+/-0.1 versus 0. 61+/-0.04 ms, P<0.05) and -50 mV (0.8+/-0.1 versus 0.39+/-0.05 ms, P<0.05). Ankyrin(B)(-/-) exhibited late single-channel openings at V(t) -40 and -50 mV, which were not seen in WT. Late I(Na) contributed to longer action potential durations measured at 90% repolarization (APD(90)) at 1 Hz stimulation in ankyrin(B)(-/-) compared with WT (354+/-26 versus 274+/-22 ms, P<0.05). From ECG recordings of neonatal mice, heart rates were slower in ankyrin(B)(-/-) than in WT (380+/-14 versus 434+/-13 bpm, P<0.01). Although the QT interval was similar in ankyrin(B)(-/-) and WT at physiological heart rates, QT-interval prolongation in response to heart rate deceleration was greater in ankyrin(B)(-/-). In conclusion, Na(+) channels in ankyrin(B)(-/-) display reduced I(Na) density and abnormal kinetics at the whole-cell and single-channel level that contribute to prolonged APD(90) and abnormal QT-rate adaptation.

Objective: Prior studies of the modulation of the Na+ current by sympathetic stimulation have yielded controversial results. Separation of the Na+ and Ca2+ currents poses a problem in myocyte preparations. The gating of cloned Na+ channels is different in oocytes compared with mammalian expression systems. We have examined the sympathetic modulation of the alpha-subunit of the wild-type human cardiac Na+ channel (hH1) and the long QT-associated mutant, delta KPQ, expressed in human embryonic kidney cells., Methods: Stable cell lines of hH1 and delta KPQ were established in human embryonic kidney cells. Whole-cell and single-channel currents were measured with the patch-clamp technique. Sympathetic stimulation was effected by exposure to isoproterenol or 8-bromo-cAMP. Na+ channel activation and inactivation were determined using standard voltage clamp protocols. Ca2+:Na+ permeability ratio was determined under bi-ionic conditions., Results: We observed a qualitatively different effect of sympathetic stimulation on the cardiac Na+ current from that reported in frog oocytes: activation and inactivation kinetics were shifted to more negative potentials. This shift was similar for both hH1 and delta KPQ. [delta V0.5 for inactivation: 8.3 +/- 1.7 mV, p < 0.001 (hH1); 6.8 +/- 0.9 mV, p < 0.001 (delta KPQ)]. Increased rate of closed-state inactivation contributed to the shifting of the inactivation-voltage relationship. Open-state inactivation was not affected as mean open times were unchanged. Reversal potential measurement in hH1 suggested a low Ca2+:Na+ permeability ratio of 0.017, uninfluenced by sympathetic stimulation. In delta KPQ, the size of the persistent relative to the peak current was increased with 8-bromo-cAMP from 3.0 +/- 0.7% to 4.3 +/- 0.6% (p = 0.056)., Conclusions: Sympathetic stimulation exerts multiple effects on the gating of hH1. Similar effects are also seen in delta KPQ which may increase arrhythmia susceptibility in long QT syndrome by modifying the Na+ channel contribution to the action potential.

Drugs remain the mainstay of treatment of patients with atrial fibrillation (AF). An understanding of the mechanisms of AF and of atrioventricular (AV) conduction provides a basis for the understanding of the mechanisms of antiarrhythmic drug action. Although ectopic activity from a focus may initiate AF, re-entry is the usual mechanism of maintenance. In its classical form, reentry takes the form of circus movements around fixed anatomic structures. However, leading circle and anisotropic variants of reentry may arise as a result of functional variations of refractoriness or anistropic conduction. Electrical remodeling during AF favors its persistence. Reentry may be prevented by prolongation of the refractory period. Class III antiarrhythmic drugs prolong refractoriness by blockade of outward potassium currents. Class I drugs prolong refractoriness by delaying the recovery of of the sodium current. Many class I drugs also have potassium channel-blocking action. In AF the rate of conduction of rapid impulses to the ventricle is controlled by conduction over the AV node. Blockade of the L-type calcium channels, activation of the muscarinic and adenosine A1 receptors, or beta-adrenergic blockade will slow conduction over the AV node. The adverse cardiovascular effects of drugs used to treat AF can be predicted on the basis of their mechanisms of action. The current focus of drug development is on specific potassium channel blockers.

