Myocardial surface PO2--an indicator of myocardial tissue oxygenation?

The validity of myocardial surface tissue PO2 (PtO2) as a reliable indicator of transmural myocardial tissue oxygenation was studied in six anaesthetised, open chest pigs. Epicardial surface PtO2 was correlated with other variables of myocardial tissue oxygenation such as regional blood flow, coronary venous PO2, O2 saturation, PCO2 and regional myocardial lactate extraction. The study design was based on an experimental model in which the effects of a pacing induced tachycardia on tissue oxygenation of ischaemic and normally supplied myocardium were measured. Two platinum multiwire surface electrodes were placed on the epicardium, on the areas supplied by the left anterior descending coronary artery (LAD) and the left circumflex coronary artery (CX). The LAD was constricted to reduce mean surface PtO2 in the LAD area to about 50% of its baseline value. This did not affect surface PtO2 in the CX area. The reduction of surface PtO2 in the LAD area was associated with decreases in coronary venous PO2 and O2 saturation and with increases in coronary venous lactate and PCO2. Subendocardial regional blood flow and the subendocardial to subepicardial flow ratio were significantly lower than in the CX area. Increasing the heart rate by pacing (+45 beats.min-1) led to an increased degree of ischaemia as shown by fall in surface PtO2 in the LAD area to values around zero kPa, by marked increase in coronary venous lactate and PCO2, by reduction in total (-10%) and subendocardial (-40%) LAD flow and by deterioration of the subendocardial to subepicardial flow ratio. The increased degree of ischaemia was not accompanied by an increase in O2 extraction. The marked decrease in surface PtO2 occurred in spite of a slight increase in the subepicardial regional blood flow (+10%); thus the increase in O2 delivery was not sufficient to meet the increase in O2 demand. Total flow was increased by 27% in the CX area without changes in the subendocardial to subepicardial flow ratio and in the surface PtO2 values. When pacing was stopped, surface values of PtO2 in the LAD area returned to prepacing values, as did lactate extraction and coronary venous PCO2. Clear and close relationships with surface PtO2 were found for regional lactate extraction, coronary venous PCO2 and the normalised subendocardial RBF. Poor or no correlations were found for the normalised subepicardial regional blood flow, the coronary venous O2 saturation and the absolute values of subendocardial and subepicardial regional blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of atherectomy specimens.

Atherectomy specimens may be regarded as biopsy tissue excised from human vascular target lesions. Proceeding from contrary histologic findings that attribute focal hypercellularity to restenosis, and hypocellularity to chronic lesions, further analysis of atherectomy specimens was performed to study ultrastructural characteristics and functional aspects propagated by both lesion types. Transmission electron microscopy examination showed that intimal smooth muscle cells (SMCs) were the predominant cells in both primary and restenotic lesions. SMCs exhibited variable degrees of metabolic activation, typically higher in SMCs of restenotic lesions. This SMC phenotype was equally expressed when tissue samples were placed in a cell culture model. In an attempt to quantify SMC activity, proliferative as well as migratory activities of cultured cells were measured by growth curves and a computer-assisted motion analysis system, respectively. A 2- to 3-fold increase of both activity determinants was observed with SMCs cultivated from restenotic lesions compared with those from primary lesions, irrespective of their coronary or peripheral origin. Drug-induced interference of human SMC metabolic activation and antagonism to their proliferative and migratory activities may be helpful in evaluation of therapeutic concepts to prevent restenosis. The antitubulin colchicine was studied for its effect on the defined determinants. The data in vitro demonstrate that colchicine decreased proliferative and migratory activity of SMCs and caused disorganization of the cytoplasmic ultrastructure. In conclusion, electron microscopy and cell culture studies may help to shed more light on the structures and mechanisms underlying restenosis and plaque growth. Deliberate counteraction of any of the specific early events implicated in these complex pathobiologic processes may eventually become effective means to suppress restenosis and may thus result in a prophylactic as well as therapeutic treatment of the diseased vascular wall.

Local photodynamic therapy reduces tissue hyperplasia in an experimental restenosis model.

