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Biomedical subjects

R F Bosch

Publications and source records attributed to R F Bosch.

At least 19 recordsLinked to original sources
PubMed2001

Characterization of a novel Kv1.5 channel blocker in Xenopus oocytes, CHO cells, human and rat cardiomyocytes.

The inhibitory effects of the novel Kv1.5 channel blocker, S9947 (2'-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide), on cloned human Kv1.5 (hKv1.5), expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells, and on native cardiac ultrarapid delayed rectifier potassium currents (IKur) in rat (ventricle myocytes) and human (atrial myocytes) were investigated. The influence of S9947 on the action potential was examined in rat ventricular myocytes. Using the two-electrode voltage-clamp technique in Xenopus oocytes and the patch-clamp technique (whole cell configuration) in CHO cells, hKv1.5 was inhibited by S9947 with IC50 values of 0.65 microM and 0.42 microM, respectively. In addition, inhibition of human Kv4.3 (hKv4.3) and HERG by 10 microM S9947 was low (approximately 20%) and absent, respectively. Using the patch-clamp technique in the whole cell configuration, IKur currents in rat ventricular (rIKur) cardiomyocytes and human atrial (hIKur) cardiomyocytes were inhibited by S9947 with IC50 values of 0.96 microM and 0.07 microM, respectively. In contrast, rat cardiac inward rectifier current (rIK1) and rat (rIto) and human (hIto) cardiac transient outward currents were only inhibited by approximately 20% with 10 microM S9947. In rat cardiomyocytes, using the patch-clamp technique, action potential duration was increased by S9947 in a concentration-dependent (0.3-10 microM) and rate-independent manner. The data show that S9947 suppresses both cloned (Kv1.5) and native (IKur) cardiac potassium currents. Furthermore, S9947 prolongs rat action potential in a rate-independent manner.

Action Potentials↗
PubMed2001

[Atrial tachycardia, atrial flutter, atrial fibrillation: curative therapy by focal ablation in a pulmonary vein].

We describe the case of a 50-year-old woman with the clinical diagnosis of cardiomyopathy associated with supraventricular tachycardia refractory to pharmacological treatment. The totally irregular tachyarrhythmia was the result of different episodes of atrial tachycardia, atrial flutter and atrial fibrillation that could be identified in the surface ECG. These findings and the patient's symptoms were all caused by a single focal tachycardia originating from the left upper pulmonary vein. Ablation of this focus represented a curative antiarrhythmic therapy also restoring a normalized ventricular function. Thus, an ablation of the AV node with consecutive pacemaker implantation could be prevented.

Atrial Fibrillation↗
PubMed2001

Atrial L-type Ca2+-channel, beta-adrenorecptor, and 5-hydroxytryptamine type 4 receptor mRNAs in human atrial fibrillation.

