block associated with anisotropy properties was examined with high-resolution optical mapping in ... more block associated with anisotropy properties was examined with high-resolution optical mapping in canine atrial muscles. Both longitudinal block and transverse block were induced.
American Journal of Physiology-Heart and Circulatory Physiology, 2000
Dogs have been used extensively to study atrial arrhythmias, but there are no published mathemati... more Dogs have been used extensively to study atrial arrhythmias, but there are no published mathematical models of the canine atrial action potential (AP). To obtain insights into the ionic mechanisms governing canine atrial AP properties, we incorporated formulations of K+, Na+, Ca2+, and Cl− currents, based on measurements in canine atrial myocytes, into a mathematical model of the AP. The rate-dependent behavior of model APs corresponded to experimental measurements and pointed to a central role for L-type Ca2+ current inactivation in rate adaptation. Incorporating previously described regional ionic current variations into the model largely reproduced AP forms characteristic of the corresponding right atrial regions (appendage, pectinate muscle, crista terminalis, and atrioventricular ring). When ionic alterations induced by tachycardia-dependent remodeling were incorporated, the model reproduced qualitatively the AP features constituting the cellular substrate for atrial fibrillati...
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, Jan 29, 2002
Atrial fibrillation (AF) is a common contributor to cardiovascular morbidity and mortality. Two g... more Atrial fibrillation (AF) is a common contributor to cardiovascular morbidity and mortality. Two generally acceptable strategies exist for long-term AF management, with ongoing studies comparing the overall mortality associated with each. One strategy aims to maintain sinus rhythm, with antiarrhythmic agents if necessary, thereby preserving physiological cardiac electrical function but exposing the patient to the potential side effects of potent drugs. The second approach is to control the ventricular rate and prevent thromboembolic complications with anticoagulants, leaving the patient with AF. Both beta-blocking agents and calcium antagonists are more effective than digoxin in achieving rate control. Several nonpharmacological therapies including catheter ablation, implantable devices and surgical interventions show promise for rate control and maintenance of sinus rhythm. This paper provides an overview of new developments in pharmacological and nonpharmacological therapy. Key fea...
American Journal of Physiology-Heart and Circulatory Physiology, 2002
Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, ... more Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K+ current ( I K1) was homogeneously reduced by ∼41% (at −60 mV) in the three cell types. Transient outward K+ current ( I to1) was decreased by 43–45% at +30 mV, and the slow component of the delayed rectifier K+ current ( I Ks) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K+ c...
American journal of physiology. Heart and circulatory physiology, 2002
Ionically based cardiac action potential (AP) models are based on equations with singular Jacobia... more Ionically based cardiac action potential (AP) models are based on equations with singular Jacobians and display time-dependent AP and ionic changes (transients), which may be due to this mathematical limitation. The present study evaluated transients during long-term simulated activity in a mathematical model of the canine atrial AP. Stimulus current assignment to a specific ionic species contributed to stability. Ionic concentrations were least disturbed with the K(+) stimulus current. All parameters stabilized within 6-7 h. Inward rectifier, Na(+)/Ca(2+) exchanger, L-type Ca(2+), and Na(+)-Cl(-) cotransporter currents made the greatest contributions to stabilization of intracellular [K(+)], [Na(+)], [Ca(2+)], and [Cl(-)], respectively. Time-dependent AP shortening was largely due to the outward shift of Na(+)/Ca(2+) exchange related to intracellular Na(+) (Na) accumulation. AP duration (APD) reached a steady state after approximately 40 min. AP transients also occurred in canine a...
The normal heart beats approximately 100,000 times a day, with beating rates finely tuned to the ... more The normal heart beats approximately 100,000 times a day, with beating rates finely tuned to the body's needs. When the beating rate is inappropriately rapid or slow because of abnormalities in cardiac rhythm referred to as 'cardiac arrhythmias' , cardiac function can be impaired, producing derangements varying from mild symptoms to severe life-threatening complications. Two particularly important cardiac arrhythmias with major clinical implications are atrial fibrillation (AF) and ventricular fibrillation (VF) (FIG. 1). AF is the most common arrhythmia in the population 1,2 , and the complex mechanisms leading to abnormal firing in AF are being rapidly elucidated 3. Its age-related occurrence rate is growing alarmingly with the ageing of the population, and it is estimated that if present trends continue more than 15 million Americans will be affected by AF by 2050 4. It is also a common identifiable cause of stroke (the single most common factor in stroke of the elderly) and is associated with particularly severe strokes 5. VF is the most common cause of sudden cardiac death, and is estimated to kill about 600,000 individuals per year in Europe and the United States combined. Anti-arrhythmic drugs have been used for more than a hundred years, ever since quinidine was identified as the active ingredient in Cinchona bark and subsequently achieved widespread use in the 1920s 6. Currently available anti-arrhythmic drug options include less than a dozen rather old agents, the majority of which were specifically designed to target ion channels, with the most recent launch more than 5 years ago. Anti-arrhythmic drug use has decreased over the past 15 years because
Inadequacies in current therapies for atrial fibrillation have made new drug development crucial.... more Inadequacies in current therapies for atrial fibrillation have made new drug development crucial. Conventional antiarrhythmic drugs increase the risk of ventricular proarrhythmia. In drug development, the focus has been on favourable multichannel-blocking profiles, atrial-specific ion-channels, and novel non-channel targets (upstream therapy). Molecular modification of the highly effective multichannel blocker, amiodarone, to improve safety and tolerability has produced promising analogues such as dronedarone, although this drug seems less effective than does amiodarone. Vernakalant, an atrial-selective drug with reduced proarrhythmic risk, might be useful for cardioversion in atrial fibrillation. Ranolazine, another atrial-selective agent initially developed as an antianginal, has efficacy for atrial fibrillation and is being tested in prospective clinical trials. So-called upstream therapy with angiotensin-converting enzyme and angiotensin-receptor inhibitors, statins, or omega-3 fatty acids and fish oil that target atrial remodelling could be effective, but need further clinical validation. We focus on the basic and clinical pharmacology of newly emerging antiarrhythmic drugs and non-traditional approaches such as upstream therapy for atrial fibrillation.
