Relevance of hemostasis on restenosis in clinically stable patients undergoing elective PTCA.

BACKGROUND: Secondary coronary thrombus formation is considered to be co-factor in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Therefore systemic factors indicating a hypercoagulable disease state may be relevant for the process of coronary renarrowing. Even though experimental data suggest that in particular thrombin may be of major relevance for restenosis induced by mechanical injury, only little clinical data has been presented so far. METHODS AND RESULTS: In 60 consecutive patients, who had been clinical stable for at least 2 months, and who underwent elective and primarily successful PTCA, follow-up films were evaluated by means of quantitative coronary angiography in respect to a categorical and a continuous definition of restenosis, luminal narrowing >50% and late luminal loss respectively. Of the chosen laboratory variables prothrombin fragment 1+2 (1.3+/-0.5 vs. 0.9+/-0.4 mmol/l, p<0.001) red blood cell aggregation at low shear stress (13.5+/-2.9 vs. 11.6+/-2.8 units, p<0.05), and plasminogen-activator inhibitor (3.7+/-1.8 vs. 5.3+/-3.2 U/ml p<0.05) differentiated between patients with (n=18) and without restenosis (n=42). Late luminal loss correlated positively with prothrombin fragment 1+2 (r=0.41, p<0.001), plasminogen-activator inhibitor (r= -0.28, p<0.05) and plasmin-alpha2-antiplasmin complex (r=0.39, p<0.01). CONCLUSIONS: A hypercoagulable disease state and in particular thrombin generation characterize a high-risk group prone for restenosis in clinically stable coronary artery disease.

[Cyanosis and dyspnoea in orthostasis]. / Zyanose und Luftnot in Orthostase.

HISTORY AND CLINICAL FINDINGS: A 69-year-old female patient was admitted to a hospital for severe dyspnoea. It was conspicuous that shortness of breath and cyanosis only occurred in upright and completely disappeared in the supine position. This finding was objectified by pulse oximetry which demonstrated a decrease of arterial oyxgen saturation from 96 % in the supine to 86 % in the upright position. INVESTIGATIONS: After exclusion of other diseases the diagnosis of platypnoe- orthodeoxia syndrome as a result of a patent foramen ovale (PFO) was established. TREATMENT AND COURSE: Cardiac catheterization in the upright and the supine position documented a high-grade right-to-left shunt of 31 % proportionally to systemic circulatory volume in the upright position with subsequent critical reduction of pulmonary perfusion to 1.4 l/min/m (2) (reference value > 2.2 l/min/m (2)) as the cause of dyspnoea. Catheter-based occlusion of the PFO was chosen as causal treatment modality. After that arterial oxygen saturation remained constant at 95 % in the supine and upright position and symptoms improved. CONCLUSIONS: Platypnoe-othodeoxia syndrome is a very rare syndrome but it can be substantiated by pathognomonic case history, clinical examination and simple machine-aided examinations. With a causative PFO a causal and save therapy is available.

A distinct "side population" of cells with high drug efflux capacity in human tumor cells.

A subset of stem cells, termed the "side population" (SP), has been identified in several tissues in mammalian species. These cells maintain a high efflux capability for antimitotic drugs. We have investigated whether functionally equivalent stem cells also may be detected in human cancers. We initially examined primary tumor cells from 23 patients with neuroblastoma and cell lines derived from a range of other tumors. A distinct SP was found in neuroblastoma cells from 15 of 23 patients (65%). The SP was capable of sustained expansion ex vivo and showed evidence for asymmetric division, generating both SP and non-SP progeny. These cells also expressed high levels of ABCG2 and ABCA3 transporter genes and had a greater capacity to expel cytotoxic drugs, such as mitoxantrone, resulting in better survival. A SP also was detected in breast cancer, lung cancer, and glioblastoma cell lines, suggesting that this phenotype defines a class of cancer stem cells with inherently high resistance to chemotherapeutic agents that should be targeted during the treatment of malignant disease.

Morphological differences of the internal thoracic artery in patients with and without coronary artery disease--evaluation by duplex-scanning.

