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Joachim R Ehrlich

Publications and source records attributed to Joachim R Ehrlich.

At least 19 recordsLinked to original sources
PubMed2006

Properties of a time-dependent potassium current in pig atrium: evidence for a role of kv1.5 in repolarization.

Cardiac electrical activity is modulated by potassium currents. Pigs have been used for antiarrhythmic drug testing, but only sparse data exist regarding porcine atrial ionic electrophysiology. Here, we used electrophysiological, molecular, and pharmacological tools to characterize a prominent porcine outward K(+) current (I(K,PO)) in atrial cardiomyocytes isolated from adult pigs. I(K,PO) activated rapidly (time to peak at +60 mV; 2.1 +/- 0.2 ms), inactivated slowly (tau(f) = 45 +/- 10; tau(s) = 215 +/- 28 ms), and showed very slow recovery (tau(f) = 1.54 +/- 0.73 s; tau(s) = 7.91 +/- 1.78 s; n = 9; 36 degrees C). Activation and inactivation were voltage-dependent, and current properties were consistent with predominant K(+) conductance. Neurotoxins (heteropodatoxin, hongatoxin, and blood depressing substance) that block K(v)4.x, K(v)1.1, -1.2, -1.3, and -3.4 in a highly selective manner as well as H(2)O(2) and tetraethylammonium, did not affect the current. Drugs with K(v)1.5-blocking properties (flecainide, perhexiline, and the novel atrial-selective antiarrhythmic 2'-{2-(4-methoxyphenyl)-acetylamino-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide; AVE0118) inhibited I(K,PO) (IC(50) of 132 +/- 47, 17 +/- 10, and 1.25 +/- 0.62 microM, respectively). 4-Aminopyridine suppressed the current and accelerated its decay, reducing charge carriage with an IC(50) of 39 +/- 15 microM. Porcine-specific K(v) channel subunit sequences were cloned to permit real-time quantitative reverse transcription-polymerase chain reaction on RNA extracted from isolated cardiomyocytes, which showed much greater abundance of K(v)1.5 mRNA compared with K(v)1.4, K(v)4.2, and K(v)4.3. Action potential recordings showed that I(K,PO) inhibition with 0.1 mM 4-AP delayed repolarization (e.g., action potential duration at -50 mV increased from 45 +/- 9 to 69 +/- 5 ms at 3 Hz; P < 0.05). In conclusion, porcine atrium displays a current that is involved in repolarization, inactivates more slowly than classic transient outward current, is associated with strong K(v)1.5 expression, and shows a pharmacological profile typical of K(v)1.5-dependent currents.

4-Aminopyridine↗
PubMed2006

Kir3-based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias.

BACKGROUND: We previously characterized a novel K+ current (IKH) with properties of constitutively active acetylcholine-related current in dog atrium. I(KH) is sensitive to tertiapin-Q (IC50 approximately 10 nmol/L), a highly selective Kir3 current blocker. This study assessed the role of IKH 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. IKH was recorded with patch-clamp methods. AT pacing increased time-dependent hyperpolarization-activated current (IKH) 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-promoting effects of AT remodeling. In AT-remodeled preparations, tachyarrhythmia duration averaged 11.0+/-5.2 seconds, with a cycle length of 108+/-6 ms. Tertiapin-Q decreased tachyarrhythmia duration (to 0.6+/-0.1 second; P<0.001) and increased tachyarrhythmia cycle length (to 175+/-10 ms; P<0.001). Atrial action potential duration (APD) was increased 65+/-6% by tertiapin in AT-remodeled hearts versus 19+/-2% (P<0.001) in control. In 2 AT-remodeled preparations, tachyarrhythmia lasted uninterrupted for >20 minutes; tertiapin-Q slowed and then terminated arrhythmia in both. Tertiapin had no effect on left ventricular cardiomyocyte currents or APD. CONCLUSIONS: AT remodeling increases IKH, and a highly selective Kir3 current antagonist, tertiapin-Q, increases APD and suppresses atrial tachyarrhythmias in AT-remodeled preparations without affecting ventricular electrophysiology. Constitutive acetylcholine-related K+ current contributes to AT-remodeling effects in dogs and is a potentially interesting antiarrhythmic target.

