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Increased activation of the renin-angiotensin system is involved in the onset and progression of cardiometabolic diseases, while natriuretic peptides (NP) may exert protective effects. We have recently demonstrated that sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, which blocks the angiotensin II type-1 receptor and augments natriuretic peptide levels, improved peripheral insulin sensitivity in obese hypertensive patients. Here, we investigated the effects of sacubitril/valsartan (400 mg QD) treatment for 8 weeks on the abdominal subcutaneous adipose tissue (AT) phenotype compared to the metabolically neutral comparator amlodipine (10 mg QD) in 70 obese hypertensive patients. Abdominal subcutaneous AT biopsies were collected before and after intervention to determine the AT transcriptome and expression of proteins involved in lipolysis, NP signaling and mitochondrial oxidative metabolism. Both sacubitril/valsartan and amlodipine treatment did not significantly induce AT transcriptional changes in pathways related to lipolysis, NP signaling and oxidative metabolism. Furthermore, protein expression of adipose triglyceride lipase (ATGL) (P time*group  = 0.195), hormone-sensitive lipase (HSL) (P time*group  = 0.458), HSL-ser660 phosphorylation (P time*group  = 0.340), NP receptor-A (NPRA) (P time*group  = 0.829) and OXPHOS complexes (P time*group  = 0.964) remained unchanged. In conclusion, sacubitril/valsartan treatment for 8 weeks did not alter the abdominal subcutaneous AT transcriptome and expression of proteins involved in lipolysis, NP signaling and oxidative metabolism in obese hypertensive patients.

Sacubitril/valsartan (LCZ696), a novel angiotensin receptor-neprilysin inhibitor, was recently approved for the treatment of heart failure with reduced ejection fraction. Neprilysin degrades several peptides that modulate lipid metabolism, including natriuretic peptides. In this study, we investigated the effects of 8 weeks' treatment with sacubitril/valsartan on whole-body and adipose tissue lipolysis and lipid oxidation during defined physical exercise compared with the metabolically neutral comparator amlodipine. This was a multicenter, randomized, double-blind, active-controlled, parallel-group study enrolling subjects with abdominal obesity and moderate hypertension (mean sitting systolic blood pressure ≥130-180 mm Hg). Lipolysis during rest and exercise was assessed by microdialysis and [1,1,2,3,3- 2 H]-glycerol tracer kinetics. Energy expenditure and substrate oxidation were measured simultaneously using indirect calorimetry. Plasma nonesterified fatty acids, glycerol, insulin, glucose, adrenaline and noradrenaline concentrations, blood pressure, and heart rate were also determined. Exercise elevated plasma glycerol, free fatty acids, and interstitial glycerol concentrations and increased the rate of glycerol appearance. However, exercise-induced stimulation of lipolysis was not augmented on sacubitril/valsartan treatment compared with amlodipine treatment. Furthermore, sacubitril/valsartan did not alter energy expenditure and substrate oxidation during exercise compared with amlodipine treatment. In conclusion, sacubitril/valsartan treatment for 8 weeks did not elicit clinically relevant changes in exercise-induced lipolysis or substrate oxidation in obese patients with hypertension, implying that its beneficial cardiovascular effects cannot be explained by changes in lipid metabolism during exercise., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01631864., (© 2017 The Authors.)

Natriuretic peptide (NP) deficiency and sustained renin-angiotensin system activation are associated with impaired oxidative metabolism and predispose to type-2 diabetes. We hypothesized that sacubitril/valsartan (LCZ696), which augments NP through neprilysin inhibition while blocking angiotensin II type-1 (AT 1 )-receptors, improves insulin sensitivity, lipid mobilization, and oxidation. After 8 weeks of treatment of obese patients with hypertension, sacubitril/valsartan 400 mg q.d., but not amlodipine 10 mg q.d., was associated with a significant increase from baseline in the insulin sensitivity index (hyperinsulinemic-euglycemic clamp), and tended to be higher in patients treated with sacubitril/valsartan compared to amlodipine. Abdominal adipose tissue interstitial glycerol concentrations increased with sacubitril/valsartan, but decreased with amlodipine. Whole-body lipolysis and substrate oxidation did not change with either treatment. Results confirm that sacubitril/valsartan treatment leads to a metabolic benefit in the study population and supports the relevance of neprilysin inhibition along with AT 1 -receptor blockade in the regulation of human glucose and lipid metabolism., (© 2016 American Society for Clinical Pharmacology and Therapeutics.)