OBJECTIVE: The internal thoracic artery is an established arterial graft for myocardial revascularisation, especially of the left anterior descending artery because of a higher patency rate compared to venous grafts. It has never been investigated, whether there are morphological differences in this vessel between patients with or without coronary artery disease or if they are comparable to morphological changes in the common carotid artery. METHODS: We investigated the internal thoracic artery and the common carotid artery of 24 patients (12 with coronary artery disease, 12 without coronary artery disease) with an ultrasonic system on both sides. The intima-media thickness and the diameter of both vessels were estimated. RESULTS: The intima-media-thickness of the internal thoracic artery was comparable in all patients, independent of the presence of a coronary artery disease (0.51+/-0.11 mm with coronary artery disease, 0.50+/-0.17 mm without coronary artery disease, P>0.05). Compared with this the intima-media-thickness of the common carotid artery was thicker in patients with coronary artery disease (0.84+/-0.13 mm with coronary artery disease, 0.73+/-0.07 mm without coronary artery disease, P< or or =0.014). There was no correlation between the thickness of the internal thoracic artery and the common carotid artery (r=0.018, P>0.05). CONCLUSIONS: It could be demonstrated for the first with non-invasive ultrasound, that the intima-media-complex of the internal thoracic artery is protected of the influence of arteriosclerosis. There are no morphological differences like the intima-media-thickness of the common carotid artery. The proven protective mechanism underlines the widespread use of the internal thoracic artery as a coronary artery bypass graft.

Vineberg graft: flow reserve of bilateral implantation after 27 years.

We report a patient who underwent bilateral internal thoracic artery implantation into the myocardium known as a Vineberg procedure 27 years ago. Coronary angiography and Doppler echocardiography revealed patent grafts with total occlusion of all native coronary arteries. We measured flow velocities at rest and under stress conditions with noninvasive ultrasonic Doppler echocardiography. The flow patterns in both grafts were biphasic as in native coronary arteries. Under stress conditions no increase in flow was detectable as a marker of end-stage coronary artery disease with refractory angina pectoris.

In vitro bleeding test with PFA-100-aspects of controlling individual acetylsalicylic acid induced platelet inhibition in patients with cardiovascular disease.

OBJECTIVES: This study investigated the usefulness and practicability of a platelet function analyzer (PFA-100(TM), DADE-Behring, Germany) to determine individual platelet inhibition in patients treated with acetylsalicylic acid (ASA). BACKGROUND: Patients with coronary artery disease (CAD) routinely and during angioplasty (PTCA) receive standard doses of ASA to avoid acute coronary syndromes and abrupt vessel closures without information of the individual efficacy of platelet inhibition. METHODS: With the PFA-100(TM) a standardized bleeding time is measured. Whole-blood anticoagulated with 3.2% sodium citrate is aspirated through a capillary ( solidus in circle 200 microm) and through an aperture ( solidus in circle 147 microm). The time until occlusion of the aperture (closure time, CT) by a stable platelet plug induced by shear stress, collagen and epinephrine (COLL/EPI-CT) or shear stress, collagen and adenosine 5'-diphosphate (COLL/ADP-CT) is determined. To examine the usefulness of the PFA-100(TM) as a rapid bedside test and the individual effect of ASA, closure time was measured in healthy individuals (n=17), in patients with stable CAD (n=19) and in patients undergoing PTCA (n=8). RESULTS: Patients with stable CAD and regular medication with 100 mg ASA per day for at least 3 month showed shorter COLL/ADP-CT in comparison to healthy individuals who took only one single dose of 100 mg ASA. Of the patients with CAD 63% had a COLL/EPI-CT within normal range suggesting a low or no response to ASA. Also only 50% of the patients undergoing PTCA reached the expected COLL/EPI-CT>300 s after an additive single dose of 500 mg ASA intravenously. Neither heparin, phenprocoumon, sex nor different blood sampling methods seem to influence the measurements relevantly. CONCLUSIONS: This pilot study indicates that with the PFA-100(TM) test device a simple and quick measurement of an in vitro bleeding time is possible. It is able to detect an increase in the bleeding time after a single dose of ASA 100 mg in healthy subjects, reflecting a sensitive detection of ASA induced changes in platelet inhibition respective activation. Differences in the individual response to ASA could be observed in healthy subjects, patients with stable CAD and patients undergoing PTCA. Further studies should validate the PFA-100(TM) with standard methods to determine ASA response in patients with cardiovascular disease and investigate implications for treatment and outcome in this patient group.

[New antithrombotic therapy approaches in coronary heart disease--prospects for gene therapy]. / Neue antithrombotische Therapieansätze bei koronarer Herzerkrankung--Perspektiven einer Gentherapie.