Local photodynamic therapy may have potential in preventing myointimal hyperplasia after angioplasty. In this study, the effect of photodynamic therapy was evaluated in an experimental model of restenosis. Standardized unidirectional arterial injury with a directional atherectomy catheter was performed in porcine arteries. Animals were randomly allocated to four groups: group 1, unidirectional injury only; group 2, injury followed by local delivery of photosensitizer; group 3, injury followed by local exposure to monochromatic light; and group 4, where injury was followed by local drug delivery of photosensitizer and subsequent exposure to light (photodynamic therapy). Seven, 14 or 21 days after treatment, all experimental vessels were excised, fixed and processed for histology. An inflammatory and myoproliferative response was observed after injury in vessels from groups 1, 2 and 3. In group 4, after injury followed by photodynamic therapy, the myoproliferative response was significantly reduced. Thus, in this study, tissue hyperplasia after unidirectional injury was effectively suppressed by photodynamic therapy.

A new catheter for prolonged local drug application.

BACKGROUND: Local drug delivery using a new 5F catheter with six small needles is described. The needles can be extended laterally into vascular tissue for drug deposition. METHODS: A fluorescent indicator (Photofrin) was injected with a new local drug delivery device into porcine carotid arteries. The vessels were explanted 15, 30, 60 min and 14 days after local drug delivery. Vascular segments were analyzed using semi-quantitative measurement of fluorescence (calculated in relation to a standard, 100% representing the maximum fluorescence achieved by systemic intravenous application of Photofrin). RESULTS: Maximum fluorescence was found in adventitia (15 min: 374%; 30 min: 388%; 60 min: 251%). In intimal tissue, the detected fluorescence was 107% after 15 min, 294% after 30 min, and 25% after 60 min. Media fluorescence was lower (15 min: 151%, 30 min: 102%, 60 min: 55%). No systemic drug content was measured. Fourteen days after local drug delivery, 15% of maximal fluorescence was still found in media but no adverse tissue hyperplasia was observed. CONCLUSIONS: These experiments demonstrate that high-dose perivascular local drug delivery is feasible and allows prolonged and selective application of drugs in a vessel segment without side effects.

High-resolution MR angiography: results in diseased arteries.

The purpose of this study was to investigate the value of a respiratory-gated three-dimensional (3D) magnetic resonance angiographic technique (MRCA) in identifying coronary arteries in healthy volunteers and patients with proximal coronary artery stenoses and to compare the results of the navigator echo technique in the assessment of coronary artery stenosis with conventional coronary angiography. Twenty healthy volunteers and twenty patients with proximal coronary artery stenosis were examined at 1.5 Teslas with a cardiac-gated and retrospective respiratory-gated 3D gradient echo sequence. Visualization of the main coronary arteries was analyzed after curved MPR-reconstruction in three defined segments. For the assessment of image quality, a grading system including six scores was used to evaluate 400 vessel segments. Detection of coronary artery stenosis was compared with conventional coronary angiography by two blinded readers. In healthy volunteers, an image quality with a score of at least 3 (i.e., completely identified coronary arteries with major luminal irregularities) was found in 55% for the proximal segment, 47% for the middle segment and 20% for the distal coronary artery segment. Respective data for patients were 69% for the proximal segment, 47% for the middle segment and 20% for the distal segment. In contrast to other studies, we compared MRCA and conventional coronary angiography in the assessment of stenoses for all coronary vessels and for selected coronary vessels with high image quality. For the assessment of coronary artery stenoses (n = 53), sensitivity was 73% and specificity was 50% after evaluation of all patients by two blinded readers. A sensitivity of 79% and a specificity of 54% were found for evaluation of coronary vessels with an image quality score of at least 3. With the navigator echo MR technique, a complete 3D visualization of the main coronary arteries is possible in cases with variable image quality, but further experience and improvement of the prospective navigator echo sequence using shorter acquisition times is necessary for reliable assessment of coronary artery stenoses.

Local drug delivery via transvascular injection.

