Propafenone and lidocaine have a rate dependent negative dromotropic effect on intraventricular conduction. We investigated the use dependent actions of propafenone and lidocaine on intraventricular conduction in isolated guinea pig hearts perfused by the method of Langendorff. Of primary interest was how the number of stimuli of the conditioning train (S1) might influence the ventricular effective refractory period (VERP) when refractoriness is assessed at a high pacing rate. Propafenone (0.3 microM) and lidocaine (50 microM) caused a comparable prolongation of the intraventricular conduction time during sinus rhythm. During ventricular pacing in the presence of propafenone an abrupt decrease of the pacing cycle length (220 to 120 ms) resulted in an initial peak of rate dependent prolongation of the QRS interval that subsequently decreased to a stable steady-state level. Lidocaine also induced a rate dependent increase of the intraventricular conduction time up to a steady-state level. The time constant, characterizing the changes of the intraventricular conduction time after shortening the ventricular pacing cycle length from 220 to 120 ms was significantly (P < 0.01) longer in the presence of propafenone (tau = 31 +/- 4 beats; mean +/- SEM; n = 11) than for lidocaine (tau = 3 +/- 1; n = 10). Both drugs caused the greatest increase of the VERP when the number of conditioning stimuli (S1, interstimulus interval = 120 ms) was in the range of their respective time constant. However, when the number of conditioning stimuli was further increased, VERP progressively diminished. These effects may be explained by a shortening of the action potential during high rates that results in a decreased binding of propafenone to Na+ channels and by the direct shortening of repolarization period by lidocaine (Class IB drug).

On the AV node the negative dromotropic action of verapamil, amiodarone, digoxin, and diltiazem is known to be rate dependent. The effective refractory period of the AV node (AV‐ERP) at o short cycle length is related to the AV conduction at that cycle length. We investigated how the numher of stimuli during the conditioning train (S 1 ) (during measurement of refractoriness at a high pacing rate [cycle length = 180 ms]) might influence the AV‐ERP in isolated guinea pig hearts in a Langendorff preparation. Verapamil (10 nM), amiodarone (10 μM), digoxin 10.G nM). and diltiazem (30 nM) caused a comparable prolongation of the AV conduction time (AVCT). All four drugs caused a significant prolongation of the AV‐ERP when evaluated by a standard stimulation protocol with a conditioning train of 10 stimuli (10 S 1 ) at a pacing cycle length of 180 ms followed by the test stimulus (S 2 ). When the number of stimuli during the conditioning train (SJ was increased (> 10), until the prolongation of AVCT reached steady state, the AV‐ERP in the presence of verapamil (132 ± 4 vs 141 ± 3 ms; P < 0.05. mean ± S.E.M.) and diltiazem (143 ± 3 vs 151 ± 3 ms; P < 0.05) was prolonged significantly further. These results indicate that the effect of drugs on AV‐ERP should be measured with a modified stimulation protocol, whereby the number of conditioning stimuli is comparable to the time constant characterizing the prolongation of AVCT at fast pacing rates.

A now 92-year-old patient presented in 1990 with a massive 6 x 4 x 4 cm aneurysm of the left internal carotid artery which completely occluded the left oro- and nasopharynx. The main complaint of dysphagia was not only a consequence of the narrowed pharynx but was also due to a palsy of the glosso-pharyngeal nerve and caused one to two episodes of aspiration pneumonia per year. The patient could not be operated on because the aneurysm extended to the base of the skull. Remarkably the patient never experienced a cerebral ischemic event and during a follow-up of five years the aneurysm did not increase in size and partial thrombosis of the aneurysm was never detected. Thus conservative management seems feasible, when partial thrombosis of the aneurysm can be ruled by CT-examination.

The calcium channel blocking agents, verapamil and diltiazem, and the digitalis compound, digoxin, caused drug specific rate-dependent changes of the atrioventricular conduction time (AVCT). The purpose of this study was to investigate this rate adaptation of the AVCT in isolated guinea pig hearts perfused by the method of Langendorff to get an insight in drug-specific binding kinetic to the respective channel. In the presence of 10 nM verapamil, 30 nM diltiazem, or 0.6 nM digoxin, the atrioventricular conduction time was prolonged to a comparable degree during sinus rhythm. The drug-specific time constant, characterizing the rate-dependent adaptation of the AVCT, in the presence of a substance was comparable if evaluated after abruptly changing the heart rate from the pacing cycle length of 240 ms to 180 ms (τ-on) or from 180 to 240 ms (τ-off). The adaptation of the AVCT in the presence of verapamil (τ-on = 178 ± 45 beats, τ-off = 125 ± 33 beats, mean ± SEM) was more pronounced than in the presence of digoxin (τ-on = 144 ± 24 beats, τ-off = 98 ± 15 beats) or diltiazem (τ-on = 70 ± 11 beats, τ-off = 98 ± 15 beats). In conclusion, the differences in the rate adaptation of the AVCT may be explained by the drug-specific association and dissociation kinetic to the calcium channel, slow in the case of verapamil, and fast in the case of diltiazem, whereas this phenomenon in the presence of digoxin may be explained by its direct effects on passive membrane properties.