Background: Studies of dipeptidyl peptidase (DPP)-4 inhibitors report heterogeneous effects on endothelial function in patients with type 2 diabetes (T2D). This study assessed the effects of the DPP-4 inhibitor linagliptin versus the sulphonylurea glimepiride and placebo on measures of macro- and microvascular endothelial function in patients with T2D who represented a primary cardiovascular disease prevention population., Methods: This crossover study randomised T2D patients (n = 42) with glycated haemoglobin (HbA1c) ≤7.5%, no diagnosed macro- or microvascular disease and on stable metformin background to linagliptin 5 mg qd, glimepiride 1-4 mg qd or placebo for 28 days. Fasting and postprandial macrovascular endothelial function, measured using brachial flow-mediated vasodilation, and microvascular function, measured using laser-Doppler on the dorsal thenar site of the right hand, were analysed after 28 days., Results: Baseline mean (standard deviation) age, body mass index and HbA1c were 60.3 (6.0) years, 30.3 (3.0) kg/m 2 and 7.41 (0.61)%, respectively. After 28 days, changes in fasting flow-mediated vasodilation were similar between the three study arms (treatment ratio, gMean [90% confidence interval]: linagliptin vs glimepiride, 0.884 [0.633-1.235]; linagliptin vs placebo, 0.884 [0.632-1.235]; glimepiride vs placebo, 1.000 [0.715-1.397]; P = not significant for all comparisons). Similarly, no differences were seen in postprandial flow-mediated vasodilation. However, under fasting conditions, linagliptin significantly improved microvascular function as shown by a 34% increase in hyperaemia area (P = 0.045 vs glimepiride), a 34% increase in resting blow flow (P = 0.011 vs glimepiride, P = 0.003 vs placebo), and a 25% increase in peak blood flow (P = 0.009 vs glimepiride, P = 0.003 vs placebo). There were no significant differences between treatments in postprandial changes. Linagliptin had no effect on heart rate or blood pressure. Rates of overall adverse events with linagliptin, glimepiride and placebo were 27.5, 61.0 and 35.0%, respectively. Fewer hypoglycaemic events were seen with linagliptin (5.0%) and placebo (2.5%) than with glimepiride (39.0%)., Conclusions: Linagliptin had no effect on macrovascular function in T2D, but significantly improved microvascular function in the fasting state. Trial registration ClinicalTrials.gov identifier-NCT01703286; registered October 1, 2012.

Aims: To evaluate the pharmacokinetics and pharmacodynamics of different doses of glucagon administered subcutaneously (s.c.) at different blood glucose levels., Methods: This study was an open-label, randomized, three-period, cross-over experiment in 6 patients with type 1 diabetes. During each of the three periods, different blood glucose levels were established in four consecutive steps (8, 6, 4 and 2.8 mmol/l) and glucagon was given at each blood glucose level in doses from 0.11 to 0.44 mg and 0.33, 0.66 and 1 mg at the lowest glucose concentration., Results: Maximum glucagon concentration and area under the curve increased with increasing glucagon dose. Maximum glucagon concentration was reached after 10-20 min. Glucagon raised blood glucose in a dose-dependent manner at different baseline blood glucose levels. The median glucose excursion ranged from 2.6 to 6.2 mmol/l. Time to maximum glucose concentration was dose-dependent for the glucagon doses at 2.8 mmol/l, with median values from 40 to 80 min., Conclusions: Glucagon administered s.c. produces a stable pharmacokinetic and pharmacodynamic response at lower doses than the usual rescue dose and across a range of hypo- to hyperglycaemic blood glucose levels. This supports the use of small glucagon doses in the artificial pancreas to correct and prevent hypoglycaemia., (© 2015 John Wiley & Sons Ltd.)

