Wolf Rafflenbeul

Role of thrombolysis and thrombin in patients with acute coronary occlusion during percutaneous transluminal coronary angioplasty

In a series of 447 patients with single vessel angioplasty, 27 (6.0%) had acute thrombotic occlusion early after the procedure. They were treated with combined intracoronary (20 mg)/intravenous (50 mg) thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and repeat mild balloon inflations. Reopening of the vessel was achieved in 22 patients (81.5%). Follow-up coronary angiography 24 to 36 h later revealed reocclusion in 12 patients (54.5%). Thrombin levels measured as thrombin-antithrombin-III complex in patients with successful thrombolysis and persistent patency decreased from 8.5 +/- 11.4 micrograms/liter at baseline to 3.5 +/- 1.4 micrograms/liter 120 min after the start of thrombolysis; these levels increased from 9.4 +/- 15.0 micrograms/liter at baseline to 15.7 +/- 13.5 micrograms/liter 120 min after the start of thrombolysis in the patients with unsuccessful thrombolysis or early reocclusion (p less than 0.05). When a borderline value for thrombin-antithrombin-III complex level of 6 micrograms/liter was selected to separate the two groups of patients, patients with an unfavorable clinical course were identified 120 min after the start of thrombolysis by levels greater than 6 micrograms/liter (sensitivity 100%, specificity 92.8%). Thus, after abrupt thrombotic vessel closure during coronary angioplasty, the short-term results of thrombolysis seem to be governed by the release of thrombin. In two thirds of patients, however, the thrombin release cannot be suppressed by concomitant aspirin and heparin therapy. Even after successful reopening of the vessel these patients should therefore undergo immediate aortocoronary bypass grafting.

Sixty-minute alteplase protocol: a new accelerated recombinant tissue-type plasminogen activator regimen for thrombolysis in acute myocardial infarction.

OBJECTIVES Our aim was to design and evaluate a new and easily administered recombinant tissue-type plasminogen activator (rt-PA) regimen for thrombolysis in acute myocardial infarction (AMI) based on established pharmacokinetic data that improve the reperfusion success rate. BACKGROUND Rapid restoration of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow is a primary predictor of mortality after thrombolysis in AMI. However, TIMI grade 3 patency rates 90 min into thrombolysis of only 50% to 60% indicate an obvious need for improved thrombolytic regimens. METHODS Pharmacokinetic simulations were performed to design a new rt-PA regimen. We aimed for a plateau tissue-type plasminogen activator (t-PA) plasma level similar to that of the first plateau of the Neuhaus regimen. These aims were achieved with a 20-mg rt-PA intravenous (i.v.) bolus followed by an 80-mg i.v. infusion over 60 min (regimen A). This regimen was tested in a consecutive comparative trial in 80 patients versus 2.25 10(6) IU of streptokinase/60 min (B), and 70 mg (C) or 100 mg (D) of rt-PA over 90 min. Subsequently, a confirmation trial of regimen A in 254 consecutive patients was performed with angiographic assessment by independent investigators of patency at 90 min. RESULTS The comparative phase of the trial yielded, respectively, TIMI grade 3 and total patency (TIMI grades 2 and 3) of 80% and 85% (regimen A), 35% and 50% (B), 50% and 55% (C) and 60% and 70% (D). In the confirmation phase of the trial, regimen A yielded 81.1% TIMI grade 3 and 87.0% total patency. At follow-up angiography 7 (4.1%) of 169 vessels had reoccluded. In-hospital mortality rate was 1.2%. Nadir levels of fibrinogen, plasminogen and alpha2-antiplasmin were 3.6 +/- 0.8 mg/ml, 60 +/- 21% and 42 +/- 16%, respectively (mean +/- SD). Fifty-seven patients (22.4%) suffered from bleeding; 3.5% needed blood transfusions. CONCLUSIONS The 60-min alteplase thrombolysis in AMI protocol achieved a TIMI grade 3 patency rate of 81.1% at 90 min with no indication of an increased bleeding hazard; it was associated with a 1.2% overall mortality rate. These results are substantially better than those reported from all currently utilized regimens. Head to head comparison with established thrombolytic regimens in a large-scale randomized trial is warranted.