The aim of the present study was to characterize the time dependence of the depressant effects of ajmaline and propafenone on the Ca2+-channel-dependent tissue of the atrioventricular node in isolated guinea pig hearts perfused by the method of Langendorff. Ajmaline at a concentration of 0.03 μM and propafenone at a concentration of 0.3 μM caused a significant and comparable prolongation of the His bundle and atrioventricular conduction time (AVCT). When the pacing cycle length was abruptly shortened from 240 to 180 ms, the mean time constant (τon) of the rate-dependent AVCT prolongation was comparable for ajmaline and propafenone. In contrast, if the pacing cycle length was abruptly increased from 180 to 240 ms the mean time constant (τoff) for ajmaline was significantly higher than for propafenone. The rate-dependent increase of the atrioventricular effective refractory period was significantly more pronounced in the presence of ajmaline than of propafenone. Ajmaline and propafenone affect the Ca2+-channel-dependent tissue of the myocardium. The more pronounced rate-dependent effect of ajmaline on the atrioventricular effective refractory period may be explained by a slower dissociation kinetic from the channel.

To compare the direct effects of verapamil and diltiazem on the ventricular rate during atrial flutter, we developed an atrial flutter model in guinea pig isolated hearts. Atrial flutter was simulated by rapid atrial pacing (cycle length = 50 ms). At this atrial pacing cycle length, the shape of the frequency of distribution of the ventricular cycle lengths was comparable to that during spontaneous atrial flutter. Verapamil (0.01, 0.03 microM) and diltiazem (0.03, 0.09 microM) caused a comparable prolongation of the atrioventricular conduction time and atrioventricular refractoriness. Also, the anterograde Wenckebach cycle length was increased to a comparable degree by both substances. The mean ventricular cycle length during atrial flutter was comparable prolonged by both substances. The prolongation of the maximal ventricular cycle length was significantly more pronounced in the presence of verapamil. The time dependence of drug-induced alterations in atrioventricular conduction time during abrupt changes of heart rate is significantly more pronounced in the presence of verapamil compared to diltiazem. In conclusion, the more pronounced effect of verapamil on the maximal ventricular cycle length compared to the action of diltiazem may be explained by the slow binding kinetic of this drug to the Ca2+ channel resulting in a longlasting blockade of the Ca2+ channel.

Detajmium (4--3'-diethylamino-2'-hydroxypropyl--ajmalin) is an Na(+)-channel-blocking drug with an extremely long recovery from use-dependent sodium channel block. The aim of the present study was to investigate the rate-dependent effects of detajmium on the intraventricular conduction of isolated, spontaneously beating, guinea pig hearts in comparison with the effects of propafenone. Detajmium (0.3 microM) and propafenone (0.3 microM) caused comparable prolongations of the intraventricular conduction time during sinus rhythm. The time to steady state of the rate-dependent QRS prolongation during rapid ventricular pacing follows an exponential function of the beat number after an abrupt change of frequency and is characterized by a drug-specific time constant. This time constant was significantly longer for detajmium (tau = 265 +/- 165 beats; mean +/- SEM; n = 6) than for propafenone (tau = 31 +/- 4 beats; n = 11; p < 0.01). In the presence of propafenone, QRS duration peaked initially before decreasing to a steady state. Detajmium, in contrast, progressively broadened the QRS complex. Both substances caused the greatest increase in the ventricular effective refractory period (V-ERP) when the number of conditioning stimuli (interstimulus interval, 120 ms) was in the range of the time constant. However, when the number of conditioning stimuli was further increased, the V-ERP for propafenone diminished progressively. In conclusion, propafenone displayed, in comparison with detajmium, only a transient rate-dependent effect on intraventricular conduction and V-ERP.