Objective: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a new insulin glargine comprising 300 units · mL(-1) (Gla-300), compared with insulin glargine 100 units · mL(-1) (Gla-100) at steady state in people with type 1 diabetes., Research Design and Methods: A randomized, double-blind, crossover study (N = 30) was conducted, applying the euglycemic clamp technique over a period of 36 h. In this multiple-dose to steady-state study, participants received once-daily subcutaneous administrations of either 0.4 (cohort 1) or 0.6 units · kg(-1) (cohort 2) Gla-300 for 8 days in one treatment period and 0.4 units · kg(-1) Gla-100 for 8 days in the other. Here we focus on the results of a direct comparison between 0.4 units · kg(-1) of each treatment. PK and PD assessments performed on the last treatment day included serum insulin measurements using a radioimmunoassay and the automated euglycemic glucose clamp technique over 36 h., Results: At steady state, insulin concentration (INS) and glucose infusion rate (GIR) profiles of Gla-300 were more constant and more evenly distributed over 24 h compared with those of Gla-100 and lasted longer, as supported by the later time (∼ 3 h) to 50% of the area under the serum INS and GIR time curves from time zero to 36 h post dosing. Tight blood glucose control (≤ 105 mg · dL(-1)) was maintained for approximately 5 h longer (median of 30 h) with Gla-300 compared with Gla-100., Conclusions: Gla-300 provides more even steady-state PK and PD profiles and a longer duration of action than Gla-100, extending blood glucose control well beyond 24 h., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims: Liraglutide reduces bodyweight in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the mechanisms underlying this effect., Methods: The comparative effects of liraglutide, glimepiride and placebo on energy intake, appetite, nausea, gastric emptying, antral distension, bodyweight, gastrointestinal hormones, fasting plasma glucose and resting energy expenditure (REE), were assessed in subjects with T2DM randomised to treatment A (liraglutide-placebo), B (placebo-glimepiride) or C (glimepiride-liraglutide). Assessments were performed at the end of each 4-week treatment period., Results: Energy intake was less (NS) with liraglutide vs placebo and glimepiride, and 24-h REE was higher (NS) with liraglutide vs placebo and glimepiride. Fasting hunger was less (p=0.01) with liraglutide vs placebo and glimepiride, and meal duration was shorter with liraglutide (p=0.002) vs placebo. Paracetamol AUC(0-60 min) and C(max) were less (p<0.01) and fasting peptide YY was lower (p ≤ 0.001) after liraglutide vs placebo and glimepiride. Bodyweight reductions of 1.3 and 2.0 kg were observed with liraglutide vs placebo and glimepiride (p<0.001). There were no differences on antral distension, nausea, or other gastro-intestinal hormones., Conclusion: Liraglutide caused decreased gastric emptying and increased reduction in bodyweight. The mechanisms of the liraglutide-induced weight-loss may involve a combined effect on energy intake and energy expenditure., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: There are increasing calls for a precise, automated system to enable tight glycemic control and to avoid hypoglycemia in an intensive care unit setting. OptiScan Biomedical has developed a glucose monitor based on mid-infrared spectroscopy that withdraws blood samples (120 µl) and measures plasma glucose. The goal of this study was to validate the performance of the OptiScan Model 5000 over a wide range of glycemic levels in patients., Research Design and Methods: Sixty people with type 1 (n = 18) or type 2 (n = 42) diabetes who were otherwise healthy were connected to OptiScanners. Their blood glucose concentrations were kept in a euglycemic, hypoglycemic (<75 mg/dl), and hyperglycemic (>180 mg/dl) range by intravenous administrations of insulin and glucose. OptiScanner venous blood samples were automatically withdrawn every 15 minutes. Reference measurements were done using the YSI 2300 glucose analyzer., Results: The aggregate data points (1155 paired readings) were within International Organization for Standardization standards, with 98.6% of the glucose values within ±20% above 75 mg/dl and ±15 mg/dl below this value. A Clarke error grid analysis showed a total of 1139 points (98.6%) in zone A. Points outside of A exceeded the A zone boundary by an average of 4.3%. The r(2) was 0.99. The total coefficient for variance was 6.4%., Conclusions: These results show that the OptiScanner is highly accurate in healthy patients with diabetes across a wide range of glucose values. Mid-infrared spectroscopy may become the method of choice for highly accurate, high frequency, automated glucose measurements and may thus enable better glycemic control in critically ill patients., (© 2011 Diabetes Technology Society.)