Journal of the American College of Cardiology, 2008
Atrial-selective pharmacologic approaches represent promising novel therapeutic options for the t... more Atrial-selective pharmacologic approaches represent promising novel therapeutic options for the treatment of atrial fibrillation (AF). Medical treatment for AF is still more widely applied than interventional therapies but is hampered by several important weaknesses. Besides limited clinical efficacy (cardioversion success and sinusrhythm maintenance), side effects like ventricular proarrhythmia and negative inotropy are important limitations to present class I and III drug therapy. Although no statistically significant detrimental survival consequences have been documented in trials, constitutional adverse effects might also limit applicability. Cardiac targets for novel atrial-selective antiarrhythmic compounds have been identified, and a large-scale search for safe and effective medications has begun. Several ionic currents (I KACh , I Kur) and connexins (Cx-40) are potential targets, because atrial-selective expression makes them attractive in terms of reduced ventricular side-effect liability. Data on most agents are still experimental, but some clinical findings are available. Atrial fibrillation generates a specifically remodeled atrial milieu for which other therapeutic interventions might be effective. Some drugs show frequency-dependent action, whereas others target structurally remodeled atria. This review focuses on potential atrial-selective compounds, summarizing mechanisms of action in vitro and in vivo. It also mentions favorable interventions on the milieu in terms of conventional (such as antifibrotic effects of angiotensin-system antagonism) and innovative gene-therapy approaches that might add to future AF therapeutic options.
Atrial fibrillation (AF) is a common arrhythmia that is difficult to treat. Anti-arrhythmic drug ... more Atrial fibrillation (AF) is a common arrhythmia that is difficult to treat. Anti-arrhythmic drug therapy, to maintain sinus-rhythm, is limited by inadequate efficacy and potentially serious adverse effects. There is increasing interest in novel therapeutic approaches that target AF-substrate development. Recent trials suggest that angiotensin converting-enzyme (ACE)-inhibitors and angiotensin-receptor blockers (ARBs) may be useful, particularly in patients with left ventricular hypertrophy or failure. The clinical potential and mechanisms of this approach are under active investigation. Angiotensin-II is involved in remodelling and may have direct electrophysiological actions. Experimental studies show protection from atrial structural and possibly electrical remodelling with ACE-inhibitors and ARBs, as well as potential effects on cardiac ion-channels. This article reviews information pertaining to the clinical use and mechanism of action of ACE-inhibitors and ARBs in AF. A lack of prospective randomized double-blind trials data limits their application in AF patients without another indication for their use, but studies under way may alter this in the near future. This exciting field of investigation may lead to significant improvements in therapeutic options for AF patients.
Atrial fibrillation (AF)-induced contractile dysfunction contributes importantly to thrombo-embol... more Atrial fibrillation (AF)-induced contractile dysfunction contributes importantly to thrombo-embolic stroke, the most serious AF complication. Atrial cardiomyocytes have a constitutively active acetylcholine-regulated K +-current (I KAChc) that is enhanced by atrial tachycardia (AT). I KAChc contributes to action potential duration (APD) shortening in AT-remodelled atrial cardiomyocytes; APD regulates contractility by controlling Ca 2+-loading and systolic Ca 2+release. This study investigated the potential role of I KAChc in AF-related contractile dysfunction. Methods and results Dogs were divided into two groups: (i) unpaced control (CTL); (ii) AT (400 bpm for at least 7 days). Tertiapin-Q (TQ), a selective I KAChc blocker, was used to define I KAChc contributions to contractility. Single-cell left atrial (LA) intracellular Ca 2+-transients (CaTrs), cell-shortening (CS), and whole LA tissue tension-generation were measured. Atrial tachycardia increased I KAChc. Whole LA contractility was decreased in AT (0.17 + 0.05 g) compared with CTL (0.40 + 0.09 g), with significant reversal (0.30 + 0.06 g) after TQ administration. Ca 2+-transient amplitude and CS in single-cell were decreased by AT compared with CTL (167 + 14 vs. 88 + 10 nM; 10.3 + 1.3 vs. 1.7 + 0.3 mm, respectively; P , 0.001). The AT-induced reductions in single-cell CaTr amplitude and CS were partly reversed by TQ administration (88 + 10 vs. 112 + 16 nM; P , 0.001; 1.7 + 0.3 vs. 3.6 + 0.7 mm; P , 0.01). We then measured CaTr and CS with carbachol and/or TQ to vary I KACh at various extracellular [Ca 2+ ]. The CaTr-CS relationship was linear and AT results fell on the regression line, indicating that AT-remodelling effects on contractility are attributable to reduced CaTr. Conclusion Up-regulated I KAChc contributes to AF-related contractile dysfunction and could be a novel target to prevent hypocontractility-related thrombo-embolic complications.