Molecular and electrical remodeling of ion channels determining action potential duration has been proposed as a major mechanism in chronic atrial fibrillation. We investigated the mRNA expression of the cardiac L-type Ca2+-channel subunits alpha1c, alpha2/delta1, beta1a, and beta1b/c in atrial tissue of patients with chronic atrial fibrillation compared to patients in sinus rhythm. In addition, the mRNA expression of the 5-hydroxytryptamine type 4-, beta1-, and beta2-adrenergic receptors, which are known to stimulate the L-type Ca2+-current in human atrium, was analyzed and the effect of chronic beta-blocker treatment on the mRNA expression of these receptors and of the L-type Ca2+-channel subunits was assessed. Total RNA was isolated from right atrial appendages of patients in sinus rhythm and of patients with chronic atrial fibrillation. Then, semiquantitative RT-PCR using 18S RNA as the "housekeeping gene" was performed. In patients with chronic atrial fibrillation, there were only mild reductions in mRNA expression of the alpha1c-subunit (-15.5 %, p = 0.13), and of the beta1-subunit isoforms a and c (-13.3 %, p = 0.14 and -16.6%, p = 0.18, respectively). However, mRNA expression of the alpha2/delta1-subunit (-31.5 %, p < 0.01) and of the beta1-subunit isoform b (-39.9 %, p < 0.0005) was significantly reduced in patients with chronic AF. Taken together, the mRNA expression of the beta1-subunit isoforms b and c, which are splice variants, was significantly down-regulated by 26.5 % (p < 0.05) in these patients. The analysis of the beta1c/beta1b ratio resulted in a significant shift by 39.2 % (p < 0.0001) in favor of beta1c in patients with chronic atrial fibrillation. In the AF patients, the abundance of the 5-HT4-receptor transcript was significantly reduced by 36 % (p < 0.05). The beta-adrenoreceptor transcription was unchanged. In both SR and AF patients, chronic beta-blocker treatment did neither significantly effect the mRNA expression of the L-type Ca2+-channel subunits, the beta-adrenoreceptor subtypes 1 and 2, nor that of the 5-HT4-receptor. Our data show that chronic AF is associated with a decrease in the atrial mRNA amount of auxiliary subunits of the L-type Ca2+-channel and of the 5-HT4-receptor. This supports the hypothesis that the observed alterations in mRNA transcription in AF patients may lead to a decrease in the availability of functional L-type Ca2+-channels and 5-HT4-receptors and/or reduce L-type Ca2+-current amplitude and density, thus, promoting and stabilizing the arrhythmia.

Adrenergic beta-Antagonists↗
PubMed2001

Enhanced detection criteria in implantable cardioverter defibrillators: sensitivity and specificity of the stability algorithm at different heart rates.

The lack of specificity in the detection of ventricular tachyarrhythmias remains a major clinical problem in the therapy with ICDs. The stability criterion has been shown to be useful in discriminating ventricular tachyarrhythmias characterized by a small variation in cycle lengths from AF with rapid ventricular response presenting a higher degree of variability of RR intervals. But RR variability decreases with increasing heart rate during AF. Therefore, the aim of the study was to determine if the sensitivity and specificity of the STABILITY algorithm for spontaneous tachyarrhythmias is related to ventricular rate. Forty-two patients who had received an ICD (CPI Ventak Mini I, II, III or Ventak AV) were enrolled in the study. Two hundred ninety-eight episodes of AF with rapid ventricular response and 817 episodes of ventricular tachyarrhythmias were analyzed. Sensitivity and specificity in the detection of ventricular tachyarrhythmias were calculated at different heart rates. When a stability value of 30 ms was programmed the result was a sensitivity of 82.7% and a specificity of 91.4% in the detection of slow ventricular tachyarrhythmias (heart rate < 150 beats/min). When faster ventricular tachyarrhythmias with rates between 150 and 169 beats/min (170-189 beats/min) were analyzed, a stability value of 30 ms provided a sensitivity of 94.5% (94.7%) and a specificity of 76.5% (54.0%). For arrhythmia episodes > or = 190 beats/min, the same stability value resulted in a sensitivity of 78.2% and a specificity of 41.0%. Even when other stability values were taken into consideration, no acceptable sensitivity/specificity values could be obtained in this subgroup. RR variability decreases with increasing heart rate during AF while RR variability remains almost constant at different cycle lengths during ventricular tachyarrhythmias. Thus, acceptable performance of the STABILITY algorithm appears to be limited to ventricular rate zones < 170 beats/min.

Aged↗
PubMed2000

High variability of retrograde fast pathway sensitivity to adenosine.

