Martin Decrinis

A prospective evaluation of sensitivity and specificity of the ankle/brachial index in the follow-up of superficial femoral artery occlusions treated by angioplasty.

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.

Effects of endothelin on the cardiovascular system and on smooth muscle preparations in different species.

Summary(1) The actions of porcine endothelin (ET), an endothelium-derived vasoconstrictor peptide, have been investigated in several in vitro smooth and cardiac muscle preparation as well as on the blood pressure of anaesthetized rats and rabbits. (2) In isolated visceral smooth muscles (guinea pig ileum, rat colon and uterus, rabbit jejunum) ET caused a long-lasting contraction which persisted after repeated rinsing. ET did not interfere with the spontaneous phasic activity of the rabbit jejunum or with contractions evoked by histamine or carbachol. (3) ET contracted isolated blood vessels (portal vein of guinea-pig and rat). In isolated perfused organs (rabbit ear, guinea-pig lung, rat mesentery and hindpaw) ET led to a long-lasting vasoconstriction. In the isolated perfused guinea-pig lung ET caused vaso- and bronchoconstriction. (4) ET produced a long-lasting positive inotropic effect in spontaneously beating isolated guinea-pig atria. The positive inotropic action of strophanthin was augmented in the presence of ET. (5) In the isolated perfused guinea-pig and rat hearts the prominent effect of ET was a long-lasting coronary vasoconstriction. (6) Pithed rats responded to i.v. injection of ET with a long-lasting increase in blood pressure. In pentobarbitone anaesthetized rats pretreated either with atropine, with guanethidine plus atropine, or with guanethidine plus atropine plus indomethacin, the long-lasting increase in blood pressure was smaller than in pithed rats whereas the initial short-lasting decrease in blood pressure was more pronounced; in pentobarbitone anaesthetized rabbits endothelin caused bronchoconstriction, a decrease in blood pressure and a pronounced increase in central venous pressure possibly resulting from pulmonary or coronary artery constriction or a combination of both effects. (7) Neither topical nor systemic application of ET influenced the bleeding time from small rat mesenteric arteries. (8) The general effect of ET on visceral, bronchial and vascular smooth muscles was a longlasting contraction. Despite its general constrictor potency seen in isolated vascular preparations ET can cause a transient decrease in arterial blood pressure in anaesthetized rats and rabbits. The role of ET when released from vascular endothelium remains a matter of speculation.

Action of Atp on Ventricular Automaticity

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.

Thrombolytic Treatment and Balloon Angioplasty in Chronic Occlusion of the Aortic Bifurcation