Proarrhythmia, the development of new or worse arrhythmias in response to drug therapy, is a majo... more Proarrhythmia, the development of new or worse arrhythmias in response to drug therapy, is a major limitation to the development and use of new drugs. There are different types of drug-induced proarrhythmia, including long-QT syndrome (LQTS), short-QT syndrome and proarrhythmia related to Na +-channel blockade/conduction impairment. By far the most important form of proarrhythmia at present is drug-induced LQTS and its associated characteristic tachyarrhythmia, torsades de pointes (TdP). TdP arises when cellular action potentials (APs) are excessively prolonged, leading to arrhythmogenic afterdepolarizations, especially early afterdepolarizations (EADs), which trigger complex re-entry in a substrate involving increased transmural
Atrial action potential heterogeneity is a major determinant of atrial reentrant arrhythmias, but... more Atrial action potential heterogeneity is a major determinant of atrial reentrant arrhythmias, but the underlying ionic mechanisms are poorly understood. To evaluate the basis of spatial heterogeneity in canine right atrial repolarization, we isolated cells from 4 regions: the crista terminalis (CT), appendage (APG), atrioventricular ring (AVR) area, and pectinate muscles. Systematic action potential (AP) differences were noted: CT cells had a "spike-and-dome" morphology and the longest AP duration (APD; value to 95% repolarization at 1 Hz, 270Ϯ10 ms [meanϮSEM]); APG and pectinate muscle cells had intermediate APDs (180Ϯ3 and 190Ϯ3 ms, respectively; PϽ0.001 versus CT for each), with APG cells having a small phase 1; and AVR cells had the shortest APD (160Ϯ4 ms, PϽ0.001 versus other regions). The inward rectifier and the slow and ultrarapid delayed rectifier currents were similar in all regions. The transient outward K ϩ current was significantly smaller in APG cells, explaining their small phase 1 and high plateau. L-type Ca 2ϩ current was greatest in CT cells and least in AVR cells, contributing to their longer and shorter APD, respectively. The E-4031-sensitive rapid delayed rectifier K ϩ current was larger in AVR cells compared with other regions. Voltage-and time-dependent current properties were constant across regions. We conclude that myocytes from different right atrial regions of the dog show systematic variations in AP properties and ionic currents and that the spatial variation in ionic current density may explain AP differences. Regional variation in atrial ionic currents may play an important role in atrial arrhythmia generation and may present opportunities for improving antiarrhythmic drug therapy.
Purkinje fibers (PFs) play key roles in cardiac conduction and arrhythmogenesis. Congestive heart... more Purkinje fibers (PFs) play key roles in cardiac conduction and arrhythmogenesis. Congestive heart failure (CHF) causes well-characterized atrial and ventricular ion channel subunit expression changes, but effects on PF ion channel subunits are unknown. This study assessed changes in PF ion channel subunit expression (real-time PCR, immunoblot, immunohistochemistry), action potential properties, and conduction in dogs with ventricular tachypacing–induced CHF. CHF downregulated mRNA expression of subunits involved in action potential propagation (Nav1.5, by 56%; connexin [Cx]40, 66%; Cx43, 56%) and repolarization (Kv4.3, 43%, Kv3.4, 46%). No significant changes occurred in KChIP2, KvLQT1, ERG, or Kir3.1/3.4 mRNA. At the protein level, downregulation was seen for Nav1.5 (by 38%), Kv4.3 (42%), Kv3.4 (57%), Kir2.1 (26%), Cx40 (53%), and Cx43 (30%). Cx43 dephosphorylation was indicated by decreased larger molecular mass bands (pan-Cx43 antibody) and a 57% decrease in Ser368-phosphorylated...
Background— We previously characterized a novel K + current ( I KH ) with properties of constitut... more Background— We previously characterized a novel K + current ( I KH ) with properties of constitutively active acetylcholine-related current in dog atrium. I KH is sensitive to tertiapin-Q (IC 50 ≈10 nmol/L), a highly selective Kir3 current blocker. This study assessed the role of I KH in atrial tachycardia (AT)–remodeled canine left atrium (LA) with the use of tertiapin-Q as a probe. Methods and Results— Dogs were subjected to 7 to 13 days of AT (400 bpm). Coronary-perfused LA preparations were studied intact or subjected to cardiomyocyte isolation. I KH was recorded with patch-clamp methods. AT pacing increased time-dependent hyperpolarization-activated current ( I KH ) at −110 mV from −1.8±0.3 (control) to −3.4±0.5 pA/pF (AT) and the 100-nmol/L tertiapin-sensitive component from −1.5±0.4 (control) to −3.3±0.6 pA/pF (AT). Prolonged atrial tachyarrhythmias could be induced with single extrastimuli in AT-remodeled, but not control, preparations, reflecting the atrial fibrillation–pro...
Background— Atrial fibrillation (AF) and congestive heart failure (CHF) produce discrete forms of... more Background— Atrial fibrillation (AF) and congestive heart failure (CHF) produce discrete forms of atrial ionic remodeling. The in vivo effects of atrial tachycardia (AT) remodeling are altered by CHF. This study evaluated underlying mechanisms at the level of ionic remodeling. Methods and Results— We studied 4 groups of dogs: (1) unpaced controls (CTLs); (2) CHF caused by 2-week ventricular tachypacing (VTP, 240 bpm); (3) AT (400 bpm ×7 days); and (4) CHF+AT (2-week VTP with AT for the last 7 days). CHF and CHF+AT groups equally increased left atrial pressure. AF duration was increased in all paced groups. Effective refractory period (ERP) was decreased by 42% in AT versus CTL but by only 24% in AT+CHF versus CHF. CHF reduced L-type Ca 2+ ( I Ca ), transient-outward ( I to ), and the slow delayed-rectifier ( I Ks ) currents while increasing the Na + -Ca 2+ exchanger ( I NCX ) and not affecting the inward-rectifier ( I K1 ) current. AT reduced I to and I Ca while increasing I K1 and ...