BACKGROUND: In this experimental series we tested drug distribution and systemic leakage using local drug delivery with a new transvascular injection system. METHODS: Porcine femoral and carotid arteries (n = 56) underwent local drug application with a new 5 French (Fr) over-the-wire needle-injection catheter system (NIC) using three needles. A radioactive indicator [C14-Carvedilol, 2.0 milliliter (ml); 0.03 milligram (mg)] was injected in two carotid and two femoral vessels in parallel. Serial blood withdrawal was performed thereafter. After randomization to different explantation times, the vessels, perivascular tissue, liver and spleen were removed [0.5, 1, 1.5, 3 and 4 hours after injection, respectively]. Radioactivity was determined in a scintillation counter or with autoradiography. The indicator amount was calculated in relation to total drug amount (100%). RESULTS: Use of the NIC caused vessel texture alteration in non-diseased porcine vessels, seen as vessel wall penetration and perivascular edema. After single injection the maximum of the indicator was found in perivascular tissue 0.5 hours at the application site (carotid perivascular tissue: 7.48%; femoral perivascular tissue: 2.56%). Thereafter, radioactivity in the artery increased and perivascular content declined. The maximum in femoral arteries (1 hour; 1.96%) occurred earlier and was significantly lower compared to carotid arteries (2 hours; 7.75%). Four hours post-injection, 1.4% of total drug amount was detectable in the carotid arteries and 0.6% was detected in the femoral arteries. Systemic content was measured after C14-Carvedilol application with a maximum in serum of 28% (10 minutes), liver 30% (0.5 hour) and spleen 0.6% (0.5 hour). After 3 hours, still 5% of the indicator was still measureable in the serum and liver and less than 0.1% was measurable in the spleen. LDD with the NIC system is dependent on the vascular anatomy. The data indicate redistribution from perivascular to vascular space thus allowing a prolonged vascular and perivascular drug delivery. The amount deliverable is lower than expected due to substantial systemic drug contamination with this catheter.

Results of directional peripheral atherectomy with reference to histology, histochemistry, and ultrastructure.

One hundred patients with symptomatic peripheral vascular disease were treated with a directional atherectomy catheter; 153 lesions comprising 98 stenoses and 55 occlusions were located in the iliac (n = 22), superficial femoral (n = 114), popliteal (n = 16), and anterior tibial (n = 1) arteries. The majority of these patients were poor candidates for balloon angioplasty because of the complexity of lesions. There were 70 eccentric and 28 concentric lesions and 55 occlusions (mean length 4.2 +/- 2.9 cm). Acute success rate was 94% for both stenoses and occlusions. Four patients were treated in both lower extremities. The stenoses were reduced from 85 +/- 12% to 12 +/- 10% acutely (occlusions 100% to 9 +/- 9%). Six-month angiographic follow-ups were performed in 81% of treated patients, the others refusing angiography. Mean stenosis after six months was 33 +/- 25% (occlusions 44 +/- 28%). Restenosis (> 50%) was found in 20% of treated lesions: 26% in concentric lesions, 8% in eccentric lesions, and 32% in occluded vessels. Treatment of peripheral vascular disease with the atherectomy device is safe and effective therapy with good long-term results. These results were obtained in complex lesions with 55 occlusions. Atherectomy seems to be particularly beneficial in the treatment of eccentric and complex stenoses and is not limited by occlusion or calcification. Furthermore, insight into the pathogenesis of arteriosclerosis and the development of restenosis is enabled by analysis of removed plaque material.

[Ultrastructural characteristics of cellular reaction to experimental catheter-induced lesions of arterial blood vessels]. / Ultrastrukturelle Charakteristika der zellulären Reaktion auf experimentelle katheterinduzierte Läsionen im arteriellen Gefässsystem.

UNLABELLED: After angioplasty, restenosis remains the major drawback of the procedure with an incidence of between 20-40%. It is a matter of concern whether the cellular alterations start immediately after directional atherectomy (DA) and if they are dependent on the depth of the lesion. METHOD: Cellular alterations immediately after DA were investigated using peripheral atherectomy in normal vessels of 30 pigs (A. femoralis, A. carotis communis). DA was used to remove material. The arteries were assigned to two groups according to the depth of vessel injury. (Group 1: lesions to the intima; Group 2: lesions to the media.) 68 arteries with 41 intimal and 27 media lacerations were excised 4 to 24 hours later and processed for transmission electron microscopy, histology and immunohistochemistry. RESULTS: Immediately after DA, thrombus formation at the site of the altered segment was found. A transient infiltration of polymorphonuclear leukocytes (PMN) occurred, especially if the media was lacerated, followed by the transformation of contractile smooth muscle cells (SMC) into the synthetic subtype. A marked myoproliferative response was found in Group 2 whereas only moderate tissue hyperplasia was seen in Group 1. CONCLUSION: The present data provides evidence that cellular alteration of the atherectomized vessel begins immediately after atherectomy. Subsequent to the initial temporary PMN infiltration, an activation of local SMC occurs at a very early stage. These effects and, in particular, a myoproliferative response were found lesions injured the internal elastic membrane, while only minor effects were seen when the lesion affected the intimal layer.