International nifedipine trial on anti-atherosclerotic therapy (INTACT) - methodologic implications and results of a coronary angiographic follow-up study using computer-assisted film analysis

Animal experiments demonstrated a significant suppressive effect of various calcium channel blockers on the formation of atherosclerotic lesions. Therefore, a prospective, placebo-controlled, randomized, double blind multicenter study was performed to investigate the inhibitory influence of the calcium channel blocker nifedipine (80 mg/day) on the progression of coronary artery disease in man. Study endpoints were changes of coronary morphology documented by coronary angiography with particular respect to the formation of new coronary stenoses. In 348 out of 425 patients included in the study, coronary angiograms were repeated after three years. The angiograms were standardized by induction of a maximal coronary vasodilation with high doses of nitrates and by using absolutely identical angiographic projections. Quantitative analysis of coronary cineangiograms was performed with the computer-assisted contour detection system CAAS. Parameters were mean and minimal diameter of all segments and minimal stenosis diameter, percent diameter stenosis, length and plaque area of all stenoses.Continuous intake of study medication was registered in 282 patients, 134 on nifedipine and 148 patients on placebo. In these patients, a total of 3808 coronary segments with 893 stenoses (⩾ 20% diameter reduction in at least one angiographic projection) were compared on the baseline and follow-up cineangiograms. The changes in all angiographic parameters analyzed averaged over all patients by considering all angiographic projections analyzed, indicated significant progression of the disease (p < 0.006). The average changes in all parameters were even about three times more profound, when in the individual patients only the respective projections indicating the maximal changes were considered for the calculation (p < 0.001). However, with neither of these two analysis modes, the differences in progression between the treatment groups were statistically significant.In the follow-up angiograms, a total of 196 new coronary lesions (185 stenoses, 11 occlusions) were found at previously normal arterial sites. In patients on nifedipine, an average of only 0.58 new lesions per patient were detected versus 0,80 lesions per patient on placebo (−27%; p=0.031).INTACT is the first prospective angiographic trial on the progression of coronary artery disease using computer-assisted quantitative coronary angiography in such a high number of patients. All parameters analyzed indicated significant progression of coronary artery sclerosis. Nifedipine had no influence on the progression of preexisting coronary stenoses, but inhibited significantly the formation of new angiographically recognizable lesions. Further prospective coronary angiographic trials with calcium channel blockers using a comparably exact method are needed to confirm the results of this study.

Vasodilatory effects of nisoldipine on coronary arteries—Correlation with plasma levels

SummaryVasomotion of angiographically normal and stenotic epicardial coronary arteries was analyzed up to 15 minutes after the onset of an intravenous infusion (4 minutes) of 0.5 mg (13 patients, group A) or 1 mg nisoldipine (13 patients, group B). After both doses the maximal increase of the mean diameters of normal coronary segments was achieved not before the 15th minute, averaging 11±6% in group A (p<0.001) and 18±9% in group B (p<0.001). Eleven of 15 and 8 of 9 coronary stenoses in groups A and B dilated to 5–80% and 15–70%, respectively.The nisoldipine concentration reached maximal levels at the end of the infusion (fourth minute) with an average of 8 ±4 ng/ml and 17±7 ng/ml in groups A and B, respectively. A significant correlation between nisoldipine plasma levels and dilation of normal coronary segments was obtained only with the individual maxima of these parameters and only in group A (p<0.01). The hysteresis of the coronary dilation in relation to the drug plasma levels may be due to the high receptor affinity of nisoldipine.In either group nisoldipine provoked a persistent increase in coronary sinus oxygen sáturation (p<0.01) and a substantial and prolonged drop in systolic and diastolic aortic pressure (p<0.001). Both doses of nisoldipine induced a rise in heart rate (p<0.01) and a slight drop in the rate-pressure product (p<0.05).