Background— The pulmonary veins (PVs) are important in the pathophysiology of atrial fibrillation... more Background— The pulmonary veins (PVs) are important in the pathophysiology of atrial fibrillation (AF), as is atrial tachycardia (AT) remodeling. The relative importance of AT remodeling in PVs versus other atrial sites is unknown. The present study assessed AT-induced cellular changes in PVs versus left atrium (LA) and their relationship to arrhythmogenesis. Methods and Results— We studied ionic currents (single-cell patch clamp) and action potentials (APs; coronary-perfused multicellular preparations) in the PVs and LA free wall of dogs after 7-day AT pacing (400 bpm), as well as in nonpaced control dogs. In controls, rapid ( I Kr ) and slow ( I Ks ) delayed-rectifier currents were larger in PVs; transient-outward ( I to ), inward-rectifier ( I K1 ), and L-type Ca 2+ ( I Ca ) currents and AP duration were smaller. AT remodeling reduced I Ca and I to , left I Kr and I Ks unchanged, and increased I K1 in both LA and PV. AT reduced action potential duration in both LA and PV. LA–PV A...
Background Cardiac Purkinje cells (PCs) are important for the generation of triggered arrhythmias... more Background Cardiac Purkinje cells (PCs) are important for the generation of triggered arrhythmias, particularly in association with abnormal repolarization. The effects of congestive heart failure (CHF) on the ionic properties of PCs are unknown. Methods and Results PCs were isolated from false tendons of control dogs and dogs with ventricular tachypacing-induced CHF. CHF PCs were hypertrophied (capacitance, mean±SEM, 149±4 pF, n=130; versus 128±3 pF, n=150, control; P <0.001). Transient outward current density was reduced in CHF PCs without change in voltage dependence or kinetics. CHF also reduced inward-rectifier current density, with no change in form of the current-voltage relationship. Densities of L- and T-type calcium, rapid and slow delayed rectifier, and Na + -Ca 2+ exchange currents were unaltered by CHF, but L-type calcium current inactivation was slowed at positive potentials. Purkinje fiber action potentials from CHF dogs showed decreased phase 1 amplitudes and elev...
Background— Sustained heart rate abnormalities produce electrical remodeling and susceptibility t... more Background— Sustained heart rate abnormalities produce electrical remodeling and susceptibility to arrhythmia. Uncontrolled tachycardia produces heart failure and ventricular tachyarrhythmia susceptibility, whereas bradycardia promotes spontaneous torsade de pointes (TdP). This study compared arrhythmic phenotypes and molecular electrophysiological remodeling produced by tachycardia versus bradycardia in rabbits. Methods and Results— We evaluated mRNA and protein expression of subunits underlying rapid ( I Kr ) and slow ( I Ks ) delayed-rectifier and transient-outward K + currents in ventricular tissues from sinus rhythm control rabbits and rabbits with AV block submitted to 3-week ventricular pacing either at 60 to 90 bpm (bradypaced) or at 350 to 370 bpm (tachypaced). QT intervals at matched ventricular pacing rates were longer in bradypaced than tachypaced rabbits (eg, by ≈50% at 60 bpm; P <0.01). KvLQT1 and minK mRNA and protein levels were downregulated in both bradypaced an...
Background: Loss of rate-dependent action potential (AP) duration (APD) adaptation is a character... more Background: Loss of rate-dependent action potential (AP) duration (APD) adaptation is a characteristic feature of atrial tachycardia-21 induced remodeling (ATR). ATR causes sarcolemmal ion-channel remodeling (ICR) and changes in Ca-handling. The present studies 21 were designed to quantify Ca-handling changes and then to apply a mathematical AP model to assess the contributions of 21 Ca-handling abnormalities and ICR to loss of APD rate-adaptation. Methods: Indo-1 fluorescence was used to measure intracellular 2 Ca-transients and whole-cell patch-clamp to record APs in atrial myocytes from control dogs and dogs subjected to atrial pacing at 21 400 / min for 6 weeks. A previously developed ionic model of the canine atrial AP was modified to reproduce measured Ca-transients of control and ATR myocytes. Results: In control, APD to 95% repolarization (APD) decreased by 91 ms experimentally and by 88 ms in 95 21 the model over the 1-6 Hz range. In ATR myocytes, APD failed to decrease over the 1-6 Hz range. Ca-handling abnormalities in 95 21 ATR myocytes included slowed upstroke, decreased amplitude and strong single-beat post-rest potentiation. Unaltered Ca-handling 21 21 properties included caffeine-releasable Ca-stores and Ca-transient relaxation before and after exposure to the sarcoplasmic reticulum 21 Ca-ATPase (SERCA) inhibitor cyclopiazonic acid (CPA). Including ICR alone in the model accounted for loss of APD 50 21 rate-adaptation; however, KR alone reduced APD rate-adaptation by only 19% to 71 ms. When both ICR and Ca-handling changes 95 were incorporated, APD rate-adaptation decreased to 6 ms, accounting for experimental observations. Conclusion: ICR alone does not 95 21 fully account for loss of APD rate-adaptation with atrial remodeling: Ca-handling changes appear to contribute to this clinically significant phenomenon.
block associated with anisotropy properties was examined with high-resolution optical mapping in ... more block associated with anisotropy properties was examined with high-resolution optical mapping in canine atrial muscles. Both longitudinal block and transverse block were induced.