Novel drugs for the treatment of patients with diabetes are of interest for cardiologists if they reduce the risk of cardiovascular events. However, as documented by the current discussion about the potential benefits of glitazones, high hopes can fail. Initial beneficial cardiovascular effects shown in proof-of-concept studies were muted by the apparent higher mortality in the metaanalysis of studies with rosiglitazone. Having this in mind, how should one judge about new, emerging antidiabetic therapies, in particular those influencing the incretin axis? The rapidly increasing use of GLP-1 analogues and DPP-4 inhibitors for the treatment of type 2 diabetes mellitus may be of major interest for the cardiologist. Potential beneficial actions on the cardiovascular system so far shown in animal experiments and small proof of concept studies may provide the rationale for using these drugs specifically in diabetic patients with secondary complications such as macrovascular disease or diabetic cardiomyopathy. Theoretically, these new therapies could also proof beneficial in patients with heart failure, independently of concomittend diabetes mellitus. However, many unanswered questions need to be addressed in the near future to extend the experimental findings to potential benefits of real life patients. In summary a new class of antidiabetic drugs, which could possibly directly influence cardiovascular effects of diabetes mellitus and thus possibly treat or even prevent life threatening complications has become available. Further studies both assessing surrogate parameters as well as hard endpoint studies are needed to support the hypothesis generated from the summarized experimental studies.

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.

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.

Objectives and Background: The internal thoracic artery is an established arterial graft for myocardial revascularization. It never had been investigated, whether there are functional differences in this vessel between patients with or without coronary artery disease., Methods: We investigated the left internal thoracic artery of 28 patients (15 with and 13 without coronary artery disease) with a duplex-system at rest and with a handgrip exercise., Results: Concerning the measured flow velocities at rest there was only a significant difference between the diastolic mean and peak velocity between the two groups, the other investigated parameters demonstrate no significant difference. The peak diastolic and the mean diastolic velocity was less in patients with coronary artery disease during the handgrip-test. The flow reserve was decreased in patients with coronary artery disease (12.6+/-24.0% vs. 32.3+/-30.9%, P < 0.05)., Conclusions: We demonstrated, that patients with coronary artery disease have a higher peripheral resistance and a lower diastolic velocity of the internal thoracic artery during stress testing. This corresponds to a disturbed vasomotion and may be an early marker of arteriosclerosis.

The synthesis of nitric oxide (NO) in the circulation has been attributed exclusively to the vascular endothelium. Red blood cells (RBCs) have been demonstrated to carry a nonfunctional NO synthase (NOS) and, due to their huge hemoglobin content, have been assumed to metabolize large quantities of NO. More recently, however, RBCs have been identified to reversibly bind, transport, and release NO within the cardiovascular system. We now provide evidence that RBCs from humans express an active and functional endothelial-type NOS (eNOS), which is localized in the plasma membrane and the cytoplasm of RBCs. This NOS is regulated by its substrate L-arginine, by calcium, and by phosphorylation via PI3 kinase. RBC-NOS activity regulates deformability of RBC membrane and inhibits activation of platelets. The NOS-dependent conversion of L-arginine in RBCs is comparable to that of cultured human endothelial cells. RBCs in eNOS-/- mice in contrast to wild-type mice lack NOS protein and activity, strengthening the evidence of an eNOS in RBCs. These data show an eNOS-like protein and activity in RBCs serving regulatory functions in RBCs and platelets, which may stimulate new approaches in the treatment of NO deficiency states inherent to several vascular and hematologic diseases.