BACKGROUND: Adenosine is widely used as a tool to assess the effectiveness of radiofrequency ablation of concealed accessory pathways. HYPOTHESIS: The goal of this study was to determine the reliability of this test by studying the retrograde fast pathway sensibility in a large patient population with typical atrioventricular (AV) nodal reentry tachycardias. We sought also to determine whether AV nodal properties were predictive of a retrograde fast pathway sensitivity to adenosine. METHODS: In all, 124 patients with inducible AV nodal reentrant tachycardia were included in this study. All patients received a clinically used standard dose of 12 mg adenosine during ventricular pacing, with 500 ms and a constant ventriculoatrial (VA) conduction via the fast pathway. Electrophysiologic parameters of the AV node were determined in all patients in order to correlate them with the adenosine sensitivity of the retrograde pathway. RESULTS: In 74 patients, the injection of 12 mg adenosine resulted in a transient VA block, whereas no VA block occurred in the remaining 50 patients. In two patients, concealed accessory pathways were unmasked after the injection of adenosine. The adenosine sensitivity of the retrograde fast pathway was associated with longer retrograde conduction times and cycle lengths during AV nodal reentrant tachycardias. CONCLUSION: This study shows a high variability of retrograde fast pathway sensitivity to adenosine. Thus, in 40% of patients the lack of VA block after adenosine injection is not specific for persistent accessory pathway function after radiofrequency ablation. Electrophysiologic properties of patients with AV nodal reentrant tachycardias were different in patients with and without adenosine-sensitive retrograde fast pathways, possibly indicating differential patterns of penetration of the retrograde fast pathway into the compact AV node.

Adenosine↗
PubMed2000

Molecular and electrophysiological evidence for "remodeling" of the L-type Ca2+ channel in persistent atrial fibrillation in humans.

Persistent atrial fibrillation (AF) is associated with shortened action potential duration (APD) and reduced atrial refractoriness. Remodeling of ion currents responsible for AP morphology has been proposed as a major mechanism in persistent AF. In the present study we investigated the activity of the cardiac L-type Ca2+ channel and the mRNA transcription of the cardiac L-type Ca2+ channel subunits in patients with persistent AF compared to patients in sinus rhythm (SR). Right atrial appendages of 10 patients in SR and of 5 patients with AF were used for myocyte isolations to record L-type Ca2+ currents (ICa,L) by the patch-clamp technique. Right atrial appendages of 16 patients in Sr and of 5 patients with AF served as sources for determining the mRNA expression of the L-type Ca2+ channel alpha 1c-, alpha 2/delta-, beta a-, and beta b/beta c-subunits by semiquantitative RT-PCR. ICa,L density was reduced by 70% (p < 0.001) in AF patients compared to the sinus rhythm group. Cell sizes, expressed as cell capacitance, were identical in both groups. mRNA expressions of the alpha 1c-subunit and the beta b/beta c-subunits were reduced in AF patients by 18.9% (p < 0.05) and 77.7% (p < 0.005), respectively, while mRNA transcriptions of the alpha 2/delta- and the beta a-subunits were not significantly different between SR and AF patients. A decrease in the availability of functional L-type Ca2+ channels in AF patients, due to reduced alpha 1c-subunit and substantial lack of beta b/beta c-subunit transcription seems to contribute to the shortening of APD and refractory periods in AF, thereby favoring increased atrial excitation rate and perpetuation of AF.

Action Potentials↗
PubMed2000

[Electrical remodeling in atrial fibrillation--cellular and molecular mechanisms].

Atrial fibrillation is associated with changes in atrial electrophysiology that facilitate the initiation and persistence of the arrhythmia. The underlying cellular and molecular mechanisms are diverse; they have intensively been investigated over the past few years. The results, that have substantially improved the understanding of the pathophysiology of atrial fibrillation are reviewed. On the cellular level, atrial fibrillation leads to a strong shortening and an impaired rate adaptation of the action potential as well as 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) seem to be involved. A trigger for many of the observations is an overload of the myocyte cytoplasm with Ca2+ and a consecutive decrease of the systolic calcium gradient, furthermore changes in calcium-handling proteins are detectable in atrial fibrillation. In the last part, the clinical relevance and potential new therapeutic approaches are discussed.