Despite considerable progress, pharmacological therapies have not provided a complete solution for common cardiovascular problems, including recurrent thrombosis, restenosis, and vein graft deterioration. Optimal drug dosage, reproducing plasma concentrations achieved in animal studies establishing proof-of-principle, would often be too toxic to administer. Local gene therapy aims at overexpressing proteins that regulate the cell cycle of vascular smooth muscle cells, inhibit vascular smooth muscle cell migration, endow the endothelium with enhanced vasoprotective properties. Alternatively, some approaches tend to suppress gene expression of proteins believed to promote vascular smooth muscle cell proliferation and migration. In sharp contrast to drug treatments, local gene therapy limits expression of the beneficial agent to the injured vascular site, where it can extend the presence of this agent to weeks and, with some gene vectors, to many months. This review summarizes and discusses antithrombotic gene therapy approaches for the prevention of restenosis and late thrombosis after catheter-based revascularizations.

Non-invasive assessment of graft patency using transcutaneous Doppler echocardiography for the validation of functional improvement after PTCA of the LAD via internal thoracic artery graft.

Percutaneous transluminal coronary angioplasty (PTCA) of a native coronary artery via internal thoracic artery (ITA) graft after bypass surgery is a relatively rare procedure. Our current study evaluates the flow velocity patterns of the graft before and after PTCA. After intervention the mean diastolic flow velocity increased under rest and stress conditions. In addition, the graft patency was proved not before control angiography after 6 months. It could be verified that the measurement of flow velocity patterns under rest and stress conditions is a useful non-invasive procedure for monitoring long-term patency and PTCA-results of this vessel.

[PTCA of the LAD via the internal thoracic artery graft with Doppler ultrasonic control of the results: a case report and review of the literature]. / RIVA-PTCA via Arteria-thoracica-interna-Bypass mit dopplersonographischer Erfolgskontrolle--Eine Kasuistik mit Literaturübersicht.

The report presents a transluminal angioplasty (PTCA) of a severe stenosis of the left anterior descending artery (LAD) behind the anastomosis; the internal thoracic artery (ITA) graft was used as a conduit. Before and after the PTCA the changing of velocity flow patterns under rest and stress conditions with a handgrip-maneuver were measured with a noninvasive transthoracic ultrasound Doppler system. The mean diastolic velocity, which represent coronary perfusion through the ITA graft, increased after successful PTCA at rest and under stress conditions. An additional increasing of the mean diastolic velocity at rest and under stress conditions was seen after six months before the catheterization proposing no signs of restenosis. For this reason the vessel could be classified prospectively patient. This could be confirmed during coronary angiography. We also present a review of the published reports concerning PTCA of ITA grafts and PTCA of the native vessel using the ITA as a conduit. In this review 286 cardiac interventions on 273 patients with a primary rate of success of 87% could be counted, the documented rate of restenosis was 30%, and the rate of complication was approximately 1%. The PTCA in ITA grafts or of the native vessel via ITA grafts, respectively, represent an alternative to reoperation. The ultrasound-duplex measurements are gaining an increasing significance for the noninvasive patency rate and post-interventional monitoring of the long-term PTCA result. With the augmentation of the ITA as a coronary bypass and expected increase of post-operative interventions, a noninvasive tool is necessary.

[Assessment of the anti-ischemic effect in patients with therapy refractory angina pectoris in end-stage coronary heart disease--results of chronic intermittent urokinase therapy]. / Antiischämischer Wirkungsnachweis bei Patienten mit therapierefraktärer Angina pectoris im Endstadium der koronaren Herzkrankheit--Ergebnisse zur chronisch-intermittierenden Urokinasetherapie.

Patients with refractory angina pectoris and end-stage coronary artery disease represent an increasing clinical problem. Numbers of these patients will increase in the future for improved survival due to effective secondary prevention of coronary artery disease. Next to the evaluation of clinical symptoms non-invasive objective parameters of myocardial ischemia are of major relevance before initiation of alternative treatment modalities and for verification of antiischemic effectiveness. Based on our own experience it can be shown that in these patients testing which is mainly based on the patients physical exercise capacity is only of limited value due to the early occurrence of clinical symptoms. Furthermore diffuse perfusion abnormalities reduce the sensitivity of electrocardiographic and scintigraphic detection of ischemic changes. In contrast indirect measures of ischemia relating to the systolic or diastolic function of the left ventricle like doppler-echocardiography and radionuclide ventriculography seem to be promising approaches. This is confirmed by the results from the application of long-term intermittent urokinase therapy. Long-term intermittent urokinase therapy leads to an absolute enhancement of myocardial perfusion, which makes this approach superior to other medical interventions which are mainly based on a reduction of cardiac work-load.

