Ralph F. Bosch

Functional mechanisms underlying tachycardia-induced sustained atrial fibrillation in a chronic dog model.

BACKGROUNDnRapid atrial activation causes electrical remodeling that promotes atrial fibrillation (AF), but underlying mechanisms are incompletely understood. We applied epicardial mapping to evaluate atrial electrophysiology and AF duration in dogs subjected to rapid atrial pacing (400/min).nnnMETHODS AND RESULTSnDogs paced for 1 (P1, n=7), 7 (P7, n=13), or 42 (P42, n=7) days were compared with sham dogs (P0, n=13). Atrial pacing progressively increased AF duration. Atrial effective refractory period (ERP) and ERP accommodation to rate were significantly decreased by pacing, with near-maximal changes within 7 days. Atrial conduction velocity decreased more slowly, with maximum changes at 42 days, contributing to increases in AF duration after ERP stabilized. Stepwise multilinear regression indicated that both wavelength (P=.02) and duration of pacing (P=.0001) were independent determinants of changes in AF duration. Mean atrial fibrillation cycle length (AFCL) at 112 recording sites decreased with increased duration of rapid pacing (P<.001), and the SD of AFCL increased progressively (P<.0001), together accounting for 72% of the variance in AF duration. Increases in AFCL variability were due to regionally determined differences in AFCL changes caused by rapid pacing. The number of zones of reactivation per cycle of AF increased as AF became more sustained, consistent with multiple-wavelet reentry.nnnCONCLUSIONSnRapid atrial activation causes time-dependent decreases in ERP, conduction velocity, and wavelength, which, along with increased regional heterogeneity, provide a substrate for AF. The conduction abnormalities and increased regional heterogeneity previously noted in patients with AF may be a consequence, as well as a cause, of the tachyarrhythmia.

Tachycardia-Induced Changes in Na+ Current in a Chronic Dog Model of Atrial Fibrillation

We have previously shown that chronic rapid atrial activation (400 bpm) reduces atrial conduction velocity in dogs, contributing to the development of a substrate supporting sustained atrial fibrillation (AF). However, the cellular and ionic mechanisms underlying these functional changes have not been defined. We applied whole-cell patch-clamp techniques to atrial myocytes from dogs subjected to atrial pacing at 400 bpm for 7 days (P7, n = 6) and 42 days (P42, n = 5) and compared the results with those from sham-operated dogs similarly instrumented but without pacemaker activation (P0, n = 6). Rapid atrial pacing allowed for the induction of sustained AF in 67% and 100% of dogs paced for 7 and 42 days, respectively, and significantly decreased conduction velocity under P7 and P42 conditions. In dogs paced for 7 days, Na+ current (INa) density was reduced by 28% at -40 mV (P < .0001, n = 59 cells). INa changes were even more decreased under P42 conditions, by approximately 52% at -40 mV (P < .0001): from -78.7 +/- 4.6 pA/pF (P0, n = 28 cells) to -37.7 +/- 3.0 pA/pF (P42, n = 43 cells). INa was significantly reduced at all voltages ranging from -65 to -10 mV. Voltage-dependent activation and inactivation properties, activation kinetics, and recovery from inactivation were not altered by rapid atrial pacing; however, inactivation kinetics were slowed. AF duration was related to mean INa in each dog (r2 = .573, P < .001). We conclude that rapid atrial activation significantly reduces both conduction velocity and INa density. Since INa is a major determinant of conduction velocity, our data point to INa reduction as a potentially important mechanism contributing to the substrate for AF in this model.

Transmembrane ICa contributes to rate-dependent changes of action potentials in human ventricular myocytes.