Animals↗
PubMed2000

[Administration of adenosine for termination of atrioventricular nodal reentry tachycardia: induction of atrial fibrillation with rapid conduction over an accessory pathway and unmasking of concomitant Wolff-Parkinson-White syndrome].

The antiarrhythmic properties of adenosine, its ultra-short half-life and the absence of frequent serious side effects make it a front-line agent in arrhythmia management, especially in the treatment of atrioventricular nodal reentrant tachycardia. Due to a shortening of atrial refractoriness, adenosine can facilitate the induction of atrial fibrillation. Life threatening tachycardias may result from a potential rapid conduction of atrial fibrillation over an accessory pathway especially if the latter one has a short antegrade refractory period. We report a case of a 59 year old female patient in which intravenous administration of adenosine during typical atrioventricular nodal reentrant tachycardia was followed by atrial fibrillation with rapid conduction over a hitherto unknown accessory pathway. After intravenous administration of adenosine the tachycardia was terminated successfully within 38 s. After a short period of asystole, spontaneous atrial fibrillation developed unmasking an antegrade preexcitation with subsequent rapid ventricular response (210 b/min). The three-lead ECG showed a narrow QRS complex tachycardia. Because of spontaneous conversion to sinus rhythm and the absence of hemodynamic compromise there was no need for external cardioversion. During electrophysiological study an antidromic atrioventricular reentrant tachycardia was recorded over a left posteroseptal accessory pathway including antegrade conduction properties only. Because of its ultrashort half-life, serious side effects after adenosine administration are rare. The possibility of life threatening proarrhythmias after intravenous adenosine administration should be taken into consideration if the etiology of a paroxysmal supraventricular tachycardia is not clear and a concomitant Wolff-Parkinson-White syndrome cannot be excluded. As with application of all intravenous antiarrhythmic agents, the administration of adenosine should only be performed if continuous ECG monitoring and cardioversion facilities are available and possible.

Adenosine↗
PubMed2000

Molecular remodeling of Kv4.3 potassium channels in human atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is associated with important alterations in cardiac ion channels that cause shortening and impaired rate adaptation of atrial repolarization. The mechanisms underlying potassium current remodeling in human AF are not clear. We investigated the effects of AF on the gene expression of the Kv4.3, Kv1.4, and Kv1.5 potassium channel subunits and correlated the findings with the transient outward (Ito) and the sustained outward (Isus or I(Kur)) potassium current. METHODS AND RESULTS: Semiquantitative reverse transcription-polymerase chain reaction was used to evaluate mRNA expression, and ion currents were studied with the patch clamp technique in right atrial appendages from patients in AF and compared with those from patients in stable sinus rhythm (SR). The presence of AF was associated with a 61% reduction in Kv4.3 mRNA expression (P < 0.001 vs SR), which was paralleled by a reduction in Ito current densities in this group of patients (i.e., at +50 mV: 7.44+/-0.76 pA/pF in SR and 1.24+/-0.28 pA/pF in AF; P < 0.001 vs SR). mRNA levels of Kv1.4 were identical in the two groups. AF did not affect either the gene expression of Kv1.5 or the current densities of Isus. CONCLUSION: Chronic AF in humans reduces Ito by transcriptional down-regulation of the Kv4.3 potassium channel. Altered gene expression is an important component of the electrical remodeling process and may contribute to repolarization abnormalities in AF.

Aged↗
PubMed1999

[Implantation of a dual chamber pacemaker-defibrillator (DDD-ICD) in a patient with hypertrophic obstructive cardiomyopathy].