Animals↗
PubMed2006

Dronedarone: an emerging agent with rhythm- and rate-controlling effects.

Of current antiarrhythmic agents, amiodarone is among the most effective with the additional advantage of having little proarrhythmic potential. However, it can cause potentially serious extracardiac side effects, stimulating the search for safer derivatives. Dronedarone, a new antiarrhythmic drug that is structurally related to amiodarone, lacks an iodine moiety and, thus, amiodarone's iodine-related organ toxicity, while its methane sulfonyl group decreases lipophilicity so shortening half-life and decreasing tissue accumulation. Electrophysiological studies show that dronedarone shares amiodarone's multichannel blocking effects, inhibiting transmembrane Na(+), K(+), Ca(2+), and slow L-type calcium channels, as well as its antiadrenergic effects. Unlike amiodarone, it has little effect at thyroid receptors. Possessing both rate- and rhythm-control properties, dronedarone has proved safe and effective in preventing recurrence of atrial fibrillation (AF) in patients with persistent AF in the Dronedarone Atrial Fibrillation Study After Electrical Cardioversion (DAFNE) trial, the first prospective randomized trial to evaluate its efficacy and safety. Dronedarone has since undergone further extensive evaluation in three pivotal phase III trials. In two sister studies, the European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS) and American-Australian-African Trial with Dronedarone in Atrial Fibrillation/Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS), dronedarone 400 mg b.i.d. showed significant efficacy against placebo in prevention of AF recurrence. Additionally, in patients with permanent AF, dronedarone was highly effective at controlling ventricular rate on top of standard rate-controlling therapies in the Efficacy and Safety of Dronedarone for the Control of Ventricular Rate during Atrial Fibrillation (ERATO) study.

Amiodarone↗
PubMed2005

Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence.

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.

Angiotensin Receptor Antagonists↗
PubMed2005

Atrial fibrillation-associated minK38G/S polymorphism modulates delayed rectifier current and membrane localization.

BACKGROUND: Atrial fibrillation (AF) is a common acquired arrhythmia with multi-factorial pathogenesis. Recently, a single nucleotide polymorphism (SNP, A/G) at position 112 in the KCNE1 gene, resulting in a glycine/serine amino acid substitution at position 38 of the minK peptide, was associated with AF occurrence (AF more frequent with minK38G); however, the functional effect of this SNP is unknown. METHODS AND RESULTS: We used patch clamp recording, confocal microscopy and protein biochemistry to study the effect of this SNP on delayed-rectifier current expression and mathematical simulation to identify potential functional consequences. The density of slow delayed rectifier current (I(Ks)) resulting from co-expression with KvLQT1 was smaller with minK38G (e.g. at +10 mV: 50+/-7 pA/pF in Chinese hamster ovary (CHO) cells, 45+/-14 pA/pF for COS-7 cells) compared to minK38S (93+/-17 pA/pF, 104+/-23 pA/pF, respectively, P<0.05 for each). I(Ks) kinetics and voltage-dependence were unaffected. Currents resulting from co-expression of human ether-a-go-go-related gene (HERG) were similar for minK38G and minK38S, e.g. upon repolarization from +10 to -50 mV: tail currents 23+/-4 pA/pF versus 22+/-5 pA/pF (P=ns). KvLQT1 membrane immunofluorescence was less in CHO cells co-expressing minK38G versus minK38S, and surface expression of KvLQT1, as determined by labelling with streptavidin/biotin, was increased with minK38S co-expression. Computer simulations with a human atrial action potential model predicted that the minK38G SNP would slightly prolong the atrial action potential and reduce the frequency for alternans behaviour. In the presence of reduced repolarization reserve, these effects were enhanced and under specific conditions early afterdepolarizations occurred. CONCLUSIONS: The minK38G isoform is associated with reduced I(Ks), likely due to decreased KvLQT1 membrane expression. This study reveals a novel amino acid determinant of the minK-KvLQT1 interaction, and if the role of minK38G in AF is confirmed, would suggest mechanistic heterogeneity in genetic determinants of AF.

Animals↗
PubMed2005

Atrial tachycardia remodeling of pulmonary vein cardiomyocytes: comparison with left atrium and potential relation to arrhythmogenesis.