[Immunohistologic cell characterization of tissue of primary and re-stenoses]. / Immunhistologische Zellcharakterisierung von Gewebe aus Primär- und Restenosen.

Smooth muscle cells and macrophages are essential parts of arteriosclerotic lesions. This study should enable the analysis of different functional and morphological features of cells in primary and restenotic biopsies. Therefore detection of specific cell markers in human arteriosclerotic material derived from directional coronary atherectomy (DCA) of primary and restenotic lesions was used. Cryosections (2-4 microns) were stained immunohistologically (44 samples from 27 patients, 12 restenosis) with monoclonal antibodies. For further analysis antibodies against 5B5 (Prolylhydroxylase), alpha-actin, desmin and collagen I and IV were used. Endothelial structures (CD 31), T-cells and monocyte derived macrophages (CD 68, KP 1) were detected. In a second set-up alpha-actin and CD 68 were double-labelled. Semi-quantitative analysis in relation to total cell count was performed. The tissue removed consisted quantitatively of 78% intima- and 22% media-compartments and thrombus. 40% of the intimal area was comprised of low cellular compartments and in 57% high cellularity and foam-cells were found. In high cellular compartments 81% of the cells were positive for alpha-actin, only 13% of these cells were also positive for desmin. In intimal compartments in 58% of the cells macrophages were detected by CD-68 marker immunohistologically. 87% of these cells showed the expression of the 5B5 antigen (Prolylhydroxylase), in 90% monocytic antigenes were detected. Typical foam cells were not alpha-actin positive, whereas 40% of the CD 68 positive cells were alpha-actin positive. In myofibroblastic cells, positive staining with 5B5, collagen IV and extracellular matrix (collagen I) was present. Staining with antibodies against contractile filaments was diminished compared to the media compartments.(ABSTRACT TRUNCATED AT 250 WORDS)

Local Drug Delivery for Restenosis and Thrombosis Ñ Progress?

Platelet activation, inflammation, recoil, tissue hyperplasia and remodeling are pivotal pathophysiologic factors in acute myocardial ischemia and restenosis development after angioplasty. Even after the rising use of stents, the tremendous amount of resulting tissue hyperplasia remains a therapeutic problem. It has been suggested that short duration of effective drug levels and poor efficiency of systemic drug administration account for the failure of therapy in clinical trials. A rational effective therapy for angina and restenosis should therefore be locally administered at the site of vascular obliteration. Special local drug delivery devices could be used to administer sufficient drug amounts at the site that needs to be treated. Local drug delivery systems using modified balloon systems, stent systems or newly designed catheters have been developed. In experimental studies, different effects can be demonstrated by using endoluminal and adventitial substance delivery. Endoluminal application usually resulted in < 1% effective drug delivery in the arterial wall and short lasting deposition. Adventitial deposition led to higher mural concentrations; the drug was detectable for up to 21 days. In media, the maximum is still comparable to the maximum obtained after systemic application. Experimental studies indicate positive therapeutic effects in restenosis models. Feasibility has been proven in clinical studies of unstable angina with anticoagulants or antithrombotics. Further preclinical and preliminary clinical studies are needed to clarify regional drug distribution, regional wash-out, adverse effects and evaluation of long-term therapeutic effects. Recent developments in catheter techniques might enable effective local drug application in angina and restenosis prophylaxis with a reduction in systemic adverse effects. (Supported by DFG Go 739/1-1).

[Drug and instrumental therapeutic approaches for prevention of restenosis]. / Medikamentöse und instrumentelle Therapieansätze zur Restenoseprophylaxe.