The maintenance of adequate local tissue perfusion is the result of control mechanisms which reside at the level of microscopic blood vessels: The constriction and relaxation of the vessels whose vascular walls are endowed with smooth muscle. This phenomenon of vasomotion guarantees homeostatic conditions in peripheral tissues. Superior disorders of homeostasis are primarily compensated by activating the vasomotion. The increase of vasomotion results in prostration of the vasomotoric activity and ends in the local biological disaster finally. Therefore an essential therapeutic strategy to avoid or remove peripheral arterial reduced or tacking perfusion is the reactivation of vasomotion. In this pilot study the effect of conservative therapeutic strategies to the vasomotion was investigated with dynamic capillaroscopy in normal perfused areas of the finger nailfold. A significant influence of buflomedil and alprostadil to the capillary blood cell velocity was found. Vasomotion was susceptible to hydroxyethylstarch and alprostadil but was influenced significantly only by buflomedil, Nevertheless we cannot conclude that the applicated substances will have a favourable effect in ischemic areas too, where maximum dilatation still exists.

To slow ventricular rate during supraventricular tachycardia, a drug must have a strong rate-dependent depressant effect on atrioventricular (AV) conduction. We investigated the frequency-dependent effects of verapamil, amiodarone, digoxin, and diltiazem on AV conduction time (AVCT) in isolated guinea pig heart perfused by Langendorff method. Verapamil (0.01 microM), amiodarone (10 microM), digoxin (0.6 nM), and diltiazem (0.03 microM) caused comparable prolongation of AVCT and also a comparable reduction in sinus rate. To evaluate the time dependence of drug-induced alterations in AVCT, we abruptly increased the atrial pacing rate and shortened the pacing cycle length (CL) from 240 to 180 ms. The resulting time constant was longest in the presence of verapamil (tau = 194 +/- 45 beats, mean +/- SEM) and the shortest during perfusion with diltiazem (tau = 89 +/- 9 beats). The magnitude of AVCT prolongation after abrupt increase in pacing rate was significantly greater for digoxin as compared with all other drugs tested. The calculated beat-to-beat increase in AVCT evaluated by dividing the magnitude of AVCT prolongation by the time constant tau was greatest with diltiazem, which may explain the high efficacy of diltiazem in controlling ventricular rate during atrial fibrillation.

Semotiadil, a new Ca2+ antagonist with a high vasoselectivity, in high concentrations depresses AV nodal conduction in a frequency-dependent manner. The aim of the present study was to investigate the effects of semotiadil on intact cardiac conduction and the pacemaker system in comparison with diltiazem, amlodipine and nifedipine. The effects were studied in isolated guinea pig hearts perfused by the method of Langendorff. Both semotiadil and diltiazem decreased markedly the sinus rate in a concentration-dependent manner whereas this was not the case in the presence of amlodipine and nifedipine. Semotiadil (10 μM) markedly prolonged sinus node recovery time and in the presence of diltiazem (10 μM) in 5 out of 7 experiments an intermittent sinus node arrest occurred. Atrioventricular conduction and the effective refractory period of the AV node were most affected by diltiazem and semotiadil. The Ca2+ channel blocking compound semotiadil showed the most pronounced rate-dependent effects on the AV node. In the presence of diltiazem the QT interval became even shorter than in untreated hearts. In contrast, semotiadil did not act on the QT interval. In conclusion, as semotiadil exerts a clear rate-dependent effect on AV nodal conduction with a long time constant, it mimics the electrophysiological behavior of a substance of the verapamil type.

Objective: To evaluate nonsurgical alternatives in reopening chronically occluded aortic bifurcation.Design: Uncontrolled randomized study.Setting: University-affiliated referral center for vascular diseases.Patients: Twenty-five of 39 consecutive patients with chronic aortoiliac disease including a totally occluded aortic bifurcation were found to be acceptable candidates for an aortobifemoral prosthetic graft.Intervention: Patients were randomly assigned to receive either streptokinase or urokinase or recombinant tissue-type plasminogen activator (rt-PA). In cases of successful thrombolysis and residual obstructions, subsequent balloon angioplasty was attempted. Prosthetic bypass grafting was done if thrombolytic treatment and balloon angioplasty failed.Results: Complete lysis was achieved in 5 of 25 patients (20%). In 10 (40%) patients, lysis showed residual obstructions, which were reopened mechanically in 8 patients; 2 patients had extra-anatomical bypass grafts. Ten patients (40%) without thrombolysis had surgical aortobifemoral bypass grafts. Overall, recanalization and clinical improvement were achieved in 13 of 25 patients (52%) by thrombolytic therapy and subsequent balloon angioplasty. The recanalization rate did not differ among the different thrombolytic drugs. However, rt-PA therapy resulted in reopening after 4 days of treatment; streptokinase, after 6 days; and urokinase, after 9 days (P < 0.005). No major complications or deaths occurred.Conclusion: Thrombolytic treatment followed by balloon angioplasty may help avoid the need for aortobifemoral prosthetic bypass grafting in more than 50% of patients with chronic aortoiliac disease.