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 Ca2+ (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 AP differences became smaller in AT than in control dogs. Premature extrastimuli induced atrial tachyarrhythmias at 4.5+/-2.8% (mean+/-SEM) sites in 6 control multicellular preparations compared with 64.2+/-7.3% sites in 9 AT-remodeled preparations (P<0.001). Resection of all PVs failed to alter atrial tachyarrhythmia inducibility in AT-remodeled preparations (67.5+/-13.1%). PV resection did not significantly change tachyarrhythmia duration (mean 3.9 seconds per heart, range 0.7 to 15.7 seconds before resection; mean 7.0 seconds per heart, range 0.9 to 36.0 seconds after resection) or cycle length (120+/-6 ms before resection, 115+/-8 ms after resection). CONCLUSIONS: AT produces qualitatively similar ionic remodeling in LA and PVs but reduces PV-LA AP differences. PVs are not essential for AT-induced atrial tachyarrhythmia promotion in this model, which may relate to the failure of PV isolation to prevent AF in some patient populations.

Action Potentials↗
PubMed2005

Comparison of ion channel distribution and expression in cardiomyocytes of canine pulmonary veins versus left atrium.

BACKGROUND: Cardiomyocytes in pulmonary vein (PV) sleeves are important in atrial fibrillation (AF), but underlying mechanisms are poorly understood. Pulmonary veins have different ionic current properties compared to left atrium, with pulmonary vein inward-rectifier currents being smaller and delayed-rectifier currents larger than in left atrium. METHODS: Expression and distribution of the inward-rectifier subunits Kir2.1 and Kir2.3, the rapid delayed-rectifier alpha-subunit ERG, the slow delayed-rectifier alpha-subunit KvLQT1, the beta-subunit minK, the L-type Ca(2+)-subunit Ca(v)1.2, and the Na(+),Ca(2+)-exchanger were quantified by Western blot on isolated cardiomyocytes and localized by immunohistochemistry in tissue sections obtained from canine hearts. RESULTS: Western blotting indicated significantly greater expression of ERG (by 28%, P<0.05) and KvLQT1 (by 34%, P<0.05) in pulmonary vein versus left atrial (LA) cardiomyocytes, but smaller Kir2.3 and similar Kir2.1, Ca(v)1.2 and Na(+),Ca(2+)-exchanger expression in PV. Kir2.1 exhibited weak transverse tubular distribution in both regions. Kir2.3 localized to intercalated disks in both regions, and to transverse tubules in left atrium but not pulmonary vein. ERG staining was more intense in pulmonary vein than left atrium, localizing to transverse tubules in both regions and intercalated disks in pulmonary veins. KvLQT1 was more intensely expressed in pulmonary veins, with a transverse tubular and intercalated disk localization, versus a more diffuse signal in left atrium. The Na(+),Ca(2+)-exchanger localized to transverse tubules, plasma membranes and intercalated disks with similar intensity in each region. CONCLUSIONS: Greater ERG and KvLQT1 abundance in pulmonary vein cardiomyocytes, lower abundance of Kir2.3 in pulmonary veins and differential pulmonary vein subcellular distribution of Kir2.3, ERG and KvLQT1 subunits may contribute to ionic current differences between pulmonary vein and left atrial cardiomyocytes.

Animals↗
PubMed2004

Atrial ionic remodeling induced by atrial tachycardia in the presence of congestive heart failure.

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 x 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 Ca2+ (I(Ca)), transient-outward (I(to)), and the slow delayed-rectifier (I(Ks)) currents while increasing the Na+-Ca2+ exchanger (I(NCX)) and not affecting the inward-rectifier (I(K1)) current. AT reduced I(to) and I(Ca) while increasing I(K1) and leaving I(Ks) unaltered. The addition of AT to CHF failed to alter I(to), I(Ks), or I(NCX) beyond the effect of CHF alone, decreased I(Ca) slightly compared with CHF alone, but had smaller effects on I(Ca) and I(K1) compared with AT alone. Thus, CHF+AT, as would occur in a CHF patient who develops AF, produced an ionic remodeling pattern different from that of CHF or AT alone and from what would have been predicted from additive effects of CHF and AT. CONCLUSIONS: The presence of CHF alters AT-induced ionic remodeling. Thus, the ionic remodeling caused by cardiac arrhythmias in the presence of cardiac pathology is not necessarily predictable from the effects of either alone, with important potential implications for understanding the pathophysiology of arrhythmias in the diseased heart.