In recent years, several of the shortcomings of coronary angioplasty have been successfully countered. With more effective measures of treating acute complications, better equipment and more experienced operators, there has been a subsequent expansion of the indications and the type of lesions suitable for angioplasty. In the long-term, however, the restenosis rate remains the limiting factor for the success of the procedure. To date, clinical studies using systemic therapy or alternative instrumental devices have not convincingly demonstrated a benefit in preventing restenosis. New devices have mostly been used to manage complications at angioplasty or to increase the type of lesions that can be tackled transluminally. This article will describe recent findings relating to the pathology of restenosis and then discuss a new therapeutic concept, local drug delivery to suppress restenosis. The aim of this method of drug application is to achieve a high local concentration of agents that inhibit restenosis, while avoiding systemic side-effects. Possible substances which could be utilized in this manner include conventional therapies such as platelet or calcium antagonists, or anti-thrombotic, anti-inflammatory or anti-proliferative treatments, and also novel agents such as gene therapy. The latter strategy might include inhibition of certain stimulatory factors that control restenosis, for example, through antisense oligonucleotides, or alternatively, augmentation of naturally occurring inhibitory factors, perhaps with expression vector plasmids and virus-mediated gene integration. The various ways in which these substances can be locally delivered to the arterial wall, together with results from initial experimental studies will be summarized. It is possible that eventually the combination of effective treatments with local drug delivery (LDD) may at last resolve the restenosis problem in patients.

[Local drug administration systems, preclinical and clinical use: perspectives and limitations]. / Lokale Medikamentenapplikationssysteme, präklinische und klinische Anwendung: Perspektiven und Limitationen.

Platelet activation, inflammation, recoil, tissue hyperplasia and remodeling are pivotal pathophysiologic factors in acute myocardial ischemia and restenosis development after angioplasty. It has been suggested that short duration of effective drug levels and poor efficiency of systemic drug administration account for the failure of therapy in clinical trials. A rational effective therapy for angina and restenosis should therefore be locally administered at the site of vascular obliteration. Special local drug delivery devices could be used to administer sufficient drug amounts at the site that needs to be treated. Local drug delivery systems using modified balloon systems, stent systems or newly designed catheters have been developed. In experimental studies different effects can be demonstrated by using endoluminal and adventitial substance delivery. Endoluminal application usually resulted in < 1% effective drug delivery in the arterial wall and short lasting deposition. Adventitial deposition led to higher mural concentrations and the drug was detectable therefore up to 21 days. In media and adventitia the maximum is still comparable to the maximum obtained after systemic application. Experimental studies indicate positive therapeutic effects in restenosis models. Feasibility has been proven in clinical studies of unstable angina with anticoagulants or antithrombotics. Further preclinical and preliminary clinical studies are needed to clarify regional drug distribution, regional wash-out, adverse effects and evaluation of long-term therapeutic effects. Recent developments in catheter techniques might enable effective local drug application in angina and restenosis prophylaxis with a reduction in systemic adverse effects.

[Percutaneous peripheral atherectomy in arterial occlusive disease. Angiographic and clinical acute and long-term results]. / Perkutane periphere Atherektomie bei arterieller Verschlusskrankheit. Angiographische und klinische Akut- und Langzeitergebnisse.

130 arteriosclerotic lesions--10 in the iliac, 109 in the superficial femoral, 10 in the popliteal and 1 in the anterior tibial artery--were treated by percutaneous atherectomy in 80 patients (62 men and 18 women: mean age 65 +/- 10 years). 23 of the lesions were concentric, 65 eccentric stenoses, while 42 were fully occlusive. 32 patients were in stage IIb (after Fontaine), 24 in stage IIa and 12 each in stage III or IV. Most of the stenoses were not suitable for conventional balloon dilatation because of their primary morphology. A good early angiographic result (residual stenosis less than 50%) was achieved in 94% of lesions. Mean stenosis degree was reduced from 85 +/- 12% to 12 +/- 10% (occlusions from 100% to 9 +/- 9%). The Doppler index increased from 0.6 +/- 0.18 to 0.85 +/- 0.15 (P less than 0.01). Follow-up angiography after 6 months in 104 lesions demonstrated an average stenosis degree of 33 +/- 25% (occlusions 44 +/- 28%). 26 of the 104 re-studied lesions fulfilled the criterion for re-stenosis (greater than 50%): six concentric ones and five eccentric ones, as well as 15 occlusions. These findings indicate that peripheral atherectomy can be employed with good short and long-term results even in morphologically unfavourable, markedly eccentric or calcified lesions and occlusions.