Complete occlusion of the subrenal aorta is usually initiated by arteriosclerotic lesions at the aortic bifurcation, including the common iliac arteries (aortoiliac disease). Aortoiliac disease is typically managed by implanting a prosthetic aortobifemoral bypass graft, which offers good long-term patency rates [1]. However, this procedure has perioperative mortality rates of 1% to 5% [1], and direct aortic surgery is accompanied by major early complications in 5% to 10% of patients [2]. Hemorrhage, acute limb ischemia due to graft thrombosis or distal thromboembolism, acute renal failure, spinal cord or bowel ischemia, and myocardial infarction are the most common major early complications [2]. In occluded arteries of the limb, thrombolytic treatment has become a successful alternative to bypass surgery [3, 4]. Reperfusion by thrombolysis might be more acceptable than surgical reconstruction to the patient with aortoiliac disease. The main disadvantages of thrombolytic treatment are the inability to predict successful thrombolysis and the risk for hemorrhage. We know of no reports on the outcome of thrombolysis or on the use of thrombolytic agents in chronic infrarenal aortic occlusions. Therefore, we did an uncontrolled pilot study on thrombolysis in aortoiliac disease using three different thrombolytic drugs. Methods Patients Forty-three patients with aortoiliac disease were referred to the Division of Angiology of the Department of Internal Medicine or to the Department of Vascular Surgery during the study period. Thirty-nine of these patients were considered eligible for aortobifemoral prosthetic bypass grafting. Twenty-five fulfilled the inclusion criteria for systemic thrombolysis: age less than 65 years, localized aortoiliac disease with occlusive lesions confined to the distal aorta or the common iliac arteries or both without obstructions of the lower-extremity arteries documented by angiography, a history of lifestyle-limiting claudication of less than 3 years, and unchanged symptoms for more than 6 months. Patients with acute gastroduodenal ulcers, previous cerebrovascular events, an obstructed carotid artery, or atrial fibrillation with dilated cardiac chambers were excluded from the study. Each patient gave written informed consent, and the study protocol was approved by the ethics committee of Karl-Franzens University. Baseline data of the patients are given in Table 1. Table 1. Baseline Characteristics of Patients with Totally Occluded Aortic Bifurcation Receiving Streptokinase, Urokinase, or Recombinant Tissue-Type Plasminogen Activator for Thrombolytic Therapy Eligible patients were randomly assigned to three groups, using a standard design for conducting clinical trials [5]. Patients received either streptokinase (Streptase, Behring; Marburg, Germany): an intravenous bolus of 250 000 IU followed by 100 000 IU/h; urokinase (Urokinase, Serono; Milano, Italy): an intravenous bolus of 600 000 IU followed by 150 000 IU/h; or recombinant tissue-type plasminogen activator (rt-PA; Actilyse, Bender; Vienna, Austria): 0.05 mg/kg body weight per hour. Heparin was administered to all patients whose thrombin times were less than twice the control value. On the basis of our experience using fibrinolytic drugs in peripheral occlusive disease and in deep venous thrombosis, we discontinued thrombolytic therapy after day 7 in the streptokinase group and in the rt-PA group and after day 14 in the urokinase group, regardless of whether recanalization had occurred. Criteria for premature cessation of therapy were major hemorrhage, cerebral embolism, anaphylactic reaction, or presumed recanalization. Peripheral arterial circulation was assessed daily by palpating pulses, obtaining the ankle/arm pressure ratio, and estimating the blood flow velocity by duplex scanning in the common femoral arteries. All patients had follow-up angiography either if recanalization of at least one iliac artery was presumed because of an increase (>0.2) in the ankle/arm pressure ratio and in the maximal systolic blood flow velocity (>0.5 m/s) in a common femoral artery or after completion of the scheduled thrombolytic treatment period. If residual stenosis or one-sided occlusion of the common iliac artery still existed after thrombolytic therapy, percutaneous transluminal angioplasty was attempted. Patients without any reopened arterial segment after thrombolytic treatment had a prosthetic aortobifemoral bypass graft inserted. All patients had anticoagulation therapy after recanalization, initially by intravenous heparin (1000 IU/h) followed by a vitamin K-antagonist for at least 24 months. Definition of Results Recanalization was considered to be complete when the aortic bifurcation was reperfused in the follow-up angiogram, regardless of any residual stenosis. Recanalization was considered to be partial when the aorta and one common and external iliac artery were reperfused and the contralateral iliac artery was still occluded. Clinical success was defined as an improvement by at least one stage according to the classification of peripheral arterial occlusive disease proposed by Rutherford and colleagues [6] and an increase of the ankle/arm pressure ratio by at least 0.2. Assays of Blood Coagulation and Fibrinolysis Blood was collected twice daily into two polyethylene tubes from a short, indwelling peripheral venous catheter. One tube contained 0.5-mL sodium citrate (final concentration, 0.01 mol/L), whereas the other contained 0.5-mL sodium citrate and aprotinin (final concentration, 250 kIU/mL) to prevent in vitro fibrinogenolysis. Plasma was obtained by centrifugation at 800g for 15 minutes and was then stored in six 0.5-mL aliquots at 70C. Complete blood counts and measurements of prothrombin time, activated partial thromboplastin time, and thrombin time were obtained twice daily within 30 minutes after the blood was drawn. Fibrinogen levels and cross-linked fibrin degradation products were estimated in the restored plasma as a single unit within 4 months. Plasma fibrinogen was measured by the sodium sulfite precipitation method [7], and cross-linked fibrin degradation products were measured by a quantitative enzyme-linked immunoassay with a specific monoclonal antibody (ELISA-D-DIMER, Boehringer Mannheim; Mannheim, Germany) [8]. Complete blood counts were obtained with a Coulter Counter (Coulter; Hialeah, Florida); prothrombin time and activated partial thromboplastin time were measured by thromboplastin C (Instrumentation Laboratory SpA; Milano, Italy) and thrombin time by the human thrombin method (Instrumentation Laboratory Sud S.p.A.; Ascoli Piceno, Italy). Statistical Analysis All values are expressed as mean SD. Significant changes from baseline values or among groups were evaluated by the paired and unpaired t-test, respectively, based on a 95% CI. Differences in the recanalization rate of three groups were assessed using the chi-square test [9]. Results Recanalization Thrombolytic treatment resulted in a complete recanalization of the aortic bifurcation in seven (28%) patients; in eight (32%) patients, recanalization of the aorta and one iliac artery was observed. Thrombolytic treatment failed in 10 (40%) patients. Subsequent balloon angioplasty of residual stenosis or one-sided iliac artery occlusion was successfully done in 8 of 15 patients with successful thrombolysis. Balloon dilatation failed in 2 patients; these 2 patients and the 10 patients in whom thrombolytic treatment had failed underwent bypass grafting (Figure 1). Figure 1. Overall results of thrombolytic treatment and subsequent therapy in patients with totally occluded aortic bifurcation. Five of the 15 patients with complete recanalization had received streptokinase; 4, urokinase; and 6, rt-PA. The failure rate was 3 of 8 (38%) in the streptokinase group; 3 of 7 (42%) in the urokinase group; and 4 of 10 (40%) in the rt-PA group. On day 5 of treatment, successful thrombolysis was ascertained in 6 of 10 patients in the rt-PA group but in none of the patients in the streptokinase group or the urokinase group (P < 0.005) (Figure 2). Figure 2. Cumulative recanalization rates with different types of thrombolytic therapy. Clinical Improvement The ankle/arm pressure ratio increased significantly (P < 0.001) in all patients after the aortic bifurcation was reopened by thrombolysis and subsequent balloon dilatation. In the patients who underwent bypass grafting, the ankle/arm pressure ratio increased as well (Figure 3). No patients had any further symptoms of claudication. Figure 3. Ankle/arm pressure ratio in patients with totally occluded aortic bifurcation before and after reopening and during the follow-up period. Side Effects and Complications No major complications occurred. Streptokinase induced fever in four of eight patients (maximum temperature, 38.5 C), which responded promptly to administration of 125 mg of prednisolone. Peripheral emboli occurred in four patients. Total lysis of the emboli was confirmed by angiography in all patients at the end of thrombolytic treatment. Minor bleeding from venous puncture sites occurred in 17 (68%) patients: in 4 patients in the streptokinase group (50%) after day 5 of treatment; in 3 patients in the urokinase group (43%) after day 8; and in 7 patients in the rt-PA group (70%) after day 3 of treatment. Thrombolytic treatment with rt-PA was discontinued on day 6 in 4 patients because of increasing hematomas located around the venous puncture sites. Eleven of the 12 patients who had bypass grafting also had no major complications; 1 patient had a nonfatal myocardial infarction 4 days after the operation. Hypertensive crisis (systolic blood pressure, 240 mm Hg) in 2 patients and angina pectoris in 3 other patients occurring during the first 3 postoperative days were treated successfully. Laboratory Findings Fibrinogen levels were significantly influenced to a greater extent by streptokinase than by urokinase (P = 0.00