Animals↗
PubMed2004

Ranolazine: ion-channel-blocking actions and in vivo electrophysiological effects.

Ranolazine is a novel anti-ischemic drug that prolongs the QT interval. To evaluate the potential mechanisms and consequences, we studied: (i) Ranolazine's effects on HERG and IsK currents in Xenopus oocytes with two-electrode voltage clamp; (ii) effects of ranolazine, compared to d-sotalol, on effective refractory period (ERP), QT interval and ventricular rhythm in a dog model of acquired long QT syndrome; and (iii) effects on selected native currents in canine atrial myocytes with whole-cell patch-clamp technique. Ranolazine inhibited HERG and IsK currents with different potencies. HERG was inhibited with an IC(50) of 106 micromol l(-1), whereas the IC(50) for IsK was 1.7 mmol l(-1). d-Sotalol caused reverse use-dependent ERP and QT interval prolongation, whereas ranolazine produced modest, nonsignificant increases that plateaued at submaximal doses. Neither drug affected QRS duration. d-Sotalol had clear proarrhythmic effects, with all d-sotalol-treated dogs developing torsades de pointes (TdP) ventricular tachyarrhythmias, of which they ultimately died. In contrast, ranolazine did not generate TdP. Effects on I(Kr) and I(Ks) were similar to those on HERG and IsK. Ranolazine blocked I(Ca) with an IC(50) of approximately 300 micromol l(-1). I(Na) was unaffected. We conclude that ranolazine inhibits I(Kr) by blocking HERG currents, inhibits I(Ca) at slightly larger concentrations, and has modest and self-limited effects on the QT interval. Unlike d-sotalol, ranolazine does not cause TdP in a dog model. The greater safety of ranolazine may be due to its ability to inhibit I(Ca) at concentrations only slightly larger than those that inhibit I(Kr), thus producing offsetting effects on repolarization.

Acetanilides↗
PubMed2004

Characterization of a hyperpolarization-activated time-dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium.

Cardiomyocytes from the pulmonary vein sleeves (PVs) are known to play an important role in atrial fibrillation. PVs have been shown to exhibit time-dependent hyperpolarization-induced inward currents of uncertain nature. We observed a time-dependent K(+) current upon hyperpolarization of PV and left atrial (LA) cardiomyocytes (I(KH)) and characterized its biophysical and pharmacological properties. The activation time constant was weakly voltage dependent, ranging from 386 +/- 14 to 427 +/- 37 ms between -120 and -90 mV, and the half-activation voltage averaged -93 +/- 4 mV. I(KH) was larger in PV than LA cells (e.g. at -120 mV: -2.8 +/- 0.3 versus-1.9 +/- 0.2 pA pF(-1), respectively, P < 0.01). The reversal potential was approximately -84 mV with 5.4 mm[K(+)](o) and changed by 55.7 +/- 2.4 mV per decade [K(+)](o) change. I(KH) was exquisitely Ba(2+) sensitive, with a 50% inhibitory concentration (IC(50)) of 2.0 +/- 0.3 microm (versus 76.0 +/- 17.9 microm for instantaneous inward-rectifier current, P < 0.01), and showed similar Cs(+) sensitivity to instantaneous current. I(KH) was potently blocked by tertiapin-Q, a selective Kir3-subunit channel blocker (IC(50) 10.0 +/- 2.1 nm), was unaffected by atropine and was significantly increased by isoproterenol (isoprenaline), carbachol and the non-hydrolysable guanosine triphosphate analogue GTPgammaS. I(KH) activation by carbachol required GTP in the pipette and was prevented by pertussis toxin pretreatment. Tertiapin-Q delayed repolarization in atropine-exposed multicellular atrial preparations studied with standard microelectrodes (action potential duration pre- versus post-tertiapin-Q: 190.4 +/- 4.3 versus 234.2 +/- 9.9 ms, PV; 202.6 +/- 2.6 versus 242.7 +/- 6.2 ms, LA; 2 Hz, P < 0.05 each). Seven-day atrial tachypacing significantly increased I(KH) (e.g. at -120 mV in PV: from -2.8 +/- 0.3 to -4.5 +/- 0.5 pA pF(-1), P < 0.01). We conclude that I(KH) is a time-dependent, hyperpolarization-activated K(+) current that likely involves Kir3 subunits and appears to play a significant role in atrial physiology.