A reduced nitric oxide availability is a hallmark of endothelial dysfunction occurring early in atherosclerosis. Recently, we have shown that plasma nitrite mirrors acute changes in endothelial nitric oxide synthase activity in various mammals, including humans. Here, we examined the hypothesis that plasma nitrite levels are reduced in humans with endothelial dysfunction and the decrease is correlated with increasing numbers of cardiovascular risk factors (RF). Plasma nitrite concentrations were quantified by flow-injection analysis. The coefficient of variation for repeated measurements of plasma nitrite was <8%, and heart rate and blood pressure at the time of blood sampling had no significant effect on nitrite values measured (n=10). Baseline levels of plasma nitrite followed a normal distribution in each group studied and decreased progressively with increasing numbers of cardiovascular risk factors (n=351, p<0.001): 351+/-13 (0 RF), 261+/-10 (1 RF), 253+/-11 (2 RF), 222+/-18 (3 RF), and 171+/-29 nmol/L (4 RF). Intima media thickness (IMT) and flow-mediated dilation (FMD) were determined via ultrasound. Plasma nitrite and FMD levels were lower, whereas IMT was greater in individuals with endothelial dysfunction (n=12) compared to healthy volunteers (n=12). Nitrite correlated significantly with FMD (r=0.56, p<0.001) and inversely with IMT (r= -0.49, p<0.01). Plasma nitrite levels are reliably measurable in humans, indicate endothelial dysfunction, and correlate with cardiovascular risk factors. Future studies are necessary to identify the prognostic relevance of plasma nitrite determination in patients suffering from cardiovascular disease.

To investigate the role of nitric oxide in controlling endothelial progenitor (EPC) and hematopoietic stem cell (HSC) mobilization, wild-type mice, L-NAME treated WT and eNOS-/- mice received either PBS or G-CSF for 5 days. Under unstimulated conditions bone marrow of either L-NAME treated WT and eNOS-/- mice, representing acute and chronic NO-deficiency, showed higher CD34(+)Flk-I+ EPC numbers compared to their WT littermates. Furthermore, CD34(+)Flk-I+ progenitors under NO-deficient conditions showed a higher cell turn over since the proliferation and apoptosis activity under in vivo as well as in vitro conditions were enhanced. In line with this finding bone marrow derived EPC differentiation towards endothelial cells was modulated in an NO-dependent manner. Administration of G-CSF resulted in an increase of EPC within the bone marrow of WT animals with a consecutive release of these cells into the peripheral circulation. Under NO-deficient conditions G-CSF failed to increase EPC numbers. In contrast, the HSC population c-kit(+)Lin- was not influenced by nitric oxide. Thus, NO differentially supports the mobilization of the endothelial committed progenitor subpopulation in bone marrow but does not have an effect on HSC in vivo.

Background: Cardiovascular complications are common in patients with obstructive sleep apnea (OSA). Blood rheology is a major determent of coagulation and an established risk factor for cardiovascular events. Since nocturnal hypoxemia could influence parameters of blood rheology, we hypothesized that OSA alters blood rheology independent of other cardiovascular risk factors., Methods: One hundred and ten consecutive patients admitted to the sleep laboratory were included. The association of plasma fibrinogen and viscosity (as parameters of blood rheology) with OSA was evaluated., Results: One hundred and ten patients aged 61.4+/-10.1 years (body mass index 28.4+/-4.1 kg/m2) were included. OSA was confirmed in 63 patients (57.2%) with an apnea-hypopnea index (AHI) of 28.7+/-14.9 events/hour. Patients with OSA showed higher levels of plasma viscosity (1.36+/-0.09 vs. 1.31+/-0.08 mPas, p=0.005). Nevertheless, hypertensive apneics have even higher levels of plasma viscosity than nonapneics (1.38+/-0.091 vs. 1.32+/-0.028 mPas, p=0.018). Similar results were found in patients with coronary artery disease, where OSA was associated with elevated plasma viscosity (1.36+/-0.076 vs. 1.31+/-0.081 mPas, p=0.007). Plasma fibrinogen was correlated with nocturnal minimal oxygen saturation (r=-0275, p=0.0036) and AHI (r=0.297, p=0.001). OSA was associated with higher plasma fibrinogen (353+/-83 vs. 317+/-62 mg/dl, p=0.015). These differences persist with control for cardiovascular risk factors., Conclusions: Patients with OSA have elevated morning fibrinogen levels and a higher plasma viscosity, which correlate positively with indices of sleep apnea severity. These changes in blood rheology are independent of cardiovascular risk factors, and therefore, might be specific mechanisms of OSA. This supports the pathophysiological concept that sleep apnea is a cardiovascular risk factor., (Copyright (c) 2005 S. Karger AG, Basel.)