Effects of semotiadil, a novel Ca2+ channel antagonist, on the electrical activity of Langendorff-perfused guinea pig hearts in comparison with diltiazem, amlodipine and nifedipine

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 microM) markedly prolonged sinus node recovery time and in the presence of diltiazem (10 microM) 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.

Frequency-dependent effects of adenosine and verapamil on atrioventricular conduction of isolated guinea pig hearts.

Frequency-dependent depressant effects of a drug on slow channels in the atrioventricular (AV) node are important in its efficacy against supraventricular tachycardias. Verapamil terminates reentrant supraventricular arrhythmias by depressing conduction through the AV node. Similar effects have been described for adenosine. We compared the use-dependent effects of both drugs on AV nodal conduction in isolated guinea pig hearts perfused by the method of Langendorff. Adenosine 3 μM and verapamil 0.01 μM caused a comparable prolongation of AV conduction time (AVCT) and reduction in sinus rate (SR). The time dependence of drug-induced changes in AV conduction was characterized after the atrial pacing rate was changed abruptly. The basic cycle length was shortened abruptly from 240 to 180 ms. The resulting time constant for adenosine (T = 467 ± 187 beats, mean ± SD) was significantly (p < 0.05) longer than that for verapamil (T = 264 ± 121 beats). At a pacing cycle length of 180 ms, the rate-dependent conduction slowing tended to be more pronounced in the presence of adenosine than of verapamil. Adenosine had more pronounced frequency-dependent effects on AV conduction than did the calcium channel blocker verapamil. This may explain the higher clinical efficacy of adenosine in supraventricular tachycardias in which the AV node forms a part of the reentrant circuit.

Comparison of the frequency-dependent effects on the atrioventricular node of verapamil, amiodarone, digoxin, and diltiazem in isolated guinea pig hearts.

Summary To slow ventricular rate during supraventric-ular 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 μM), amiodarone (10 μM), digoxin (0.6 nM), and diltiazem (0.03 μM) 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 (T = 194 ± 45 beats, mean ± SEM) and the shortest during perfusion with diltiazem (T = 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 T was greatest with diltiazem, which may explain the high efficacy of diltiazem in controlling ventricular rate during atrial fibrillation.

Frequency-dependent effects of propafenone decrease with duration of ventricular tachycardia in isolated guinea pig hearts

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.

How to Measure AV Nodal Refractoriness in the Presence of Verapamil, Amiodarone, Digoxin, and Diltiazem

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 (S1) (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 S1) at a pacing cycle length of 180 ms followed by the test stimulus (S2). 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.

Rate-dependent effects of ajmaline and propafenone on atrioventricular conduction.

The aim of the present study was to characterize the time dependence of the depressant effects of ajmaline and propafenone on the Ca(2+)-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 microM and propafenone at a concentration of 0.3 microM 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 (tau on) 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 (tau off) 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 Ca(2+)-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.