Action Potentials↗
PubMed2004

Dissociation between ionic remodeling and ability to sustain atrial fibrillation during recovery from experimental congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) downregulates atrial transient outward (I(to)), slow delayed rectifier (I(Ks)), and L-type Ca(2+) (I(Ca,L)) currents and upregulates Na(+)-Ca(2+) exchange current (I(NCX)) (ionic remodeling) and causes atrial fibrosis (structural remodeling). The relative importance of ionic versus structural remodeling in CHF-related atrial fibrillation (AF) is controversial. METHODS AND RESULTS: We measured hemodynamic and echocardiographic parameters, mean duration of burst pacing-induced AF (DAF), and atrial-myocyte ionic currents in dogs with CHF induced by 2-week ventricular tachypacing (240 bpm), CHF dogs allowed to recover without pacing for 4 weeks (REC), and unpaced controls. Left ventricular ejection fraction averaged 58.6+/-1.2% (control), 36.2+/-2.3% (CHF, P<0.01), and 57.9+/-1.6% (REC), indicating full hemodynamic recovery. Similarly, left atrial pressures were 2.2+/-0.3 (control), 13.1+/-1.5 (CHF), and 2.4+/-0.4 (REC) mm Hg. CHF reduced I(to) density by approximately 65% (P<0.01), decreased I(Ca,L) density by approximately 50% (P<0.01), and diminished I(Ks) density by approximately 40% (P<0.01) while increasing I(NCX) density by approximately 110% (P<0.05). In REC, all ionic current densities returned to control values. DAF increased in CHF (1132+/-207 versus 14.3+/-8.8 seconds, control) and remained increased with REC (1014+/-252 seconds). Atrial fibrous tissue content also increased in CHF (2.1+/-0.2% for control versus 10.2+/-0.7% for CHF, P<0.01), with no recovery observed in REC (9.4+/-0.8%, P<0.01 versus control, P=NS versus CHF). CONCLUSIONS: With reversal of CHF, there is complete recovery of ionic remodeling, but the prolonged-AF substrate and structural remodeling remain. This suggests that structural, not ionic, remodeling is the primary contributor to AF maintenance in experimental CHF.

Animals↗
PubMed2004

Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device: implications for optimal patient care.

OBJECTIVES: The present study determined the incidence and time course of atrial fibrillation (AF) recurrences in patients with a history of AF and fitted with an implantable monitoring device. BACKGROUND: The long-term risk of undetected recurrence of AF in patients receiving stable antiarrhythmic therapy remains uncertain. METHODS: In 110 patients with a class I indication for physiologic pacing and a history of AF, a pacemaker with dedicated functions for AF detection and electrogram storage was implanted, and antiarrhythmic drug treatment was optimized. Patients were regularly followed up with evaluation of AF-related symptoms, a resting electrocardiogram (ECG), and interrogation of device memory. The incidence of AF recurrences lasting >48 h in asymptomatic patients presenting in sinus rhythm (SR) at the respective follow-up visit constituted the primary end point of this prospective study. RESULTS: During 19 +/- 11 months, 678 follow-up visits were performed. Atrial fibrillation was documented in 51 patients (46%) by ECG recording and in 97 patients (88%) by a review of stored electrograms (p < 0.0001). Device interrogation revealed AF recurrences lasting >48 h in 50 patients, 19 of whom (38%) were completely asymptomatic and in SR at subsequent follow-up. In 11 (16%) of 67 patients with device-confirmed freedom from AF for > or =3 months, AF lasting >48 h recurred subsequently. CONCLUSIONS: This prospective study demonstrates a high incidence of recurrent AF despite optimized antiarrhythmic therapy. Of particular note, AF relapses >48 h remained totally asymptomatic in a significant proportion of patients. Freedom from AF for > or =3 months did not preclude subsequent long-lasting AF recurrence.