Several aspects of the effect of the KPQ deletion mutation on Na+ channel gating remain unresolved. We have analyzed the kinetics of the early and late currents by recording whole cell and single-channel currents in a human embryonic kidney (HEK) cell line (HEK293) expressing wild-type and KPQ deletion mutation in cardiac Na+ channels. The rate of inactivation increased three- to fivefold between -40 and -80 mV in the mutant channel. The rate of recovery from inactivation was increased twofold. Two modes of gating accounted for the late current: 1) isolated brief openings with open times that were weakly voltage dependent and the same as the initial transient and 2) bursts of opening with highly voltage-dependent prolonged open times. Latency to first opening was accelerated, suggesting an acceleration of the rate of activation. The delta KPQ mutation has multiple effects on activation and inactivation. The aggregate effects may account for the increased susceptibility to arrhythmias.

The goal of developing an antiarrhythmic agent effective against malignant ventricular arrhythmias while maintaining a low side-effect profile remains elusive. The class III drugs amiodarone and sotalol are the best available agents. However, both drugs possess properties outside the realm of a pure class III effect, and their use is limited by a variety of dose-related side effects. There are several drugs with more selective class III properties currently in development. This review provides an overview of the optimal characteristics of an effective theoretical class III drug and a summary of the properties of a number of class III drugs under active investigation. An ideal class III antiarrhythmic agent for a reentrant arrhythmia should provide use-dependent prolongation of the action potential duration with slow onset and rapid offset kinetics. This drug would prolong the effective refractory period of cardiac tissue selectively at the rapid heart rates achieved during ventricular tachycardia or fibrillation with a delayed onset of action, and a rapid resolution of its effects on resumption of physiologic heart rates. With little effect on the refractory period at normal or slow heart rates, the ability to induce torsade de pointes would be lessened. In contrast to these ideal properties, most currently available and investigational agents have a reverse use-dependent effect on the action potential duration, producing more effects on the refractory period at slower heart rates. This property results in part from preferential block of the rapidly activating component of the delayed rectifier potassium channel (IKr), with little or no effect on the slowly activating component (IKs). The development of a drug with favorable blocking kinetics that selectively blocks IKs may results in lower proarrhythmic events while still maintaining effective antiarrhythmic properties.

Over the past decade, the strategies for arrhythmia management have been in transition. Physical methods to treat arrhythmias, such as ICDs and RF ablation, have undergone considerable refinement and wider application. Ischemic heart disease and congestive heart failure have been identified as clinical situations in which antiarrhythmic drugs have a significant proarrhythmic potential. However, drugs retain an important role in arrhythmia management. Strategies to mitigate the structural and functional changes that occur in hypertrophy, ischemia, and infarction have not been thoroughly explored. Membrane ion channels and receptors are the targets for the action of currently available drugs. The cloning and sequencing of these ion channels and receptors should improve the efficacy and specificity of drug design. Cardiac Na+, Ca2+, K+, and nonspecific cation channels have a clearly defined role in the generation of the normal action potential. Their specific roles in the various clinical arrhythmias is less certain. There are sufficient data to associate specific ionic channels with normal and abnormal automaticity and with reentry occurring in specific regions of the heart. A rational choice of antiarrthymic drugs can be made when an arrhythmogenic mechanism and the putative underlying membrane currents can be identified based on the clinical characteristics of the arrhythmia. For a majority of clinical arrhythmias, this ideal has not been achieved. When a particular drug is used to treat an arrhythmia, the full complement of its actions will depend on which multiple ion channels or receptors are blocked and the kinetics of drug interaction with these sites.

Our laboratory has been testing the hypothesis that genetic modulation of the beta-adrenergic signaling cascade can enhance cardiac function. We have previously shown that transgenic mice with cardiac overexpression of either the human beta2-adrenergic receptor (beta2AR) or an inhibitor of the beta-adrenergic receptor kinase (betaARK), an enzyme that phosphorylates and uncouples agonist-bound receptors, have increased myocardial inotropy. We now have created recombinant adenoviruses encoding either the beta2AR (Adeno-beta2AR) or a peptide betaARK inhibitor (consisting of the carboxyl terminus of betaARK1, Adeno-betaARKct) and tested their ability to potentiate beta-adrenergic signaling in cultured adult rabbit ventricular myocytes. As assessed by radioligand binding, Adeno-beta2AR infection led to approximately 20-fold overexpression of beta-adrenergic receptors. Protein immunoblots demonstrated the presence of the Adeno-betaARKct transgene. Both transgenes significantly increased isoproterenol-stimulated cAMP as compared to myocytes infected with an adenovirus encoding beta-galactosidase (Adeno-betaGal) but did not affect the sarcolemmal adenylyl cyclase response to Forskolin or NaF. beta-Adrenergic agonist-induced desensitization was significantly inhibited in Adeno-betaARKct-infected myocytes (16+/-2%) as compared to Adeno-betaGal-infected myocytes (37+/-1%, P < 0.001). We conclude that recombinant adenoviral gene transfer of the beta2AR or an inhibitor of betaARK-mediated desensitization can potentiate beta-adrenergic signaling.