[Uptake and distribution of hematoporphyrin derivatives (HPD) in arteriosclerotic and normal vessel segments]. / Aufnahme und Verteilung von Hämatoporphyrinderivaten (HPD) in arteriosklerotischen und normalen Gefässsegmenten.

Percutaneous treatment of vascular disease is limited by a relatively high long-term restenosis rate. Proliferation of smooth muscle cells may be one of the major reasons for restenosis. Therefore, due to its selective cytotoxic effect, photodynamic therapy (PDT) with HPD-injection and local laser light-application might be a promising therapeutic principle as prophylaxis of restenosis. Up to now, PDT has been used clinically in the treatment of superficial tumors. We studied its potential application as an antiproliferative modality for restenosis prophylaxis. Basic conditions for therapeutic use are: uptake of HPD in arteriosclerotic vessels; arteriosclerotic lesions show a higher photosensitivity than normal vessel after application of HPD. We investigated the uptake of HPD (Photofrin II) in normal (n = 15) and arteriosclerotic (primary lesions n = 52; restenosis n = 10) human vessel segments using quantitative fluorescence detection after incubation with 2.5 micrograms and 5 micrograms HPD/ml cell culture medium. HPD content, as reflected by fluorescence intensity, was measured after 15, 30, 60 min, and 24 h of incubation. Fluorescence intensity was concentration-dependent, with 80% of the maximal uptake reached at 1 h. A preferential uptake of HPD was measured in arteriosclerotic as compared to normal vessel segments (primary lesion: fluorescence-ratio of 3:1 at 1 h; restenosed lesion: fluorescence-ratio of 4:1 at 1 h). In addition, highly cellular plaque segments like restenosed material showed markedly increased fluorescence as compared to acellular matrix. Uptake of HPD was quickly (within 1 h) and preferentially detected in arteriosclerotic segments. A selective cytotoxic effect when combined with laser light may result and could be applied to restenosis prophylaxis.

Ultrastructural characteristics of cellular reaction after experimentally induced lesions in the arterial vessel.

UNLABELLED: Restenosis after angioplasty occurs with an incidence of 20-50% and remains a major drawback. Certain randomized studies suggest that a bigger post-angioplasty lumen predicts a better long-term outcome. Conversely other studies showed a better outcome with limited injury. The present study aimed to investigate the depth of the lesion and relate this to cellular alterations after graded vascular injury. METHOD: Vessel segments of 30 pigs underwent injury using a directional atherectomy catheter. Vessels were assigned according to the extent of injury to Group 1 (intima lesion) or Group 2 (media injury). 2 hours to 7 days after injury, 68 arteries showing 41 intimal and 27 media lacerations were excised and processed for histology and transmission electron microscopy. RESULTS: Immediately after injury, thrombus formation was found at the site of the altered segment. A marked, transient infiltration of polymorphonuclear leukocytes (PMN) occurred only if the media was lacerated, starting within the first hours and increasing up until the 12 hours time point. The cellular infiltration was followed by a transformation of contractile myocytes to a synthetic subtype. The ratio of myofilaments to organelles decreased. A pronounced myoproliferative response was found in Group 2 after 7 days (p < 0.01), whereas only moderate tissue hyperplasia was seen in Group 1. CONCLUSION: The data presented provide evidence that the cellular alteration of injured vessels begins immediately. Subsequent to an initial temporary PMN infiltration, an activation of local myocytes occurs at a very early stage. In particular, a myoproliferative response was found only after deep injury with rupture of the internal elastic lamina.

[Coronary sinus blood flow after intracoronary or intravenous administration of bisoprolol in coronary disease]. / Koronarsinusdurchblutung nach intrakoronarer oder intravenöser Gabe von Bisoprolol bei koronarer Herzkrankheit.