The mechanism of action potential abbreviation caused by increasing rate in human ventricular myocytes is unknown. The present study was designed to determine the potential role of Ca2+ current ( I Ca) in the rate-dependent changes in action potential duration (APD) in human ventricular cells. Myocytes isolated from the right ventricle of explanted human hearts were studied at 36°C with whole cell voltage and current-clamp techniques. APD at 90% repolarization decreased by 36 ± 4% when frequency increased from 0.5 to 2 Hz. Equimolar substitution of Mg2+ for Ca2+ significantly decreased rate-dependent changes in APD (to 6 ± 3%, P < 0.01). Peak I Ca was decreased by 34 ± 3% from 0.5 to 2 Hz ( P < 0.01), and I Ca had recovery time constants of 65 ± 12 and 683 ± 39 ms at -80 mV. Action potential clamp demonstrated a decreasing contribution of I Ca during the action potential as rate increased. The rate-dependent slow component of the delayed rectifier K+current ( I Ks) was not observed in four cells with an increase in frequency from 0.5 to 3.3 Hz, perhaps because the I Ks is so small that the increase at a high rate could not be seen. These results suggest that reduction of Ca2+influx during the action potential accounts for most of the rate-dependent abbreviation of human ventricular APD.The mechanism of action potential abbreviation caused by increasing rate in human ventricular myocytes is unknown. The present study was designed to determine the potential role of Ca2+ current (ICa) in the rate-dependent changes in action potential duration (APD) in human ventricular cells. Myocytes isolated from the right ventricle of explanted human hearts were studied at 36 degreesC with whole cell voltage and current-clamp techniques. APD at 90% repolarization decreased by 36 +/- 4% when frequency increased from 0.5 to 2 Hz. Equimolar substitution of Mg2+ for Ca2+ significantly decreased rate-dependent changes in APD (to 6 +/- 3%, P < 0.01). Peak ICa was decreased by 34 +/- 3% from 0.5 to 2 Hz (P < 0.01), and ICa had recovery time constants of 65 +/- 12 and 683 +/- 39 ms at -80 mV. Action potential clamp demonstrated a decreasing contribution of ICa during the action potential as rate increased. The rate-dependent slow component of the delayed rectifier K+ current (IKs) was not observed in four cells with an increase in frequency from 0.5 to 3.3 Hz, perhaps because the IKs is so small that the increase at a high rate could not be seen. These results suggest that reduction of Ca2+ influx during the action potential accounts for most of the rate-dependent abbreviation of human ventricular APD.

Electrophysiological mechanisms by which hypothyroidism delays repolarization in guinea pig hearts

Thyroid hormone is known to exert important effects on cardiac repolarization, but the underlying mechanisms are poorly understood. We investigated the electrophysiological mechanisms of differences in repolarization between control guinea pigs and hypothyroid animals (thyroidectomy plus 5-propyl-2-thiouracil). Hypothyroidism significantly prolonged the rate-corrected Q-T interval in vivo and action potential duration (APD) of isolated ventricular myocytes. Whole cell voltage-clamp studies showed no change in current density or kinetics of L-type Ca(2+) current, inward rectifier K(+) current, or Na(+) current in hypothyroid hearts. Dofetilide-resistant current (I(Ks)) step current densities were smaller by approximately 65%, and tail current densities were reduced by 80% in myocytes from hypothyroid animals compared with controls. The ratio of delayed rectifier step current at +50 mV to tail current at -40 mV was significantly larger in hypothyroid cells for test pulses from 60- to 4,200-ms duration, reflecting a smaller I(Ks). Dofetilide-sensitive current (I(Kr)) densities were not significantly changed. I(Ks) half-activation voltage shifted to more positive voltages in hypothyroidism (29.5 +/- 2.2 vs. 21.3 +/- 2.7 mV in control, P < 0.01), whereas I(Kr) voltage dependence was unchanged. We conclude that hypothyroidism delays repolarization in the guinea pig ventricle by decreasing I(Ks), a novel and potentially important mechanism for thyroid regulation of cardiac electrophysiology.Thyroid hormone is known to exert important effects on cardiac repolarization, but the underlying mechanisms are poorly understood. We investigated the electrophysiological mechanisms of differences in repolarization between control guinea pigs and hypothyroid animals (thyroidectomy plus 5-propyl-2-thiouracil). Hypothyroidism significantly prolonged the rate-corrected Q-T interval in vivo and action potential duration (APD) of isolated ventricular myocytes. Whole cell voltage-clamp studies showed no change in current density or kinetics of L-type Ca2+current, inward rectifier K+current, or Na+ current in hypothyroid hearts. Dofetilide-resistant current ( I Ks) step current densities were smaller by ∼65%, and tail current densities were reduced by 80% in myocytes from hypothyroid animals compared with controls. The ratio of delayed rectifier step current at +50 mV to tail current at -40 mV was significantly larger in hypothyroid cells for test pulses from 60- to 4,200-ms duration, reflecting a smaller I Ks. Dofetilide-sensitive current ( I Kr) densities were not significantly changed. I Kshalf-activation voltage shifted to more positive voltages in hypothyroidism (29.5 ± 2.2 vs. 21.3 ± 2.7 mV in control, P < 0.01), whereas I Kr voltage dependence was unchanged. We conclude that hypothyroidism delays repolarization in the guinea pig ventricle by decreasing I Ks, a novel and potentially important mechanism for thyroid regulation of cardiac electrophysiology.