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.

Background: A potentially harmful complication of cardiac catheterization is the arteriovenous fistula. Precise knowledge of possible factors predisposing for acquisition of iatrogenic AV-fistulae could enable cardiologists to perform a risk stratification for cardiac patients prior to catheterization., Methods: Over a period of 2 years, 10,271 consecutive patients who underwent cardiac catheterization were included in this study. Auscultation of a new femoral bruit was followed by a duplex scan to confirm the suspected diagnosis of an AVF. Every patient was investigated on the day after catheterization., Results: The incidence of iatrogenic AVF was 0.86%. A multivariate regression analysis revealed five significant and independent risk factors: (1) procedural heparin dosage >or=12,500 IU (Odds Ratio (OR)=2.88), (2) coumadin therapy (OR=2.34), (3) puncture of the left groin (OR=2.21), (4) arterial hypertension (OR=1.86) and (5) female gender (OR=1.84). Coronary angioplasty (instead of diagnostic procedure), size and number of sheaths, age and body mass index did not significantly affect the incidence of AVF., Conclusions: The overall incidence of AV-fistulae following cardiac catheterization approximates 1%. Determination of significant risk factors will facilitate identification of patients at risk for iatrogenic arteriovenous fistulae prior to cardiac catheterization and thus help to develop strategies to reduce the incidence of AV-fistulae.

Objectives: We sought to determine the incidence of arteriovenous fistulas (AVF), identify risk factors for AVF, and follow up the clinical outcome of femoral AVF., Background: Arteriovenous fistulas are a potential harmful complication of cardiac catheterization. Incidence and clinical outcome of iatrogenic AVF are unknown so far, although important for risk stratification and treatment., Methods: A total of 10,271 consecutive patients undergoing cardiac catheterization were followed up prospectively over a period of three years. Diagnosis of AVF was performed by duplex sonography., Results: The incidence of AVF was 0.86% (n = 88). The following significant and independent risk factors for AVF were identified: high heparin dosage (odds ratio [OR]) = 2.88), coumadin therapy (OR = 2.34), puncture of the left groin (OR = 2.21), arterial hypertension (OR = 1.86), and female gender (OR = 1.84). Within 12 months 38% of all AVF closed spontaneously. No signs of cardiac volume overload or limb damage were observed in patients with persisting AVF. None of the risk factors for AVF influenced the incidence or the rate of AVF closure. Only intensified anticoagulation showed a tendency to extend AVF persistence., Conclusions: Almost 1% of patients undergoing cardiac catheterization acquire femoral AVF, for which patient- and procedure-related risk factors could be identified. One-third of iatrogenic AVF close spontaneously within one year. Cardiac volume overload and limb damage are highly unlikely with AVF persistence. Thus, a conservative management for at least one year seems to be justified.

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.

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.

Congestive heart failure is a major and growing health care concern worldwide, and mortality in patients with severe heart failure is high. Few options are available to patients with New York Heart Association class IV heart failure refractory to oral medical therapy. Over the last 15-20 years milrinone, a phosphodiesterase-III inhibitor, has been used occasionally to treat patients with acute heart failure and as a bridge to heart transplantation and, more recently, has been used intermittently or continuously on an outpatient basis. We report a patient with severe, chronic congestive heart failure, whom we treated successfully with continuous milrinone infusions as an outpatient. We were able to wean him of the milrinone after successful up-titration of carvedilol. Nine months after discontinuation of milrinone the patient remains stable in New York Heart Association class I on high dose carvedilol. Research is required to validate the possibility that patients with severe heart failure may be successfully weaned from milrinone using carvedilol and achieve significant improvement of their functional status and quality of life. This may prove to be an effective strategy for the treatment of selected patients with severe, chronic congestive heart failure. (c)2001 by CHF, Inc.