[Diastolic function parameters and atrial arrhythmias in patients with arterial hypertension]. / Diastolische Funktionsparameter und atriale Rhythmusstörungen bei Patienten mit arterieller Hypertonie.

OBJECTIVE: To investigate in patients with arterial hypertension (HT) the extent of left ventricular (LV) hypertrophy and diastolic function in relation to atrial arrhythmias. PATIENTS AND METHODS: In 112 hypertensive patients (40 women, 72 men; mean age 50 +/- 6.6 years) with a mean systolic blood pressure for the cohort of 170 +/- 5 mmHg, their first invasive coronary angiography was performed between July 1995 and October 1997 because of angina pectoris and/or an abnormal stress electrocardiogram. After excluding coronary heart disease LV dimensions and diastolic function were measured by echocardiography; in 59 of the 112 patients LV hypertrophy was demonstrated. In addition, long-term blood pressure monitoring, exercise and long-term electrocardiography, late-potential analysis and measurement of heart rate variability were undertaken. The control group consisted of 51 patients without arterial hypertension after exclusion of coronary heart disease. RESULTS: Even in the hypertensive patients without LV hypertrophy diastolic LV function and ergometric exercise capacity were reduced. The risk of LV arrhythmias was significantly higher in patients with LV hypertrophy than those without and in the control group, as measured by the complexity of atrial arrhythmias (P < 0.001), the incidence of abnormal late potentials (P < 0.001) and reduction in heart rate variability (29.3 +/- 5.3 ms vs 47.8 +/- 12.1 ms vs 60.7 +/- 6.6 ms; P < 0.001). There were similar results regarding severe complex atrial arrhythmias (38.5 vs 15.0 vs 0%; P < 0.001). The incidence of atrial arrhythmias correlated with the LV diameter (r = 0.68, P < 0.001), LV morphological dimensions and diastolic function (isovolumetric relaxation time r = 0.44, P < 0.001) and the ratio of early to late diastolic inflow (r = 0.46; P < 0.001). CONCLUSIONS: Hypertensive patients have a higher risk of atrial and ventricular arrhythmias, depending on the degree of LV hypertrophy. But atrial arrhythmias, in contrary to ventricular arrhythmias, are also closely related to abnormalities in LV diastolic function.

Restenosis after elective coronary balloon angioplasty in patients with end stage renal disease: a case-control study using quantitative coronary angiography.

OBJECTIVE: To assess the rate of angiographic restenosis in patients with end stage renal disease after elective coronary angioplasty. DESIGN: A retrospective case-control study of 20 patients with end stage renal disease and 20 sex and age matched controls without renal disease, who had undergone primarily successful coronary angioplasty. Control coronary angiography was performed regardless of worsening or renewed incidence of anginal symptoms. MAIN OUTCOME MEASURES: Group comparison of coronary morphology, as evaluated by quantitative coronary angiography, and of cardiovascular risk factors. RESULTS: The rate of angiographic restenosis was 60% in patients with renal disease and 35% in controls. In patients with end stage renal disease the following differences (mean (SD) were found versus controls: raised plasma fibrinogen (483 (101) v 326 (62) mg/dl, p < 0.001); raised plasma triglyceride (269 (163) v 207 (176) mg/dl, p < 0.01); smaller diameter of the coronary reference segment (2.59 (0.87) v 2.90 (0.55) mm, p < 0.10); smaller minimum luminal diameter of the dilated stenosis (0.77 (0.46) v 0.97 (0.27) mm, p < 0.05). Discriminant analysis showed that minimum luminal diameter before angioplasty (r = -0.79) and fibrinogen (r = +0.34) had the highest statistical association with restenosis. CONCLUSIONS: The high rate of angiographic restenosis in patients with end stage renal disease seems to be related to the size of the vessel dilated and to an increased prothrombotic risk, as indicated by higher fibrinogen concentrations.

Refractory angina pectoris in end-stage coronary artery disease: evolving therapeutic concepts.