Quantitative angiographic follow-up studies on the development of coronary artery disease: which coronary segments should be analyzed? Experience from INTACT

Angiographic follow-up studies on the evolution of coronary artery disease are of increasing relevance. It has still to be evaluated which coronary segments are predominantly involved in the process of atherosclerosis and, thus, should be preferably included in the analysis. Therefore, the correlation of progression and regression of coronary disease with the diameter and location (proximal, mid or distal) of coronary segments was investigated from the data of the INTACT-study, in which 25 different coronary segments were defined including anatomic variants of rather distal segments. In 348 patients with coronary artery disease, standardized coronary angiograms were repeated within 3 years and were quantitatively analyzed (CAAS). In 1063 coronary stenoses (% diameter stenosis > 20%) compared from both angiograms, progression and regression were not influenced by diameter nor location of arterial segments. In the follow-up angiograms, the number of new lesions (stenoses and occlusions) per coronary segment differed with regard to segment diameter (> 3 mm: 64/1125 (6%); 2–3 mm: 139/1967 (7%);<2 mm: 44/1756 (2%); p<0.001) and location of segments (proximal: 86/1285 (7%); mid: 84/1193 (7%); distal: 77/2370 (3%); p<0.001). Out of 77 distal new lesions, only 25 (32%) were found in segments<2 mm in diameter.Since the absolute number of new lesions was high in distal coronary segments, but low in segments with diameters<2 mm, angiographic follow-up studies should analyze coronary segments at any location, but may neglect segments with diameters smaller than 2 mm.

Update on cardiac catheterization and coronary arteriography.

Indications for cardiac catheterization--including coronary angiography--have substantially broadened with the advent of nonsurgical therapeutic interventions performed in the catheterization laboratory. Consequently, the increasing number of facilities performing these procedures require clear and unmistakable guidelines regarding the indications for and the safety and ethical aspects of the procedure. Technical developments in image acquisition and evaluation, such as quantitative analysis, allow the exact, reproducible assessment of minute changes in cardiac morphology and function, the evaluation of which becomes increasingly important in prognosis-related clinical trials.

Behandlung der Myokardischämie mit Kalziumantagonisten

Kalzium ist das haufigste Kation im menschlichen Korper. Seine Bewegungen durch die Membran erregbarer Zellen und seine Akkumulation innerhalb der Zelle sind von fundamentaler Bedeutung fur die spezifische Aktivitat von Geweben. Allgemein ist die Konzentration von Kalzium im Zytosol nur ein geringer Anteil der Kalziumkonzentration im Plasma und weitgehend unabhangig von den normalen Schwankungen im Plasma-Kalzium [12]. Daher liegt eine wesentliche Voraussetzung fur die intrazellulare Kalziumhomoostase in einem sehr prazisen Modulationsmechanismus der Eintritts- und Austrittsrate von Kalzium im Zusammenwirken mit der Funktion des sarkoplasmatischen Retikulums und der Mitochondrien. Eine Steigerung des intrazellularen Kalziums auf abnormal hohe Spiegel kann Zellschaden oder Zelltod verursachen. Zellmembranen weisen eine niedrige Permeabilitat fur Kalzium auf, das in die Zellen im wesentlichen durch spezifische Kalziumkanale eintritt.

Treatment of Myocardial Ischemia with Calcium Antagonists

Calcium is the most common cation in the human body. Its movements through the membrane of excitable cells and its accumulation within the cell are of fundamental importance for the specific activity of tissues. Generally, the concentration of calcium in the cytosol is only a small fraction of the calcium concentration in the plasma, and it is largely independent of the normal variations in plasma calcium [12]. Therefore, a prerequisite for intracellular calcium homeostasis is a very precise modulation mechanism of the entry and efflux rate of calcium together with functioning sarcoplasmic reticulum and mitochondria. Increasing intracellular calcium to abnormally high levels may cause cell injury or cell death. Cell membranes exhibit a low permeability to calcium which enters cells predominantly through specific calcium channels.