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.

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.

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.

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.

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, especially when given over prolonged periods of time. Local gene therapy aims at overexpressing proteins that: (1) regulate the cell cycle of VSMC; (2) inhibit VSMC migration; (3) endow the endothelium with its vasoprotective properties; and (4) stimulate growth of endothelium and angiogenesis. Alternatively, some approaches tend to suppress gene expression of proteins believed to promote VSMC proliferation and migration. In sharp contrast to drug treatments, local gene therapy limits expression of the beneficial agent to the injured vascular site, and there, it can extend the presence of this agent to weeks and, with some gene vectors, to many months. The clinical potential of this approach has led to the initiation of trials that currently evaluate gene therapy approaches to the attenuation of peripheral and myocardial ischaemia and the prevention of vein graft disease., (Copyright 1999 Harcourt Publishers Ltd.)

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.

During the last 25 years the internal thoracic artery has become a well established conduit for coronary revascularization. Next to angiography, duplex-sonography is increasingly used as a non-invasive imaging procedure for the evaluation of this graft vessel. Preoperative investigation in 117 patients has yielded a high level of agreement between angiography and duplex-sonography. While the preoperative flow-pattern is dominated by systolic flow as it is typical for vessels supplying skeletal muscle, the postoperative findings show an adaptation to the coronary vascular bed as the diastolic flow increases. These non-invasive measurements are well matched with invasive intravascular recordings. Coronary angiography and duplex-sonography of the internal thoracic artery yielded comparable findings in respect to the procedural result. Considering the increasing use of the internal thoracic artery in coronary artery bypass surgery, this non-invasive method should gain increasing relevance.

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.

Despite progress in the invasive revascularization procedures and even though conventional antianginal treatment has improved the quality of life in patients with symptomatic coronary artery disease considerably, an increasing number of patients suffers from end-stage coronary artery disease and refractory angina pectoris. For these refractory patients long-term intermittent urokinase therapy was developed as an antithrombotic intervention, which is based on its capacity to enhance thrombolysis and blood rheology, and may possibly lead to plaque regression. The coronary syndrome of refractory angina pectoris is characterized by a mismatch of severe coronary insufficiency and a relatively large amount of viable myocardium as indicated by an only moderately impaired left ventricular function. Prior to initiation of long-term intermittent urokinase therapy all potential measures to improve myocardial perfusion have to be considered in each patient. These supportive measures include rigorous reduction of LDL-cholesterol, which has proven antiischemic properties due to an improved endothelial function of epicardial conductance vessels possibly resulting in an antianginal effect. Apart from the proven antiischemic properties of long-term intermittent urokinase therapy in patients with refractory angina pectoris, objective signs of ischemic myocardial heart failure improve. Follow-up studies demonstrated a significant increase of left ventricular ejection fraction as evaluated with multi-gated blood pool analysis. Furthermore, left ventricular diastolic function normalized after a treatment period of 12 weeks. As the clinical effects last well beyond the actual treatment period and as they are accompanied by a remarkable increase in the quality of life, a complex approach as this one is justified in this highly symptomatic patient group.

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.

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.

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.

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.

Objective: Earlier investigations have demonstrated that inactivation of the p53 tumor suppressor gene might play a role in the development and progression of bladder cancer. Complex formation with the MDM2 oncogene product is one mechanism inactivating the p53 protein. Therefore, the MDM2 and the p53 protein were investigated to study potential interactions in bladder cancer., Method: 200 archival bladder tissue specimens from 92 patients were studied by immunohistochemistry using monoclonal antibodies DO-1 against p53 and IF2 against MDM2., Results: No staining was observed for p53 or MDM2 in normal urothelium. Alterations of both genes were rare in dysplasia. p53 accumulation was observed in 27-44% of the tumor stages examined. MDM2 overexpression increased from 18% in carcinoma in situ to 49% in T1 tumors, but was present in only 22% of the advanced tumors. Alterations of both genes were more frequent in high-grade lesions. To investigate the prognostic impact of these alterations 61 patients with superficial bladder tumors were followed for at least 2 years (mean 51 months). Multivariate analysis demonstrated that multifocal disease and p53 accumulation were significantly correlated with tumor progression (p = 0.0099 and 0.0135). MDM2 overexpression alone had no prognostic significance. Patients with alterations of both genes had a very high risk of tumor progression (p = 0.0064)., Conclusion: These results demonstrate a positive correlation between p53 accumulation and MDM2 overexpression in the progression of bladder cancer which may have prognostic value.