The aim of this study was to provide estimates of sensitivity and specificity of clinical history, pulses, and ankle/brachial index (ABI) in the follow-up of atherosclerotic occlusions of the superficial femoral artery treated by peripheral transluminal angioplasty (PTA). A total of 116 patients were followed prospectively for 1 year after angioplasty with follow-up visits immediately after angioplasty, and at 3, 6, and 12 months. All patients underwent digital subtraction angiography after 1 year or if they reported a deterioration of their symptoms. Reobstruction was defined as reocclusion or as restenosis exceeding 70%. Patency rates were calculated separately by clinical and ankle/ brachial criteria; sensitivity and specificity were derived using angiography as standard. The presence or absence of pulses distal to the treated vessel segment had a sensitivity of 78% and a specificity of 66% for a reocclusion or significant restenosis; subjective complaints evaluated by history had a sensitivity of 83% and a specificity of 51%. The sensitivity of the ABI was 72% and 66%, with a specificity of 82% and 100% for cutoff values of 0.10 and 0.15, respectively. One year after PTA the angiographic patency rate was 39 % ± 5 %; the patency rate based on ABI criteria 34% ± 5%. A deterioration in the ABI by 0.15 indicated with reasonable certainty a reocclusion or significant restenosis whereas the sensitivity of the ABI was poor in detecting significant restenosis after PTA of occlusions of the superficial femoral artery. When only clinical criteria were used, the true patency rate was significantly overestimated as more than half of all reobstructions remained asymptomatic.

An unserer Klinik wurden in den letzten zwei Jahren 7 Patienten (3 Zentralarterienverschlüsse, 3 Astarterienverschlüsse, 1 Apoplexia papillae) mit rt-PA (recombinant tissue plasminogen activator) behandelt. Voraussetzung war, daß der Verschluß der Arterie nicht länger als 12 Stunden bestand. Vor der Lysetherapie wurden eine Visusbestimmung, Tonometrie, Fundus- und Gesichtsfelduntersuchung sowie eine Fluoreszenzangiographie durchgeführt, durch welche der Verschluß in allen Fällen verifiziert werden konnte. Um mögliche Emboliequellen aufzufinden, gehörten auch eine Echokardiographie und eine Duplexsonographie der Carotiden zu den Voruntersuchungen. Ausschlußkriterien für die Lyse waren: Ulcerierte Plaques bzw. höhergradige Stenosen an den Carotiden, nicht einstellbarer Hypertonus, Schwangerschaft und Patienten älter als 75 Jahre. Unmittelbar nach den Untersuchungen wurden die Patienten mit 70 mg rt-PA über 2 Stunden, gefolgt von 0,05 mg rt-PA/kg KG für die nächsten 4 Stunden behandelt. Während der Therapie erhieltend die Patienten zusätzlich 500 IE Heparin/h. Anschließend wurden die Patienten für 3 Tage heparinisiert und danach antikoaguliert. Die nach der Therapie durchgeführte Kontrollangiographie zeigte die Wiedereröffnung aller Gefäße. Schon während der Lyse bemerkten die Patienten eine Visusverbesserung. Abhängig von der Zeitdauer zwischen Eintritt des Verschlusses und Beginn der Therapie (in unseren Fällen zwischen 4 und 7 Stunden) kam es zu Verbesserungen der Sehleistung um 5 bis 10 Visusstufen, sowie damit verbunden zu deutlichen Gesichtsfeldverbesserungen. Während der gesamten Beobachtungszeit (zwischen 1/2 bis 2 Jahre) blieb das Sehvermögen praktisch konstant.

The maintenance of adequate local tissue perfusion is the result of control mechanisms which reside at the level of microscopic blood vessels: The constriction and relaxation of the vessels whose vascular walls are endowed with smooth muscle. This phenomenon of vasomotion guarantees homeostatic conditions in peripheral tissues. Superior disorders of homeostasis are primarily compensated by activating the vasomotion. The increase of vasomotion results in prostration of the vasomotoric activity and ends in the local biological disaster finally. Therefore an essential therapeutic strategy to avoid or remove peripheral arterial reduced or lacking perfusion is the reactivation of vasomotion. In this pilot study the effect of conservative therapeutic strategies to the vasomotion was investigated with dynamic capillaroscopy in normal perfused areas of the finger nailfold. A significant influence of buflomedil and alprostadil to the capillary blood cell velocity was found. Vasomotion was susceptible to hydroxyethylstarch and alprostadil but was influenced significantly only by buflomedil. Nevertheless we cannot conclude that the applicated substances will have a favourable effect in ischemic areas too, where maximum dilatation still exists.