American Journal of Physiology-Heart and Circulatory Physiology, 2000
Dogs have been used extensively to study atrial arrhythmias, but there are no published mathemati... more Dogs have been used extensively to study atrial arrhythmias, but there are no published mathematical models of the canine atrial action potential (AP). To obtain insights into the ionic mechanisms governing canine atrial AP properties, we incorporated formulations of K+, Na+, Ca2+, and Cl− currents, based on measurements in canine atrial myocytes, into a mathematical model of the AP. The rate-dependent behavior of model APs corresponded to experimental measurements and pointed to a central role for L-type Ca2+ current inactivation in rate adaptation. Incorporating previously described regional ionic current variations into the model largely reproduced AP forms characteristic of the corresponding right atrial regions (appendage, pectinate muscle, crista terminalis, and atrioventricular ring). When ionic alterations induced by tachycardia-dependent remodeling were incorporated, the model reproduced qualitatively the AP features constituting the cellular substrate for atrial fibrillati...
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, Jan 29, 2002
Atrial fibrillation (AF) is a common contributor to cardiovascular morbidity and mortality. Two g... more Atrial fibrillation (AF) is a common contributor to cardiovascular morbidity and mortality. Two generally acceptable strategies exist for long-term AF management, with ongoing studies comparing the overall mortality associated with each. One strategy aims to maintain sinus rhythm, with antiarrhythmic agents if necessary, thereby preserving physiological cardiac electrical function but exposing the patient to the potential side effects of potent drugs. The second approach is to control the ventricular rate and prevent thromboembolic complications with anticoagulants, leaving the patient with AF. Both beta-blocking agents and calcium antagonists are more effective than digoxin in achieving rate control. Several nonpharmacological therapies including catheter ablation, implantable devices and surgical interventions show promise for rate control and maintenance of sinus rhythm. This paper provides an overview of new developments in pharmacological and nonpharmacological therapy. Key fea...
American Journal of Physiology-Heart and Circulatory Physiology, 2002
Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, ... more Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K+ current ( I K1) was homogeneously reduced by ∼41% (at −60 mV) in the three cell types. Transient outward K+ current ( I to1) was decreased by 43–45% at +30 mV, and the slow component of the delayed rectifier K+ current ( I Ks) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K+ c...
American journal of physiology. Heart and circulatory physiology, 2002
Ionically based cardiac action potential (AP) models are based on equations with singular Jacobia... more Ionically based cardiac action potential (AP) models are based on equations with singular Jacobians and display time-dependent AP and ionic changes (transients), which may be due to this mathematical limitation. The present study evaluated transients during long-term simulated activity in a mathematical model of the canine atrial AP. Stimulus current assignment to a specific ionic species contributed to stability. Ionic concentrations were least disturbed with the K(+) stimulus current. All parameters stabilized within 6-7 h. Inward rectifier, Na(+)/Ca(2+) exchanger, L-type Ca(2+), and Na(+)-Cl(-) cotransporter currents made the greatest contributions to stabilization of intracellular [K(+)], [Na(+)], [Ca(2+)], and [Cl(-)], respectively. Time-dependent AP shortening was largely due to the outward shift of Na(+)/Ca(2+) exchange related to intracellular Na(+) (Na) accumulation. AP duration (APD) reached a steady state after approximately 40 min. AP transients also occurred in canine a...
The normal heart beats approximately 100,000 times a day, with beating rates finely tuned to the ... more The normal heart beats approximately 100,000 times a day, with beating rates finely tuned to the body's needs. When the beating rate is inappropriately rapid or slow because of abnormalities in cardiac rhythm referred to as 'cardiac arrhythmias' , cardiac function can be impaired, producing derangements varying from mild symptoms to severe life-threatening complications. Two particularly important cardiac arrhythmias with major clinical implications are atrial fibrillation (AF) and ventricular fibrillation (VF) (FIG. 1). AF is the most common arrhythmia in the population 1,2 , and the complex mechanisms leading to abnormal firing in AF are being rapidly elucidated 3. Its age-related occurrence rate is growing alarmingly with the ageing of the population, and it is estimated that if present trends continue more than 15 million Americans will be affected by AF by 2050 4. It is also a common identifiable cause of stroke (the single most common factor in stroke of the elderly) and is associated with particularly severe strokes 5. VF is the most common cause of sudden cardiac death, and is estimated to kill about 600,000 individuals per year in Europe and the United States combined. Anti-arrhythmic drugs have been used for more than a hundred years, ever since quinidine was identified as the active ingredient in Cinchona bark and subsequently achieved widespread use in the 1920s 6. Currently available anti-arrhythmic drug options include less than a dozen rather old agents, the majority of which were specifically designed to target ion channels, with the most recent launch more than 5 years ago. Anti-arrhythmic drug use has decreased over the past 15 years because
Inadequacies in current therapies for atrial fibrillation have made new drug development crucial.... more Inadequacies in current therapies for atrial fibrillation have made new drug development crucial. Conventional antiarrhythmic drugs increase the risk of ventricular proarrhythmia. In drug development, the focus has been on favourable multichannel-blocking profiles, atrial-specific ion-channels, and novel non-channel targets (upstream therapy). Molecular modification of the highly effective multichannel blocker, amiodarone, to improve safety and tolerability has produced promising analogues such as dronedarone, although this drug seems less effective than does amiodarone. Vernakalant, an atrial-selective drug with reduced proarrhythmic risk, might be useful for cardioversion in atrial fibrillation. Ranolazine, another atrial-selective agent initially developed as an antianginal, has efficacy for atrial fibrillation and is being tested in prospective clinical trials. So-called upstream therapy with angiotensin-converting enzyme and angiotensin-receptor inhibitors, statins, or omega-3 fatty acids and fish oil that target atrial remodelling could be effective, but need further clinical validation. We focus on the basic and clinical pharmacology of newly emerging antiarrhythmic drugs and non-traditional approaches such as upstream therapy for atrial fibrillation.