Delayed sodium channel inactivation mimics long QT syndrome 3.

&NA; DPI 201–106 delays sodium channel inactivation. Acute administration of DPI 201–106 prolonged the QT interval, provoked spontaneous torsades de pointes in one patient, and facilitated stimulation‐induced polymorphic ventricular tachyarrhythmias in two patients. Similar to the observations in animal studies, delaying sodium channel inactivation is a new form of the acquired long QT syndrome, mimicking long QT syndrome type 3.

Effects of the chromanol HMR 1556 on potassium currents in atrial myocytes.

PurposeThe chromanol HMR 1556 is a potent blocker of KvLQT1/minK potassium channels expressed in Xenopus oocytes. The compound is therefore a new class III antiarrhythmic drug with a distinct mechanism of action. However, the effect of HMR 1556 on atrial ion channels and the selectivity of block in the human heart has not been investigated. We tested the effects of HMR 1556 on repolarizing potassium currents in human and guinea pig atrial myocytes.Methods and resultsSingle atrial myocytes were isolated by enzymatic dissociation. Atrial potassium currents (IKs, IKr, in guinea pig, Ito, IKur, IK1 in humans) were recorded at 36°C in the whole cell mode of the patch clamp technique. HMR 1556 produced a concentration-dependent and reversible block of IKs with a half maximal concentration (EC50) of 6.8xa0nmol/l. 10xa0μmol/l HMR 1556 almost completely inhibited IKs (97.2±3.2%, n=6). Steady-state activation as well as kinetic properties of the current were not altered by HMR 1556. IKr currents were not affected up to concentrations of 10xa0μmol/l. HMR 1556 did not inhibit other potassium currents in human atrium: Ito, IKur and the classical inward rectifier potassium current IK1 were not significantly affected up to concentrations that completely blocked IKs (10xa0μmol/l).ConclusionsHMR 1556 is a highly-potent blocker of IKs channels without exerting effects on other potassium currents involved in atrial repolarization. Given the potential advantages of IKs vs. IKr blockade, the drugs new mechanism of action warrants further investigation to clarify its role as an antiarrhythmic agent.

Ambasilide prolongs the action potential and blocks multiple potassium currents in human atrium.

Ambasilide (LU 47110) is a new class III antiarrhythmic drug with a unique profile of action in mammals; however, the effects on human atrial repolarization are not known. We tested the effects of ambasilide on action potentials and repolarizing potassium currents in single atrial myocytes. Ambasilide delayed all phases of repolarization in a concentration-dependent manner [i.e., 10 microM prolonged the action potential duration to 90% repolarization at 1 Hz from 217.8 +/- 34.1 to 360.6 +/- 63.0 ms (p < 0.05 vs. control)]. Action-potential prolongation was independent of the applied stimulation frequency over a range of 0.5-2 Hz; the drug therefore did not display reverse use dependence. Ambasilide produced a concentration-dependent block of the inward rectifier potassium current (IK1) and the acetylcholine-activated potassium current (IKACh) with a median effective concentration (EC50) of 6.0 and 2.3 microM, respectively. Ambasilide also led to a concentration-dependent inhibition of the transient outward current (Ito1; EC50 = 5.7 microM) and the sustained potassium outward current (ISO; EC50 = 43.6 microM). The effect of ambasilide was independent of the step voltage (in the range of +20 to +60 mV) or the applied stimulation frequency (0.5-2 Hz). Inactivation kinetics were not altered. Ambasilide is a new class III antiarrhythmic drug with a distinct profile of action. Its frequency-independent prolongation of the human atrial action potential makes this group of compounds a promising alternative to currently available class III antiarrhythmic drugs.

