Aspirin reduces the prothrombotic activity of C-reactive protein.

AIM: C-reactive protein (CRP) is a risk marker and a potential modulator of vascular disease. Previous studies support a prothrombotic activity of CRP, with impaired thromboregulation. The present study examined the antithrombotic effect of aspirin in mice transgenic for human CRP (CRPtg mice). Mechanistic investigations further elucidated the effect of CRP on prostanoid metabolism in vivo and in vitro. METHODS AND RESULTS: Administration of aspirin (30 mg kg(-1) day(-1)) to CRPtg mice slowed the accelerated thrombosis after photochemical injury to the carotid (99 +/- 32 vs. 45 +/- 24 min and 75 +/- 23 vs. 82 +/- 26 min in wild-type mice vs. CRPtg mice, without and following aspirin treatment, respectively). Vascular injury modulated the expression of key pathways in prostanoid metabolism differently in CRPtg mice and wild-type mice. Suppression of cyclo-oxygenase 2 (COX-2)-derived metabolism with suppression of prostaglandin I2 (PGI2) synthase and PGI2 metabolism was recorded in the injured artery with increased thromboxane receptor expression. Aspirin therapy reduced the difference in PGI2 biosynthesis between CRPtg mice and wild-type mice. In vitro studies in human-derived cells further supported these findings. Incubation of human umbilical vein endothelial cells (HUVECs) with human recombinant CRP (5 microg mL(-1)) suppressed PGI2 synthase expression and significantly increased thromboxane receptor levels. Incubation of smooth muscle cells with CRP did not affect prostanoid expression. CONCLUSIONS: CRP modulates prostanoid metabolism to favor vascular occlusion. Elevated CRP levels might predispose to the cardiovascular hazard conferred by selective COX-2 inhibitors, and the risk mediated by CRP may be limited by aspirin.

Beta glycosphingolipids suppress rank expression and inhibit natural killer T cell and CD8+ accumulation in alleviating aortic valve calcification.

CD8 lymphocytes play a role in aortic valve inflammation leading to aortic valve calcification (AVC). RANK is a transmembrane protein that is important in osteoclast differentiation and calcification. Beta-glucosylceramide (beta-GC) together with beta-lactosylceramide (beta-LC), the 1:1 combination of beta- glucosylceramide and beta-lactosylceramide, designated IGL, exerts an immune modulatory effect in various inflammatory disorders in a CD8- and NKT (natural killer T cell)-dependent manner. We hypothesized that IGL may affect the inflammatory condition associated with AVC. AVC was induced in rats by oral administration of a high-adenine, high-phosphorus diet and was assessed by multislice computer tomography. Administration of this diet was associated with a marked increase in CD8 and NKT lymphocyte accumulation in the aortic valve. Administration of IGL led to marked suppression of RANK expression, associated with inhibition of both NKT and CD8 lymphocyte accumulation in the aortic valve. These effects were associated with a significant improvement in the degree of AVC in IGL-treated animals (25 and 53 by Agatston Score, in IGL-treated and controls, respectively). CD8 and NKT lymphocytes play a role in the pathogenesis of AVC, and RANK-mediated NKT inhibition by beta-glycosphingolipids can alleviate AVC.

The discrete and combined effect of SREBP-2 and SCAP isoforms in the control of plasma lipids among familial hypercholesterolaemia patients.

BACKGROUND AND AIM: Hypercholesterolaemia is a major risk factor for atherosclerosis. Cholesterol is modulated by genetic and environmental factors. An important regulatory pathway is controlled by the sterol-regulatory element-binding proteins (SREBPs) and the SREBP cleavage-activating protein (SCAP). Both SREBP-2 and SCAP are candidates to contribute to the development of atherosclerosis. We investigated the possible effects of the variability of proteins involved in this regulatory pathway on plasma lipids among familial hypercholesterolaemia patients. METHODS AND RESULTS: Single nucleotide polymorphisms (SNPs) in the genes encoding SREBP-2 and SCAP causing amino acid changes at positions 595 (595G/A) and 796 (796I/V), respectively, were genotyped in 801 FH individuals originating from Israel, The Netherlands, and Switzerland. A linear regression model to examine the associations between SREBP-2 and SCAP isoforms and lipid and lipoprotein levels was used. In females, homozygosity either for the SREBP-2-595A or for the SCAP-796I isoform was associated with higher LDL-cholesterol plasma concentrations (14.7 mg/dl and 20.3 mg/dl, respectively). Surprisingly, heterozygosity for the combination SREBP-2-595A/SCAP-796I was associated with a decrease of 30.28 mg/dl in LDL-C (p-value for gene-gene interaction=0.09). No such effect was observed among FH males. Subgroup analysis considering the most frequent (N>/=24) LDL receptor mutations (del191-2, ins313+1-2, C660X, E207K, S285L) revealed further gene-dosage- and gender-dependent effects of the SCAP mutations on LDL-cholesterol concentrations (p=0.0345). These effects were, however, not present when less frequent LDL receptor mutations were investigated. CONCLUSIONS: These results suggest a possible gene-gene interaction between the genes encoding SREBP-2 and SCAP that modulate plasma lipids in a strictly gender-specific fashion. Further investigation is needed to confirm this effect. A study in a larger FH group or in non-FH hypercholesterolaemic subjects may further define the role of this regulatory mechanism in determining plasma lipid concentration.