Journal of the American College of Cardiology, 2008
Atrial-selective pharmacologic approaches represent promising novel therapeutic options for the t... more Atrial-selective pharmacologic approaches represent promising novel therapeutic options for the treatment of atrial fibrillation (AF). Medical treatment for AF is still more widely applied than interventional therapies but is hampered by several important weaknesses. Besides limited clinical efficacy (cardioversion success and sinusrhythm maintenance), side effects like ventricular proarrhythmia and negative inotropy are important limitations to present class I and III drug therapy. Although no statistically significant detrimental survival consequences have been documented in trials, constitutional adverse effects might also limit applicability. Cardiac targets for novel atrial-selective antiarrhythmic compounds have been identified, and a large-scale search for safe and effective medications has begun. Several ionic currents (I KACh , I Kur) and connexins (Cx-40) are potential targets, because atrial-selective expression makes them attractive in terms of reduced ventricular side-effect liability. Data on most agents are still experimental, but some clinical findings are available. Atrial fibrillation generates a specifically remodeled atrial milieu for which other therapeutic interventions might be effective. Some drugs show frequency-dependent action, whereas others target structurally remodeled atria. This review focuses on potential atrial-selective compounds, summarizing mechanisms of action in vitro and in vivo. It also mentions favorable interventions on the milieu in terms of conventional (such as antifibrotic effects of angiotensin-system antagonism) and innovative gene-therapy approaches that might add to future AF therapeutic options.
Atrial fibrillation (AF) is a common arrhythmia that is difficult to treat. Anti-arrhythmic drug ... more Atrial fibrillation (AF) is a common arrhythmia that is difficult to treat. Anti-arrhythmic drug therapy, to maintain sinus-rhythm, is limited by inadequate efficacy and potentially serious adverse effects. There is increasing interest in novel therapeutic approaches that target AF-substrate development. Recent trials suggest that angiotensin converting-enzyme (ACE)-inhibitors and angiotensin-receptor blockers (ARBs) may be useful, particularly in patients with left ventricular hypertrophy or failure. The clinical potential and mechanisms of this approach are under active investigation. Angiotensin-II is involved in remodelling and may have direct electrophysiological actions. Experimental studies show protection from atrial structural and possibly electrical remodelling with ACE-inhibitors and ARBs, as well as potential effects on cardiac ion-channels. This article reviews information pertaining to the clinical use and mechanism of action of ACE-inhibitors and ARBs in AF. A lack of prospective randomized double-blind trials data limits their application in AF patients without another indication for their use, but studies under way may alter this in the near future. This exciting field of investigation may lead to significant improvements in therapeutic options for AF patients.
Atrial fibrillation (AF)-induced contractile dysfunction contributes importantly to thrombo-embol... more Atrial fibrillation (AF)-induced contractile dysfunction contributes importantly to thrombo-embolic stroke, the most serious AF complication. Atrial cardiomyocytes have a constitutively active acetylcholine-regulated K +-current (I KAChc) that is enhanced by atrial tachycardia (AT). I KAChc contributes to action potential duration (APD) shortening in AT-remodelled atrial cardiomyocytes; APD regulates contractility by controlling Ca 2+-loading and systolic Ca 2+release. This study investigated the potential role of I KAChc in AF-related contractile dysfunction. Methods and results Dogs were divided into two groups: (i) unpaced control (CTL); (ii) AT (400 bpm for at least 7 days). Tertiapin-Q (TQ), a selective I KAChc blocker, was used to define I KAChc contributions to contractility. Single-cell left atrial (LA) intracellular Ca 2+-transients (CaTrs), cell-shortening (CS), and whole LA tissue tension-generation were measured. Atrial tachycardia increased I KAChc. Whole LA contractility was decreased in AT (0.17 + 0.05 g) compared with CTL (0.40 + 0.09 g), with significant reversal (0.30 + 0.06 g) after TQ administration. Ca 2+-transient amplitude and CS in single-cell were decreased by AT compared with CTL (167 + 14 vs. 88 + 10 nM; 10.3 + 1.3 vs. 1.7 + 0.3 mm, respectively; P , 0.001). The AT-induced reductions in single-cell CaTr amplitude and CS were partly reversed by TQ administration (88 + 10 vs. 112 + 16 nM; P , 0.001; 1.7 + 0.3 vs. 3.6 + 0.7 mm; P , 0.01). We then measured CaTr and CS with carbachol and/or TQ to vary I KACh at various extracellular [Ca 2+ ]. The CaTr-CS relationship was linear and AT results fell on the regression line, indicating that AT-remodelling effects on contractility are attributable to reduced CaTr. Conclusion Up-regulated I KAChc contributes to AF-related contractile dysfunction and could be a novel target to prevent hypocontractility-related thrombo-embolic complications.