Inactivation has been implicated as an important determinant of the block of Na+ channel by local anesthetic-class drugs. This proposition has been difficult to examine because agents used to modify inactivation change other channel properties and both inactivated and blocked channels do not conduct. We used site-directed mutagenesis of Phe1304 to glutamine in the linker between the third and fourth domains of the mu-1 Na+ channel to slow inactivation. Wild-type and mutant channels were expressed in frog oocytes. Macropatch and single-channel currents were recorded in cell-attached membrane patches. The F1304Q mutation increased mean open time (1.7 fold at -20 mV) and reduced the probability that the channel would fail to open. Closed times were best fit by a double-exponential function, suggesting that the inactivated state transitions were no longer absorbing. In wild-type channels, 100 microM disopyramide decreased mean open time from 1.64 +/- 0.08 to 0.34 +/- 0.04 msec. Total open time per trial was decreased 2-fold. There also was a marked increase in the fraction of null sweeps. In the inactivation-deficient mutant channel, mean and total open times were also reduced. These data indicate that even when inactivation is slowed by a localized specific mutation, open-channel block by disopyramide persists. Inactivation may not be a necessary requirement for open-channel block.

Propafenone is a sodium channel blocking antiarrhythmic drug. It also has beta-adrenergic, potassium channel, and weak calcium channel blocking activity. The drug is metabolized in the liver with rates dependent on the debrisoquin phenotype. The saturable metabolism results in nonlinear pharmacokinetics. The metabolites retain sodium channel blocking activity but little beta-adrenergic blocking activity. Both controlled and noncontrolled studies have documented its efficacy in a variety of supraventricular arrhythmias. Intravenous propafenone is effective in converting atrial fibrillation to normal sinus rhythm. Chronic oral administration decreases the frequency of recurrence of atrial fibrillation and paroxysmal supraventricular tachycardia. The drug is particularly effective in the Wolff-Parkinson-White syndrome. The drug may produce SA block in patients with underlying sinus node dysfunction. Propafenone has comparatively few noncardiac side effects. It is a useful primary drug or an alternative to more commonly used drugs used for the treatment of supraventricular arrhythmias.

Recent voltage-clamp studies of isolated myocytes have demonstrated widespread occurrence of a transient outward current (I(to)) carried by potassium ions. In the canine ventricle, this current is well developed in epicardial cells but not in endocardial cells. The resultant spatial dispersion of refractoriness is potentially proarrhythmic and may be amplified by channel blockade. The inactivation and recovery time constants of this channel are in excess of several hundred milliseconds, and consequently channel availability is frequency dependent at physiological stimulation rates. When the time constants associated with transitions between different channel conformations are rapid relative to drug binding kinetics, the interactions between drugs and an ion channel can be approximated by a sequence of first-order reactions, in which binding occurs in pulses in response to pulse train stimulation (pulse chemistry). When channel conformation transition time constants do not meet this constraint, analytical characterizations of the drug-channel interaction must then be modified to reflect the channel time-dependent properties. Here we report that the rate and steady-state amount of frequency-dependent inactivation of I(to) are consistent with a generalization of the channel blockade model: channel availability is reduced in a pulsatile exponential pattern as the stimulation frequency is increased, and the rate of reduction is a linear function of the pulse train depolarizing and recovery intervals. I(to) was reduced in the presence of quinidine. After accounting for the use-dependent availability of I(to) channels, we found little evidence of an additional use-dependent component of block after exposure to quinidine, suggesting that quinidine reacts with both open and closed I(to) channels as though the binding site is continuously accessible. The model provides a useful tool for assessing drug-channel interactions when the reaction cannot be continuously monitored.

Antiarrhythmic drugs have relative specificity for blocking each of the major classes of ion channels that control the action potential. The kinetics of block is determined by the state of the channel. Those channel states occupied at depolarized potentials generally have greater affinity for the blocking drugs. The kinetics of the drug-channel interaction is important in determining the blocking profile observed clinically. The increased mortality resulting from drug treatment in CAST and several atrial fibrillation trials has resulted in a shift in antiarrhythmic drug development from the Na+ channel blocking (Class I) drugs to the K+ channel blocking (Class III) drugs. While both Classes of drugs have a proarrhythmic potential, this may be less for the Class III agents. Their lack of negative inotropy also make them more attractive. It is important that the potential advantages of these agents be evaluated in controlled clinical trials. In several laboratories, the techniques of molecular biology and biophysics are being combined to determine the block site of available drugs. This information will aid in the future development of agents with greater specificity, and hopefully greater efficacy and safety than those currently in clinical use.