Ultrasound-guided thrombin injection for the treatment of iatrogenic pseudoaneurysm of the femoral artery.

BACKGROUND: Pseudoaneurysm occurring after catheterization of the femoral artery is associated with significant morbidity. Percutaneous ultrasound-guided thrombin injection has recently emerged as a potential first-line therapy. OBJECTIVES: To evaluate the efficacy of this treatment in eight patients with iatrogenic femoral artery pseudoaneurysm. METHODS: After attempted treatment with external compression had failed, eight patients with iatrogenic femoral artery pseudoaneurysm were treated with thrombin injection. Treatment performed between 2 and 9 days following arterial puncture. The study group comprised seven males and one female ranging in age from 23 to 89 years (median 70). Seven had undergone cardiac catheterization with or without intervention, and five were receiving antiplatelet and/or anticoagulant drugs. Arterial pseudoaneurysm resulted from femoral vein catheterization in one patient. Using a sterile technique and real-time Doppler ultrasound guidance, a dilute solution of bovine thrombin (average dose 250 units, range 100-600), was slowly injected directly into the pseudoaneurysm until cessation of flow was seen. Patients were allowed to walk within 2 hours of the procedure and were followed up clinically and by color Doppler ultrasound during the admission. RESULTS: Cardiac catheterization had been inadvertently performed via the superficial or profunda femoris arteries in four of the eight patients. Thrombin injection was initially successful in all eight patients without complication. Thrombosis occurred immediately in every case. Early recanalization of pseudoaneurysm occurred in one patient despite repeat thrombin injection and attempted ultrasound-guided compression. He eventually required surgical repair. The final success rate was 87.5% (7/8). CONCLUSION: Faulty puncture technique is an important risk factor for the development of post-catheterization femoral artery pseudoaneurysm. Ultrasound-guided thrombin injection is a safe, rapid, well-tolerated, inexpensive and successful therapy. If initial external compression with a sandbag fails to result in thrombosis of the pseudoaneurysm then thrombin injection should be considered as first-line therapy. If unsuccessful, it does not preclude the use of alternative treatment modalities. Further study is necessary to assess the long-term effects of thrombin injection.

Stents in total occlusion for restenosis prevention. The multicentre randomized STOP study. The Israeli Working Group for Interventional Cardiology.

AIMS: This multicentre randomized study set out to evaluate whether coronary stenting improves the results of successful balloon angioplasty for chronic total occlusion. Balloon angioplasty for chronic total occlusion has a high restenosis rate. Several reports have suggested that coronary stenting may decrease the likelihood of restenosis and reocclusion. METHODS AND RESULTS: Patients with total coronary artery occlusions who had an optimal PTCA result were randomized either to no further treatment or additional stent implantation. The AVE microstent was used and all patients were scheduled for a 1-, 3-, and 6-month clinical follow-up. Repeat coronary angiography to assess the rate and pattern of restenosis was performed at 6 months or earlier if clinically indicated. Ninety-six patients were enrolled in this study. The mean age was 59. 3+/-10.3 years and 15 were females. Forty-eight patients were randomized to the stent arm, receiving 52 stents (lengths 18-39 mm). Stent implantation was successful in all and there were no major procedure-related complications. Sixty-nine patients (72%) were restudied after 6 months. The binary restenosis rates (50%), in the PTCA arm were 70.9% with a minimal lumen diameter of 1.01+/-0.79 mm compared to 42.1% in the stent arm with a minimal lumen diameter of 1.63+/-1.02 mm (P=0.034). Reocclusion occurred in 7.9% in the stent group compared to 16.1% in the PTCA group. Restenosis in the PTCA group was focal in 88% of patients and occurred at the point of total obstruction (within 5 mm), compared to diffuse instent restenosis, which occurred in 54% of the patients in the stent group. CONCLUSION: Coronary stenting can significantly decrease the rate of restenosis and reocclusion of total occlusions. As restenosis in the stent group was more diffuse, care should be taken to implant short stents at the site of occlusion.