Aged↗
PubMed2003

KvLQT1 modulates the distribution and biophysical properties of HERG. A novel alpha-subunit interaction between delayed rectifier currents.

Cardiac repolarization is under joint control of the slow (IKs) and rapid (IKr) delayed rectifier currents. Experimental and clinical evidence indicates important functional interactions between these components. We hypothesized that there might be more direct interactions between the KvLQT1 and HERG alpha-subunits of IKs and IKr and tested this notion with a combination of biophysical and biochemical techniques. Co-expression of KvLQT1 with HERG in a mammalian expression system significantly accelerated HERG current deactivation at physiologically relevant potentials by increasing the contribution of the fast component (e.g. upon repolarization from +20 mV to -50 mV: from 20 +/- 3 to 32 +/- 5%, p < 0.05), making HERG current more like native IKr. In addition, HERG current density was approximately doubled (e.g. tail current after a step to +10 mV: 18 +/- 3 versus 39 +/- 7 pA/picofarad, p < 0.01) by co-expression with KvLQT1. KvLQT1 co-expression also increased the membrane immunolocalization of HERG by approximately 2-fold (p < 0.05). HERG and KvLQT1 co-immunolocalized in canine ventricular myocytes and co-immunoprecipitated in cultured Chinese hamster ovary cells as well as in native cardiac tissue, indicating physical interactions between HERG and KvLQT1 proteins in vitro and in vivo. Protein interaction assays also demonstrated binding of KvLQT1 (but not another K+ channel alpha-subunit, Kv3.4) to a C-terminal HERG glutathione S-transferase fusion protein. Co-expression with HERG did not affect the membrane localization or ionic current properties of KvLQT1. This study shows that the alpha-subunit of IKs can interact with and modify the localization and current-carrying properties of the alpha-subunit of IKr, providing potentially novel insights into the molecular function of the delayed rectifier current system.

Animals↗
PubMed2003

Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties.

Pulmonary vein (PV) cardiomyocytes play an important role in atrial fibrillation; however, little is known about their specific cellular electrophysiological properties. We applied standard microelectrode recording and whole-cell patch-clamp to evaluate action potentials and ionic currents in canine PVs and left atrium (LA) free wall. Resting membrane potential (RMP) averaged -66 +/- 1 mV in PVs and -74 +/- 1 mV in LA (P < 0.0001) and action potential amplitude averaged 76 +/- 2 mV in PVs vs. 95 +/- 2 mV in LA (P < 0.0001). PVs had smaller maximum phase 0 upstroke velocity (Vmax: 98 +/- 9 vs. 259 +/- 16 V s(-1), P < 0.0001) and action potential duration (APD): e.g. at 2 Hz, APD to 90% repolarization in PVs was 84 % of LA (P < 0.05). Na+ current density under voltage-clamp conditions was similar in PV and LA, suggesting that smaller Vmax in PVs was due to reduced RMP. Inward rectifier current density in the PV cardiomyocytes was approximately 58% that in the LA, potentially accounting for the less negative RMP in PVs. Slow and rapid delayed rectifier currents were greater in the PV (by approximately 60 and approximately 50 %, respectively), whereas transient outward K+ current and L-type Ca2+ current were significantly smaller (by approximately 25 and approximately 30%, respectively). Na(+)-Ca(2+)-exchange (NCX) current and T-type Ca2+ current were not significantly different. In conclusion, PV cardiomyocytes have a discrete distribution of transmembrane ion currents associated with specific action potential properties, with potential implications for understanding PV electrical activity in cardiac arrhythmias.

Action Potentials↗
PubMed2003

Immediate reinitiation of atrial tachyarrhythmias after spontaneous restoration of sinus rhythm in patients with an implanted monitoring device.