A 70-year-old woman with severely symptomatic hypertrophic obstructive cardiomyopathy was unresponsive to drug treatment. She had recurrent ventricular tachyarrhythmias and syncope and was at high risk for sudden death; a dual chamber pacemaker defibrillator (DDD-ICD) was implanted. Her initial left ventricular outflow tract gradient was 80 mm Hg and fell to 40 mm Hg during dual-chamber pacing at an atrial ventricular delay of 140 ms. In the follow-up over six months she was asymptomatic with respect to angina pectoris; ventricular tachycardias could be successfully terminated by antitachycardia pacing or by shocks. A dual chamber pacemaker defibrillator is an important therapeutic option for patients with symptomatic hypertrophic obstructive cardiomyopathy and ventricular tachyarrhythmias.

Aged↗
PubMed1999

Ionic mechanisms of electrical remodeling in human atrial fibrillation.

OBJECTIVES: Atrial fibrillation (AF) is associated with a decrease in atrial ERP and ERP adaptation to rate as well as changes in atrial conduction velocity. The cellular changes in repolarization and the underlying ionic mechanisms in human AF are only poorly understood. METHODS: Action potentials (AP) and ionic currents were studied with the patch clamp technique in single atrial myocytes from patients in chronic AF and compared to those from patients in stable sinus rhythm (SR). RESULTS: The presence of AF was associated with a marked shortening of the AP duration and a decreased rate response of atrial repolarization. L-type calcium current (ICa,L) and the transient outward current (Ito) were both reduced about 70% in AF, whereas an increased steady-state outward current was detectable at test potentials between -30 and 0 mV. The inward rectifier potassium current (IKI) and the acetylcholine-activated potassium current (IKACh) were increased in AF at hyperpolarizing potentials. Voltage-dependent inactivation of the fast sodium current (INa) was shifted to more positive voltages in AF. CONCLUSIONS: AF in humans leads to important changes in atrial potassium and calcium currents that likely contribute to the decrease in APD and APD rate adaptation. These changes contribute to electrical remodeling in AF and are therefore important factors for the perpetuation of the arrhythmia.

Acetylcholine↗
PubMed1999

Suppression of sustained ventricular tachyarrhythmias: a comparison of d,l-sotalol with no antiarrhythmic drug treatment.

OBJECTIVES: This study evaluates the clinical efficacy of d,l-sotalol in patients with sustained ventricular tachyarrhythmias. BACKGROUND: D,l-sotalol is an important antiarrhythmic agent to prevent recurrences of sustained ventricular tachyarrhythmias (VT/VF). However, evidence is lacking that an antiarrhythmic agent like d,l-sotalol can reduce the incidence of sustained ventricular tachyarrhythmias in comparison to no antiarrhythmic drug treatment. METHODS: A prospective study was performed in 146 consecutive patients with inducible sustained ventricular tachycardia or ventricular fibrillation. In 53 patients, oral d,l-sotalol prevented induction of VT/VF during electrophysiological testing and patients were discharged on oral d,l-sotalol (sotalol group). In 93 patients, VT/VF remained inducible and a defibrillator (ICD) was implanted. After implantation of the device patients were randomly assigned to oral treatment with d,l-sotalol (ICD/sotalol group, n=46) or no antiarrhythmic medication (n=47, ICD-only group). RESULTS: During follow-up, 25 patients (53.2%) in the ICD-only group had a VT/VF recurrence in comparison to 15 patients (28.3%) in the sotalol group and 15 patients (32.6%) in the ICD/sotalol group (p=0.0013). Therapy with d,l-sotalol, amiodarone or metoprolol was instituted in 12 patients (25.5%) of the ICD-only group due to frequent VT/VF recurrences or symptomatic supraventricular tachyarrhythmias. In nine patients, 17% of the sotalol group, an ICD was implanted after VT/VF recurrence, three patients (5.7%) received amiodarone. Total mortality was not different between the three groups. CONCLUSIONS: D,l-sotalol significantly reduces the incidence of recurrences of sustained ventricular tachyarrhythmias in comparison to no antiarrhythmic drug treatment.

Administration, Oral↗
PubMed1999

Long-term reproducibility of electrophysiologically guided therapy with sotalol in patients with ventricular tachyarrhythmias.