Na+ channel blockers terminate tachyarrhythmias primarily by rate-dependent effects. The purpose of this study was to investigate the use-dependent effects of propafenone in isolated guinea pig and rabbit hearts perfused by the method of Langendorff. In the presence of propafenone (0.3 microM) during ventricular pacing, an abrupt decrease of the pacing cycle length (220 ms to 120 ms) slowed the intraventricular conduction with a transient peak QRS prolongation of 33.8 +/- 2.0% after 5.7 +/- 0.5 s (P < 0.01) which subsequently decreased to a steady state of 14.0 +/- 2.5% after 38.0 +/- 5.5 s (mean +/- S.E.M.; n = 10; P < 0.01). The ventricular effective refractory period was significantly prolonged if evaluated by a train of 10 basic stimuli (S1) (interstimulus interval: 120 ms) followed by a premature stimulus (S2). However, when the train of basic stimuli was increased the effective refractory period diminished progressively. An initial increase in total activation time vanished with continued rapid ventricular stimulation. These effects may be explained by a shortening of the action potential during high rates resulting in a decreased binding of propafenone to Na+ channels.

ATP is an effective treatment of supraventricular tachycardia when the atrioventricular (AV) node is part of the reentrant circuit. However, the lower a pace-maker in the pacemaker hierarchy, the more sensitive it is to adenosine. Therefore, we investigated the effects of ATP on ventricular automaticity in in vivo and in vitro conditions. Wide and narrow QRS complex tachycardia in 46 patients was treated with 6, 12, and 18 mg ATP as sequential intravenous (i.v.) bolus. ATP terminated tachycardias in 67%. Bolus infusion ATP caused < or = 6.4-s asystole that was self-limited. Perfusion of isolated spontaneously beating guinea pig heart with 100 microM ATP completely suppressed ventricular automaticity. After ATP-infusion was discontinued, the first ventricular beat was evident after 3.1 +/- 0.9 s and sinus node activity recovered with a time constant of 3.0 +/- 1.1 s. Because sinus node and ventricular automaticity recovered within seconds after ATP infusion was discontinued in vitro, recovery in vivo is also likely to be determined by the short half-life (+1/2) of ATP.

Negative chronotropic and dromotropic effects of adenosine seem to be responsible for its antiarrhythmic action on supraventricular tachyarrhythmias. To further characterize the effects of adenosine on supraventricular arrhythmias heart rate, conduction, refractoriness, the time to steady-state of AV-nodal conduction slowing and of sinus rate reduction were evaluated.

One-hundred and fifty patients with thrombotic and 60 patients with embolic occlusions of the superficial femoral and/or popliteal artery underwent a simplified IAT (intra-arterial thrombolysis) procedure. Ten mg rt-PA combined with 3000 IU Heparin were infused over 6 h, thereafter the extent of thrombolysis was checked fluoroscopically and the above mentioned treatment course repeated up to four times if necessary. The IAT regimen employed did not involve mechanical recanalization attempts; if complete thrombolysis revealed an underlying stenosis, a PTA (percutaneous transluminal angioplasty) was subsequently performed. IAT resulted in complete recanalization of 88 thrombotic occlusions (59%; 95% confidence interval: 50.8%-66.8%) and of 53 embolic occlusions (88%; 95% confidence interval: 77.1%-94.8% P < 0.001). In a further 33 (22%) thrombotic and four (7%) embolic occlusions IAT reduced the length of the occluded segment. At discharge, 102 (67%) patients with thrombotic and 55 (92%) patients with embolic occlusions were clinically improved. Overall, untoward effects occurred in 60 patients (29%): 47 (22%) were minor. Four patients (2%) suffered a systemic haemorrhage (three gastrointestinal, one macrohaematuria). The cumulative potency rate was significantly higher in patients with embolic occlusions throughout follow-up (82% vs 49% for thrombotic occlusions at 2 years, P < 0.001). Although all amputations were carried out in patients with thrombotic occlusions, follow-up mortality did not differ significantly between patients with embolic and thrombotic occlusions.