Refractory angina pectoris in coronary artery disease is defined as the persistence of severe anginal symptoms despite maximal conventional antianginal combination therapy. Further, the option to use an invasive revascularization procedure such as percutaneous coronary balloon angioplasty or aortocoronary bypass grafting must be excluded on the basis of a recent coronary angiogram. This coronary syndrome, which represents end-stage coronary artery disease, is characterized by severe coronary insufficiency but only moderately impaired left ventricular function. Almost all patients demonstrated severe coronary triple-vessel disease with diffuse coronary atherosclerosis, had had one or more myocardial infarctions, and had undergone aortocoronary bypass grafting (70% of cases). We present three new approaches with antiischemic properties: long-term intermittent urokinase therapy, transcutaneous and spinal cord electrical nerve stimulation, and transmyocardial laser revascularization.

Activation of the fibrinolytic system in patients with coronary artery disease and hyperfibrinogenemia.

Elevated fibrinogen levels as well as an impaired activity of the fibrinolytic system are regarded as important cardiovascular risk factors. To elucidate a potential interrelation between fibrinogen as an indicator of a hypercoagulable state and the endogenous fibrinolytic function hemostatic and rheological as well as lipid parameters were determined in 224 consecutive patients, who underwent elective coronary angiography. In the selected study population of 81 men and 19 women with fibrinogen concentration either > or = 3.5 g/l (n = 70) or < or = 2.5 g/l (n = 30) hyperfibrinogenemia was found to be significantly associated with increased concentrations of plasmin-alpha 2-antiplasmin complex [PAP [median (25.-75. percentile)], 534 (361-680) micrograms/l vs. 289 (243-440) micrograms/l; p < 0.001] and tissue plasminogen activator (t-PA) antigen [9 (6-11) micrograms/l vs 8 (5-9) micrograms/l; p < 0.05] while this association was lost in the subgroup of patients with angiographically normal coronary arteries (n = 26). In addition to these findings fibrinogen was significantly correlated with PAP (r = 0.40, p < 0.001; n = 224) and t-PA antigen (r = 0.2, p < 0.01; n = 224) after adjustment for age, diabetes mellitus, lipid parameters and leucocyte counts. It can be argued that elevated fibrinogen levels in patients with coronary artery disease are concomitant with an activation of the fibrinolytic system.

[Rate of restenosis after PTCA in patients with terminal renal failure. A quantitative coronary angiography study]. / Restenoserate nach PTCA bei Patienten mit terminaler Niereninsuffizienz. Eine quantitativ-koronarangiographische Untersuchung.

Patients with end-stage renal disease (ESRD) have a high incidence of coronary artery disease. In 30-60% of these patients coronary artery disease can be demonstrated by coronary angiography often prompting myocardial revascularization. Previous studies on PTCA in patients with ESRD have suggested a high rate of procedural complications and restenosis. We studied the rate of restenosis after PTCA in 23 patients with chronic renal failure (17 males, 6 females, age: 52.5 +/- 18.3 years). After primarily successful PTCA all patients were restudied angiographically within 6-12 months. Using quantitative coronary angiography 13 patients (56%) demonstrated restenosis (stenosis > 50% luminal diameter). In 11 of these patients further revascularization therapy was indicated (6 x PTCA, 5 x CABG). Before follow-up angiography 12 patients demonstrated recurrence of angina pectoris, the sensitivity of clinical symptoms for angiographic restenosis was 69%. High concentrations of triglycerides (265 +/- 160 mg/dl), total cholesterol (258 +/- 53 mg/dl) with low HDL-levels (34 +/- 14 mg/dl) as well as elevated plasma levels of fibrinogen (481 +/- 114 mg/dl) were measured before PTCA. The mechanisms contributing to the high rate of coronary restenosis in patients with ESRD remain unclear, influence of lipid abnormalities, hemostatic factors and fibrinolytic state as well as primarily uremic factors have to be discussed. Prospective interventional studies are needed to address the relevance of PTCA for myocardial revascularization in this patient group.

Antithrombotic treatment in stable coronary syndromes: long-term intermittent urokinase therapy in end-stage coronary artery disease and refractory angina pectoris.