OBJECTIVES: Goal of this study was to assess the long-term reproducibility of electrophysiologic drug testing in patients with ventricular tachyarrhythmias (VT/VF). BACKGROUND: Programmed ventricular stimulation (PVS) is still widely used to guide antiarrhythmic therapy in patients with sustained ventricular tachycardia/fibrillation (VT/VF). Sotalol is considered as one of the most effective drugs for VT/VF. Because there is no proof of long-term reproducibility of a successful drug test with sotalol, we investigated the long-term reproducibility of drug testing with sotalol. METHODS: Thirty patients with VT/VF (age: 57+/-11 years, 20 patients with coronary heart disease, 7 patients with no structural heart disease, 3 with others) and reproducible induction of VT/VF (28 patients VT, two patients VF) in a baseline PVS, were suppressible with sotalol (mean dosage 395+/-137 mg) in a subsequent PVS. After a mean follow-up of 13+/-10 months a PVS was again performed in patients, who had no evidence of progressive cardiac disease, who did not experience any arrhythmia recurrences or who were drug compliant. Irrespective of the inducibility after long-term therapy with sotalol, all patients were kept on the initial sotalol regimen. All 30 patients had a stable cardiac condition, were free of VT/VF recurrences and were drug compliant. RESULTS: Despite the clinical efficacy of sotalol, in 12 patients (40%) VT/VF could again be induced after 13+/-10.2 months. Inducibility was independent of age, heart disease, ejection fraction and follow-up time. During a further follow-up of 22.1+/-10.9 months, five patients experienced nonfatal VT recurrences independently of the prior inducibility. CONCLUSIONS: This study shows a lacking long-term reproducibility of an initial effective PVS with sotalol. Despite an uneventful clinical follow-up, late electrophysiologic testing showed a VT/VF inducibility in a high portion of patients. Hence, electrophysiologic testing performed late after the initial drug test may no longer be predictive of outcome.

Anti-Arrhythmia Agents↗
PubMed1999

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.

Action Potentials↗
PubMed1999

Clinical experience with the new detection algorithms for atrial fibrillation of a defibrillator with dual chamber sensing and pacing.

INTRODUCTION: A major drawback of therapy with an implantable defibrillator is the nonspecificity of detection. Theoretically, adding atrial sensing information to a decision algorithm could improve specificity of detection. METHODS AND RESULTS: This open-label nonrandomized study compares the detection algorithm of the Ventak AV and the Ventak Mini implantable defibrillators. The Ventak AV (n = 39) uses dual chamber detection as opposed to single chamber detection (with rate stability) in the Ventak Mini (n = 55). Programmed zone configurations, rate thresholds, and stability criteria were identical in all patients. In the Ventak AV group, 235 ventricular tachyarrhythmias were adequately detected and treated by the device. In the Mini group, 699 episodes of ventricular fibrillation/tachycardia occurred. All but six of the latter episodes were correctly identified and treated: one patient with incessant ventricular tachycardia had five episodes not terminated by the device, another episode occurred in a patient with a device/lead defect. In the Ventak AV group, 33 episodes of sinus tachycardia and 166 episodes of atrial fibrillation/flutter activated the device; inappropriate therapy was applied to 41% of atrial fibrillation/flutter episodes. In the Ventak Mini group, 226 supraventricular tachyarrhythmias activated the device, eight of which were sinus tachycardia and 218 were atrial fibrillation or flutter; of the atrial fibrillation/ flutter episodes 24% were treated inappropriately (fewer vs Ventak AV, P < 0.001). CONCLUSION: The new detection algorithm incorporated in the Ventak AV did not inadvertently withhold therapy for ventricular tachyarrhythmias, but at the same time the number of inappropriate therapies for atrial fibrillation was not decreased in comparison to a single chamber device.

Aged↗
PubMed1999

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 (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.

Action Potentials↗
PubMed1999

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.

Action Potentials↗