Immediate reinitiation of atrial tachyarrhythmia (IRAT) has been observed after cardioversion. After spontaneous restoration of sinus rhythm (SR), incidence and characteristics of IRAT have not been described. Therefore, in patients with atrial tachyarrhythmias (ATs) and bradycardia, a pacemaker with dedicated memory functions was implanted. Devices were interrogated after 1 month and stored episodes of AT were analyzed: incidence of IRAT, duration and rate of the preceding episode, sinus rate before AT, coupling interval of atrial premature beats (APBs) initiating AT, and incidence of repetitive APBs. A potential association with IRAT was assessed for clinical characteristics. In 36 of 68 patients, stored electrograms confirmed correct detection of AT onset and termination in 545 episodes. IRAT was present in 212 (39%, 24 patients) episodes of AT. Episodes of AT preceding IRAT were longer than those before non-IRAT (156 vs 46 s, P < 0.001), and occurred during a higher atrial rate before onset of AT (cycle length 775 +/- 111 vs 856 +/- 133 ms, P < 0.001). The coupling interval of APBs initiating IRAT was shorter (502 +/- 83 vs 538 +/- 89 ms; P < 0.001) while the percentage of episodes with repetitive APBs before AT onset and the median atrial cycle length of the preceding AT were not different. On stepwise logistic regression analysis, none of the clinical factors evaluated independently predicted IRAT. In conclusion, IRAT is frequent after spontaneous restoration of SR. Changes of atrial electrophysiological properties promoting IRAT may already develop during AT of short duration.

Aged↗
PubMed2003

Prevention of immediate reinitiation of atrial tachyarrhythmias by high-rate overdrive pacing: results from a prospective randomized trial.

INTRODUCTION: Immediate reinitiation of atrial tachyarrhythmia (IRAT) is an important cause of failure to maintain sinus rhythm. IRAT prevention by overdrive pacing has not been evaluated in a prospective randomized trial. METHODS AND RESULTS: Patients with a DDDRP pacemaker offering temporary atrial overdrive pacing after AT termination (Post Mode Switching Overdrive Pacing [PMOP]) were enrolled into the prospective PIRAT (Prevention of IRAT) trial if paroxysmal AT episodes occurred after implantation. PMOP was randomly activated (120 beats/min for 2 min) or inactive. After 3 months, device memory was interrogated, symptoms and quality of life assessed, and patients crossed over to the alternative treatment arm for another 3 months. Primary study endpoint was the number of AT episodes; secondary endpoints were the cumulative time in AT (AT burden), percentage of AT episodes with IRAT, symptoms, and quality of life with PMOP active versus inactive. In 37 patients (21 men; 69 +/- 9 years), there was no difference in the median number of AT episodes (0.37 vs 0.34 per day), AT burden (both 1%), percentage of episodes with IRAT (30%vs 28%), symptoms, and quality of life during PMOP off versus on. With PMOP active, 29% of 439 ATs restarted during and 18% before PMOP intervention. The PMOP-induced rate increase appeared to be associated with IRAT in 9% of AT episodes. CONCLUSION: Automatic overdrive pacing after AT termination did not prevent IRAT, mainly due to insufficient overdrive suppression even at 120 beats/min and the delay between AT termination and PMOP intervention.

Aged↗
PubMed2002

Atrial fibrillation and congestive heart failure: specific considerations at the intersection of two common and important cardiac disease sets.

Atrial fibrillation (AF) and congestive heart failure (CHF) are two increasingly common cardiac disorders with a growing prevalence in the overall population. Improved treatment of acute medical conditions has increased the incidence of these cardiac disorders. AF and CHF have similar epidemiologic characteristics and adversely affect quality of life and life expectancy of affected patients. CHF predisposes to AF, and AF may worsen the prognosis of CHF. The relevant literature was intensively reviewed with emphasis on aspects at the intersection of both disease sets. Recent advances in basic research have provided a more in-depth view of changes promoting the occurrence of AF in CHF. Data from clinical trials have provided means to improve medical treatment of AF. Precautions must be taken for specific CHF-related side effects, such as torsades de pointes tachycardia, when treating AF. The specific electrophysiologic basis of AF associated with CHF may provide targets for improved treatment modalities. New treatment approaches, both pharmacologic and nonpharmacologic, as well as the results of ongoing controlled clinical studies are likely to greatly alter AF therapy over the next 5 to 10 years in patients with CHF.

Anti-Asthmatic Agents↗