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.

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.

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.

The case of a 17-year-old boy is described, who had myocardial infarction during scholastic sports 15 minutes after scrotal trauma. Cardiac catheterization revealed a nonstenosed aberrant left circumflex artery originating from the right (anterior) sinus of Valsalva with retroaortic course, which has to be regarded the infarct vessel according to electrocardiographic, ventriculographic, and scintigraphic findings.

Objectives: This dose-response study was designed to test two low dose regimens of urokinase administered over a prolonged time period in patients with chronic refractory angina pectoris with respect to effects on clinical symptoms and objective variables of myocardial ischemia., Background: Patients with severe and chronic refractory angina pectoris in end-stage coronary artery disease represent an increasing clinical problem. Favorable therapeutic effects on myocardial ischemia have been reported for long-term application of low dose urokinase., Methods: Ninety-eight patients with chronic refractory and end-stage coronary artery disease were randomly assigned to two treatment groups: group A (49 patients) received 50,000 IU and group B (49 patients) 500,000 IU of urokinase as an intravenous bolus infection three times a week over a period of 12 weeks. Variables evaluated were number of weekly anginal events, data from ergometric exercise testing with simultaneous electrocardiographic registration, semiquantitative evaluation of Tc-99m 2-methoxy isobutyl isonitrile (MIBI) scans and rheologic variables., Results: After 12 weeks of treatment, anginal symptoms (events/week) were reduced significantly in group B by 70% compared with 24% in group A (p < 0.001). Fibrinogen decreased by 3% in group A and by 33% in group B (p < 0.001). Plasma viscosity and red blood cell aggregation were reduced by 6.4% (p < 0.001) and 19.9% (p < 0.001), respectively, in group B. Objective variables of myocardial ischemia were improved significantly in group B only. No cumulation of coronary ischemic events was observed in group B., Conclusions: Long-term intermittent urokinase therapy in an applied dose of 3 X 500,000 IU/week represents an effective anti-ischemic and antianginal approach for patients with refractory angina pectoris and end-stage coronary artery disease. Apart from rheologic improvement, antithrombotic properties and plaque regression are likely anti-ischemic mechanisms.

Patients with coronary artery disease and severe angina pectoris refractory to conventional medical treatment (beta blockers, nitrates, calcium antagonists) and without the option for invasive revascularization procedures represent an increasing clinical problem. For these patients, chronic-intermittent urokinase therapy has been developed. Twenty patients received 500,000 IU urokinase as intravenous bolus injection 3 times a week over a period of 12 weeks. The average reduction in anginal symptoms in 19 patients was 74%, from 23.5 +/- 10.8 to 5.2 +/- 4.8 events/week (p < 0.001); 1 patient was excluded from further treatment because of an increase of > 66% in anginal events. Fibrinogen decreased by 34% from 370 +/- 57 to 244 +/- 44 mg/dl (p < 0.001), the rheological parameters plasma viscosity by 6.1% from 1.39 +/- 0.04 to 1.31 +/- 0.03 mPas (< 0.001), and red blood cell aggregation by 18% from 13.9 +/- 2.4 to 11.2 +/- 2.2 (p < 0.001). Exercise tolerance increased by 51%. Average ST-segment depression decreased from 0.16 +/- 0.10 to 0.12 +/- 0.09 (p < 0.01). After 12 weeks of follow-up, angina pectoris and fibrinogen levels were still significantly reduced compared with baseline values. Chronic-intermittent urokinase therapy represents an effective anti-ischemic and antianginal approach in patients with refractory angina pectoris and end-stage coronary artery disease. Improvement of rheological blood properties and thrombolytic effects are likely therapeutic mechanisms.