Interventions that modify lipid metabolism and blood coagulation have been shown to favourably influence the natural course of coronary artery disease in terms of the primary prevention and treatment of acute cardiovascular events. Various findings suggest that such interventions may also preserve and enhance myocardial perfusion in the chronic stage of the disease. Long-term intermittent urokinase therapy was developed for patients with end-stage coronary artery disease and refractory angina pectoris. A dose of 500,000 IU of urokinase given intravenously as a bolus three times a week for of 12 weeks reduced symptoms by 70% and was accompanied by objective improvements in myocardial perfusion and an increase of ergometric exercise capacity. The possible therapeutic mechanisms of long-term intermittent urokinase therapy-improvement of rheological blood properties mediated by fibrinogen reduction, thrombolysis of non-occlusive subclinical thrombi, and regression of atherosclerotic plaques-are discussed in the context of other antithrombotic approaches.

[Significance of coronary thrombosis for chronic myocardial ischemia]. / Die Bedeutung der Koronarthrombose für die chronische Myokardischämie.

Apart from the relevance of disorders of lipid metabolism for the clinical and morphological progression of coronary artery disease, coronary thrombosis has received increasing attention in recent years. It is undoubtedly the decisive factor in the pathogenesis of acute coronary syndromes, which is underlined by the therapeutic success of various antithrombotic interventions. Furthermore coronary thrombosis is regarded to be a key factor for morphological disease progression also in stable coronary syndromes, which eventually may lead to critical limitation of myocardial perfusion. This is caused by the formation of subclinical coronary thrombi, which either undergo endogenous lysis or become morphologically fixed as they are incorporated into the plaque. Besides local factors, systemic disturbances of hemostasis and endogenous thrombolysis are of relevance. The concept of thrombotic progression of coronary thrombosis is supported by data on the reduction of morphological disease progression or antiischemic effectiveness of anti-thrombotic interventions like aspirin, low-molecular weight heparin and low-dose intermittent urokinase therapy. Percutaneous transluminal coronary angioplasty results in deep mechanical injury of the vessel wall, which is accompanied by secondary coronary thrombosis in the majority of the cases, not necessarily leading to abrupt vessel closure. Particularly, dilatation of primary thrombus as it has been described as the substrate of the culprit lesion in unstable coronary syndromes, promotes release of thrombin and activation of platelets, which in turn furthers the proliferative processes in the pathogenesis of restenosis. Even though data on the reduction of the rate of restenosis by the use of platelet aggregation inhibitors like aspirin, ticlopidin and dipyridamole have not consistently supported this concept, the EPIC. Study has shown that even in patients with stable angina pectoris clinical restenosis rate may be reduced by a platelet-IIb/IIIa-antagonist.

[Chronic intermittent urokinase therapy: anti-ischemic and hemodynamic effects]. / Chronisch-intermittierende Urokinasetherapie: anti-ischämische und hämodynamische Effekte.

Long-term intermittent urokinase therapy has been developed for patients with severe coronary artery disease and refractory angina pectoris. This therapeutic approach is predominantly effective at the microcirculatory level based on a combination of rheologic and fibrinolytic effects; furthermore, plaque regression seems to be a possible mechanism. Patients with refractory angina pectoris are characterized by severe coronary artery disease without a therapeutic option for conventional revascularization procedures, only slight impairment of left ventricular systolic function and hyperfibrinogenemia, which results in further enhancement of myocardial ischemia due to microcirculatory impairment of blood flow. In this article data on the anti-ischemic effectiveness as well as first results on the impact of this therapeutic approach on hemodynamics are described. A dose-response study, which compared 3 x 50,000 IU with 3 x 500,000 IU urokinase three times a week over a treatment period of 12 weeks demonstrated subjective as well as objective antiischemic effectiveness. Only patients who were treated with 500,000 IU per injection achieved marked increases in exercise capacity, while some patients in the low-dose group presented even with a deterioration of exercise performance. First hemodynamic studies could not show marked changes of systolic parameters, either at rest or during exercise. But a decrease of pulmonary capillary wedge pressure at rest after treatment with 500,000 IU per injection indicates an improvement of diastolic function as a result of enhanced myocardial perfusion. Echocardiographic measurements of transmitral Doppler flow in 21 patients with end-stage coronary artery disease demonstrated normalization of early and late diastolic filling rates in most cases. These changes were accompanied by a reduction of clinical signs of heart failure. Long-term intermittent urokinase therapy is a valuable approach as it not only improves quality of life during the actual treatment period but by the persistence of therapeutic effects following the cessation of therapy.