Proarrhythmia, the development of new or worse arrhythmias in response to drug therapy, is a majo... more Proarrhythmia, the development of new or worse arrhythmias in response to drug therapy, is a major limitation to the development and use of new drugs. There are different types of drug-induced proarrhythmia, including long-QT syndrome (LQTS), short-QT syndrome and proarrhythmia related to Na +-channel blockade/conduction impairment. By far the most important form of proarrhythmia at present is drug-induced LQTS and its associated characteristic tachyarrhythmia, torsades de pointes (TdP). TdP arises when cellular action potentials (APs) are excessively prolonged, leading to arrhythmogenic afterdepolarizations, especially early afterdepolarizations (EADs), which trigger complex re-entry in a substrate involving increased transmural
Atrial action potential heterogeneity is a major determinant of atrial reentrant arrhythmias, but... more Atrial action potential heterogeneity is a major determinant of atrial reentrant arrhythmias, but the underlying ionic mechanisms are poorly understood. To evaluate the basis of spatial heterogeneity in canine right atrial repolarization, we isolated cells from 4 regions: the crista terminalis (CT), appendage (APG), atrioventricular ring (AVR) area, and pectinate muscles. Systematic action potential (AP) differences were noted: CT cells had a "spike-and-dome" morphology and the longest AP duration (APD; value to 95% repolarization at 1 Hz, 270Ϯ10 ms [meanϮSEM]); APG and pectinate muscle cells had intermediate APDs (180Ϯ3 and 190Ϯ3 ms, respectively; PϽ0.001 versus CT for each), with APG cells having a small phase 1; and AVR cells had the shortest APD (160Ϯ4 ms, PϽ0.001 versus other regions). The inward rectifier and the slow and ultrarapid delayed rectifier currents were similar in all regions. The transient outward K ϩ current was significantly smaller in APG cells, explaining their small phase 1 and high plateau. L-type Ca 2ϩ current was greatest in CT cells and least in AVR cells, contributing to their longer and shorter APD, respectively. The E-4031-sensitive rapid delayed rectifier K ϩ current was larger in AVR cells compared with other regions. Voltage-and time-dependent current properties were constant across regions. We conclude that myocytes from different right atrial regions of the dog show systematic variations in AP properties and ionic currents and that the spatial variation in ionic current density may explain AP differences. Regional variation in atrial ionic currents may play an important role in atrial arrhythmia generation and may present opportunities for improving antiarrhythmic drug therapy.
Purkinje fibers (PFs) play key roles in cardiac conduction and arrhythmogenesis. Congestive heart... more Purkinje fibers (PFs) play key roles in cardiac conduction and arrhythmogenesis. Congestive heart failure (CHF) causes well-characterized atrial and ventricular ion channel subunit expression changes, but effects on PF ion channel subunits are unknown. This study assessed changes in PF ion channel subunit expression (real-time PCR, immunoblot, immunohistochemistry), action potential properties, and conduction in dogs with ventricular tachypacing–induced CHF. CHF downregulated mRNA expression of subunits involved in action potential propagation (Nav1.5, by 56%; connexin [Cx]40, 66%; Cx43, 56%) and repolarization (Kv4.3, 43%, Kv3.4, 46%). No significant changes occurred in KChIP2, KvLQT1, ERG, or Kir3.1/3.4 mRNA. At the protein level, downregulation was seen for Nav1.5 (by 38%), Kv4.3 (42%), Kv3.4 (57%), Kir2.1 (26%), Cx40 (53%), and Cx43 (30%). Cx43 dephosphorylation was indicated by decreased larger molecular mass bands (pan-Cx43 antibody) and a 57% decrease in Ser368-phosphorylated...
Background— We previously characterized a novel K + current ( I KH ) with properties of constitut... more Background— We previously characterized a novel K + current ( I KH ) with properties of constitutively active acetylcholine-related current in dog atrium. I KH is sensitive to tertiapin-Q (IC 50 ≈10 nmol/L), a highly selective Kir3 current blocker. This study assessed the role of I KH in atrial tachycardia (AT)–remodeled canine left atrium (LA) with the use of tertiapin-Q as a probe. Methods and Results— Dogs were subjected to 7 to 13 days of AT (400 bpm). Coronary-perfused LA preparations were studied intact or subjected to cardiomyocyte isolation. I KH was recorded with patch-clamp methods. AT pacing increased time-dependent hyperpolarization-activated current ( I KH ) at −110 mV from −1.8±0.3 (control) to −3.4±0.5 pA/pF (AT) and the 100-nmol/L tertiapin-sensitive component from −1.5±0.4 (control) to −3.3±0.6 pA/pF (AT). Prolonged atrial tachyarrhythmias could be induced with single extrastimuli in AT-remodeled, but not control, preparations, reflecting the atrial fibrillation–pro...
Background— Atrial fibrillation (AF) and congestive heart failure (CHF) produce discrete forms of... more Background— Atrial fibrillation (AF) and congestive heart failure (CHF) produce discrete forms of atrial ionic remodeling. The in vivo effects of atrial tachycardia (AT) remodeling are altered by CHF. This study evaluated underlying mechanisms at the level of ionic remodeling. Methods and Results— We studied 4 groups of dogs: (1) unpaced controls (CTLs); (2) CHF caused by 2-week ventricular tachypacing (VTP, 240 bpm); (3) AT (400 bpm ×7 days); and (4) CHF+AT (2-week VTP with AT for the last 7 days). CHF and CHF+AT groups equally increased left atrial pressure. AF duration was increased in all paced groups. Effective refractory period (ERP) was decreased by 42% in AT versus CTL but by only 24% in AT+CHF versus CHF. CHF reduced L-type Ca 2+ ( I Ca ), transient-outward ( I to ), and the slow delayed-rectifier ( I Ks ) currents while increasing the Na + -Ca 2+ exchanger ( I NCX ) and not affecting the inward-rectifier ( I K1 ) current. AT reduced I to and I Ca while increasing I K1 and ...