Remodeling bei Vorhofflimmern

HintergrundVorhofflimmern verändert die atriale Elektrophysiologie, wodurch das Auftreten und der Erhalt der Arrhythmie begünstigt werden. Dies wird als elektrisches Remodeling bei Vorhofflimmern bezeichnet. Die zellulären und molekularen Mechanismen dieses Prozesses wurden in den letzten Jahren intensiv bei Patienten mit Vorhofflimmern und in verschiedenen experimentellen Modellen charakterisiert. Die Ergebnisse trugen wesentlich zum besseren Verständnis der Pathophysiologie dieser Rhythmusstörungen bei.n Zelluläre und molekulare Mechanismen: Auf zellulärer Ebene komt es bei Vorhofflimmern zu einer deutlichen Verkürzung und verminderten Frequenzadaptation der Aktionspotentialdauer sowie zu einer veränderten Aktionspotentialmorphologie. Vorhofflimmern führt zu einer Modulation der Genexpression des L-Typ Calciumkanals (ICa, L) und von Kaliumkanälen (Ito, IK1, IKACh).Die molekularen Mechanismen der bei Vorhofflimmern beobachteten intraatrialen Leitungsverzögerungen sind weniger klar. Veränderungen der Expression und Verteilung von Gap-Junction-Proteinen oder eine Verminderung des schnellen Natriumkanals (INa) wurden berichtet. Ein Auslöser vieler der gemachten Beobachtungen ist die Überladung der Myozyten mit Ca2+ mit einer Verminderung des systolischen Calciumtransienten, ebenso lassen sich Veränderungen der die Calciumhomöostase beeinflussenden Proteine bei Vorhofflimmern nachweisen.n Schlussfolgerung: Die Veränderungen des zellulären und molekularen Milieus bei Vorhofflimmern haben erhebliche Auswirkungen auf den klinischen Verlauf und auf die therapeutische Beeinflussbarkeit der Rhythmusstörung. Die klinische Bedeutung der gemachten Beobachtungen und daraus potentiell resultierende neuartige Therapieansätze werden diskutiert.BackgroundAtrial fibrillation is associated with alterations in atrial electrophysiology that facilitate the initiation and persistence of the arrhythmia. This process was termed electrical remodeling in atrial fibrillation. The underlying cellular and molecular mechanisms have intensively been investigated over the past few years in patients with atrial fibrillation and in different experimental models. The results, that have substantially improved the understanding of the pathophysiology of atrial fibrillation, are reviewed.n Cellular and Molecular Mechanisms: On the cellular level, atrial fibrillation leads to a strong shortening and an impaired rate adaptation of the action potential as well as to changes in action potential morphology. Atrial fibrillation is associated with an altered gene expression of the L-type calcium channel (ICa, L) and of potassium channels (Ito, IK1, IKACh)The molecular mechanisms of intraatrial conduction slowing are less well understood, changes in the expression or distribution of gap junction proteins or a decrease of the fast sodium inward channel (INa) have been reported in some studies. A trigger of initiation for electrical remodeling is an overload of the cytoplasm with Ca2+ and a consecutive decrease of the systolic calcium gradient, furthermore changes in calcium-handling proteins are detectable in atrial fibrillation.n Conclusion: These changes in the cellular and molecular milieu importantly determine the clinical course and the efficacy of therapeutical interventions in atrial fibrillation. The clinical relevance and potential new therapeutic approaches are discussed in the last part.

Ablation von atrialen Extrasystolen und Vorhofflimmern

Einleitung Die Katheterablation ist heute bei symptomatischen Patienten mit typischen paroxysmalen supraventrikulären Tachykardien die Therapie der ersten Wahl. Atriale Tachykardien und Vorhofflattern werden ebenfalls mit großem Erfolg kurativ angegangen. Vorhofflimmern ist die häufigste supraventrikuläre Herzrhythmusstörung. Eine alleinige medikamentöse Therapie mit dem Ziel, Sinusrhythmus zu erhalten, ist in ca. 50% der Fälle ineffektiv. Es ist daher naheliegend, dass in den letzten Jahren Konzepte entwickelt wurden mit dem Ziel, auch Vorhofflimmern mittels Katheterablation zu behandeln. Anfangs stand allein die Ablation der AV-Überleitung mit der konsekutiven Notwendigkeit der Schrittmacherimplantation zur Verfügung. Hierbei handelt es sich jedoch um einen palliativen Therapieversuch, da Vorhofflimmern nicht beeinflusst wird und allein die Symptome, bedingt durch den unregelmäßigen und schnellen Herzschlag bei Vorhofflimmern, beseitigt werden [1]. In den letzten Jahren wurden entscheidende neue Erkenntnisse zur Entstehung von Vorhofflimmern gewonnen, die es heute bei einem Teil der Patienten ermöglichen, auch Vorhofflimmern mittels Katheterablation zu beseitigen. Im Folgenden sollen diese Erfahrungen an mehreren Fallbeispielen erläutert werden.