OBJECTIVE: To measure changes in haemodynamics and myocardial blood flow after acute intravenous (i.v.) and intracoronary (i.c.) injection of bisoprolol in patients with coronary heart disease. PATIENTS AND METHODS: A prospective, randomized controlled study of 14 patients (12 men, 2 women; mean age 65 [50-73] years) with angio-graphically proven coronary artery stenosis (reduced in lumen of at least 70%) in one or more major vessels. Seven patients received, before balloon angioplasty, either 0.01 mg/kg body weight directly into the coronaries (group 1, infusion through the guiding catheter) or 2.5 mg (group 2, via the sheath). Heart rate and blood pressure were measured before and after bisoprolol injection. Coronary blood flow was measured by the thermodilution method via two indwelling catheters in the coronary sinus. RESULTS: After bisoprolol there was a reduction in heart rate (group 1: from 83/min to 75/min; group 2: from 77/min to 72/min) and blood pressure (group 1: from 137/80 mm Hg to 125/70 mm Hg; group 2: from 135/86 mm Hg to 126/80 mm Hg). Coronary blood flow was lower after i.c. bisoprolol injection than before (group 1: 383 ml/min vs 352 ml/min, but higher after i.v. injection (group 2: 353 ml/min vs 384 ml/min). These differences were statistically not significant. CONCLUSION: While after-load was clearly reduced and myocardial blood flow remained unchanged, bisoprolol improved myocardial oxygen balance. No different effects could be detected after intracoronary vs intravenous application of bisoprolol.

[Pathophysiology and pathobiochemistry of restenosis]. / Pathophysiologie und Pathobiochemie der Rezidivstenose.

The high rate of restenosis after percutaneous transluminal angioplasty obviously depends on multiple factors. Predictors for the clinical outcome seem to be the selection of lesion morphology, the acute result and the biological vessel response in the first months after treatment. Thrombus formation and recoil have been considered to be pivotal events. Thus, anticoagulation and Ca-antagonists were routinely applied after treatment. Multiple studies with medical intervention have been performed, mostly with anticoagulants. However, no effective reduction of restenosis has been achieved so far. Analysis of autopsy tissue obtained after angioplasty indicated the importance of early vascular wall "response to injury" that might as a consequence lead to restenosis formation. This was confirmed by systematic experimental data. With introduction of directional atherectomy "biopsies" of primary and restenotic tissue were obtained. Thus, a subtile diagnostic spectrum including histological, immunohistochemical, electron microscopical, and molecular tissue analysis could be established. In vitro cultures of obtained tissue were performed routinely. They enable a characterization of proliferative and synthetic cellular features. Moreover, the effects of therapeutic measures can be quantified and used for pre-clinical screening. To date, the above described methods indicate as pivotal event the angioplasty induced transformation of contractile myocytes to a synthesizing type of myocytes. The transformation to synthetic active cells is not device dependent, but seems to be a major feature of restenosis. This process is mostly terminated in a period of 3-6 months. To accelerate this physiologic termination would be one interesting therapeutic option. Alternatively, special local drug delivery devices could be used to administer sufficient antiproliferative drugs at the site that needs to be treated.

[Directional coronary atherectomy: acute results and angiography follow-up in 42 treated patients]. / Gerichtete koronare Atherektomie: Akutergebnisse und angiographische Verlaufskontrolle bei 42 behandelten Patienten.

We used directional coronary atherectomy (DCA) as a therapeutic option for coronary lesions unsuitable for PTCA (eccentric, ostial, branching or restenotic) and as "rescue device" for failed PTCA. Forty-two patients were treated by DCA using the Simpson coronary atherectomy device, including four female and 38 male patients with an average age of 55.7 years. Atherectomy as primary intervention was performed in 16 patients (Group I), because morphology of their lesions was assumed to be unsuitable for PTCA. DCA was also used after failed balloon dilatation in eight patients with unsuccessful, but uneventful treatment (Group II). In 18 cases (Group III) DCA was performed as "rescue procedure" after failed PTCA and resulting critical ischemia (local dissection, signs and symptoms of ongoing ischemia, occlusion after PTCA). Target lesions were located in LM 1, LAD 33, RCA 9, CABG 3. Mean length of lesion was 8.1 mm (2-25 mm). The overall success rate for 46 lesions was 93%. Mean stenosis was reduced from 92% to 17% in cases with primary success. Presently, available follow-up angiography (24) showed six restenoses (defined as greater than 50% stenoses). Major complications occurred in seven cases (death: 0, MI: 2, CABG within 24 h: 5; 3 in Group III). "Rescue indication" (Group III) after failed balloon dilatation procedure showed a favorable primary result with a success rate of 78%; only three cases of this group needed CABG. Our results show that DCA is a safe and effective technique which can extend the indication for percutaneous procedures and gives a successful nonoperative option in cases of failed PTCA.