Background— The pulmonary veins (PVs) are important in the pathophysiology of atrial fibrillation... more Background— The pulmonary veins (PVs) are important in the pathophysiology of atrial fibrillation (AF), as is atrial tachycardia (AT) remodeling. The relative importance of AT remodeling in PVs versus other atrial sites is unknown. The present study assessed AT-induced cellular changes in PVs versus left atrium (LA) and their relationship to arrhythmogenesis. Methods and Results— We studied ionic currents (single-cell patch clamp) and action potentials (APs; coronary-perfused multicellular preparations) in the PVs and LA free wall of dogs after 7-day AT pacing (400 bpm), as well as in nonpaced control dogs. In controls, rapid ( I Kr ) and slow ( I Ks ) delayed-rectifier currents were larger in PVs; transient-outward ( I to ), inward-rectifier ( I K1 ), and L-type Ca 2+ ( I Ca ) currents and AP duration were smaller. AT remodeling reduced I Ca and I to , left I Kr and I Ks unchanged, and increased I K1 in both LA and PV. AT reduced action potential duration in both LA and PV. LA–PV A...
Background Cardiac Purkinje cells (PCs) are important for the generation of triggered arrhythmias... more Background Cardiac Purkinje cells (PCs) are important for the generation of triggered arrhythmias, particularly in association with abnormal repolarization. The effects of congestive heart failure (CHF) on the ionic properties of PCs are unknown. Methods and Results PCs were isolated from false tendons of control dogs and dogs with ventricular tachypacing-induced CHF. CHF PCs were hypertrophied (capacitance, mean±SEM, 149±4 pF, n=130; versus 128±3 pF, n=150, control; P <0.001). Transient outward current density was reduced in CHF PCs without change in voltage dependence or kinetics. CHF also reduced inward-rectifier current density, with no change in form of the current-voltage relationship. Densities of L- and T-type calcium, rapid and slow delayed rectifier, and Na + -Ca 2+ exchange currents were unaltered by CHF, but L-type calcium current inactivation was slowed at positive potentials. Purkinje fiber action potentials from CHF dogs showed decreased phase 1 amplitudes and elev...
Background— Sustained heart rate abnormalities produce electrical remodeling and susceptibility t... more Background— Sustained heart rate abnormalities produce electrical remodeling and susceptibility to arrhythmia. Uncontrolled tachycardia produces heart failure and ventricular tachyarrhythmia susceptibility, whereas bradycardia promotes spontaneous torsade de pointes (TdP). This study compared arrhythmic phenotypes and molecular electrophysiological remodeling produced by tachycardia versus bradycardia in rabbits. Methods and Results— We evaluated mRNA and protein expression of subunits underlying rapid ( I Kr ) and slow ( I Ks ) delayed-rectifier and transient-outward K + currents in ventricular tissues from sinus rhythm control rabbits and rabbits with AV block submitted to 3-week ventricular pacing either at 60 to 90 bpm (bradypaced) or at 350 to 370 bpm (tachypaced). QT intervals at matched ventricular pacing rates were longer in bradypaced than tachypaced rabbits (eg, by ≈50% at 60 bpm; P <0.01). KvLQT1 and minK mRNA and protein levels were downregulated in both bradypaced an...
Background: Loss of rate-dependent action potential (AP) duration (APD) adaptation is a character... more Background: Loss of rate-dependent action potential (AP) duration (APD) adaptation is a characteristic feature of atrial tachycardia-21 induced remodeling (ATR). ATR causes sarcolemmal ion-channel remodeling (ICR) and changes in Ca-handling. The present studies 21 were designed to quantify Ca-handling changes and then to apply a mathematical AP model to assess the contributions of 21 Ca-handling abnormalities and ICR to loss of APD rate-adaptation. Methods: Indo-1 fluorescence was used to measure intracellular 2 Ca-transients and whole-cell patch-clamp to record APs in atrial myocytes from control dogs and dogs subjected to atrial pacing at 21 400 / min for 6 weeks. A previously developed ionic model of the canine atrial AP was modified to reproduce measured Ca-transients of control and ATR myocytes. Results: In control, APD to 95% repolarization (APD) decreased by 91 ms experimentally and by 88 ms in 95 21 the model over the 1-6 Hz range. In ATR myocytes, APD failed to decrease over the 1-6 Hz range. Ca-handling abnormalities in 95 21 ATR myocytes included slowed upstroke, decreased amplitude and strong single-beat post-rest potentiation. Unaltered Ca-handling 21 21 properties included caffeine-releasable Ca-stores and Ca-transient relaxation before and after exposure to the sarcoplasmic reticulum 21 Ca-ATPase (SERCA) inhibitor cyclopiazonic acid (CPA). Including ICR alone in the model accounted for loss of APD 50 21 rate-adaptation; however, KR alone reduced APD rate-adaptation by only 19% to 71 ms. When both ICR and Ca-handling changes 95 were incorporated, APD rate-adaptation decreased to 6 ms, accounting for experimental observations. Conclusion: ICR alone does not 95 21 fully account for loss of APD rate-adaptation with atrial remodeling: Ca-handling changes appear to contribute to this clinically significant phenomenon.
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Papers by Stanley Nattel