Acute myocardial infarction--a late complication of intracoronary stent placement.

BACKGROUND: Myocardial infarction (MI) as the first indication of postangioplasty restenosis is extremely rare, and it has been speculated that the fibroproliferative restenotic lesion is less likely to undergo plaque rupture than the lipid-laden native atherosclerotic lesion. HYPOTHESIS: The present study was designed to examine whether intracoronary stent implantation affects this course. METHODS: In all, 994 consecutive patients who underwent angioplasty and intracoronary stent implantation in our hospital were reviewed retrospectively for the occurrence of MI. RESULTS: Eight patients (0.8%), all male and hypertensive, aged 33-83 years, presented with an MI due to stent occlusion more than 30 days following stenting (range: 35-398 days). In two patients, MI occurred 3 and 5 h, respectively, following completion of a maximal high-level exercise test that was negative for ischemia. Angiography revealed complete occlusion or significant stenosis of the stent in all eight patients, with an obvious intimal dissection in either edge of the stent in six patients. Except for gender and hypertension, no correlation was found with other risk factors, vessel involved, initial angiographic results, or with stent design, diameter, or length. CONCLUSIONS: Myocardial infarction as a late complication of successful stent implantation occurred in 0.8% of our patients. This is only the lower bound of the estimated frequency for such an event. We hypothesize that the transition point between the relatively fixed stent and the normal artery is exposed to high deformation stress which makes it vulnerable to rupture and dissection. Strenuous exercise and hypertension may increase the deformation stress and the risk of intimal rupture.

Coronary vasospasm associated with uncontrolled carcinoid tumour.

We report on a 74-year-old carcinoid patient who, following acute myocardial infarction (MI) and percutaneous transluminal coronary angioplasty, suffered recurrent episodes of chest pain and ST-segment elevation on ECG. This was accompanied by elevation of urinary 5-hydroxy-indole acetic acid. A review of the patient's file revealed that during the 3 weeks prior to the MI, she had been treated inadvertently with a fivefold lower dosage of octreotide. Following the correction of octreotide dosage, episodes of chest pain resolved immediately. We therefore suggest that this patient suffered from recurrent coronary vasospasm due to uncontrolled carcinoid tumour.

Late effects of dose fractionation on the mechanical properties of breast skin following post-lumpectomy radiotherapy.

PURPOSE: Late radiation-induced skin effects were studied in a multicenter project using our new sensitive noninvasive viscoelasticity skin analyzer (VESA). METHODS AND MATERIALS: Skin viscoelasticity and anisotropy were examined quantitatively in symmetric areas of both breasts in healthy women and in 110 breast cancer patients who underwent lumpectomy and radiotherapy. These parameters were evaluated by the VESA measurement of the speed of elastic wave propagation in the skin; higher VESA readings correspond to higher skin stiffness. Effect of radiation was estimated by comparison of the data recorded in the irradiated versus nonirradiated breast of the same patient. RESULTS: Skin viscoelasticity and anisotropy were similar in contralateral areas of the breasts in healthy controls as well as in the nonirradiated breasts of the patients. With age, skin viscoelasticity decreased and anisotropy increased similarly in both breasts. Radiotherapy, by a total radiation dose in the range of 45-50 Gy given with 1.8 Gy/fraction (fx) resulted in a similar minor, but still statistically significant, increase of skin stiffness relative to control. The effect was more pronounced when a dose of 50 Gy was given in a higher dose/fraction of 2.5 Gy. CONCLUSION: We found that the increase in dose of radiation per fraction had much more impact on the development of late skin effects than elevation in the total dose given.

Effectiveness of nifedipine GITS in combination with atenolol in chronic stable angina.

Nifedipine gastrointestinal therapeutic system (GITS) is a once-daily formulation of nifedipine that provides stable plasma concentrations over the entire 24 h dosing interval. Two-hundred and one patients with Canadian Cardiovascular Society class II to III angina who were on 50 mg of atenolol yet still experiencing angina symptoms were randomized to receive either placebo or nifedipine GITS 30, 60 or 90 mg/day. After four weeks of treatment, the changes in time from baseline to onset of 1 mm ST segment depression in the 183 eligible patients were 26.7+/-10.2 s, 40.9+/-11.3 s, 63.2+/-12.9 s and 70.3+/-12.6 for the placebo, and 30, 60 and 90 mg/day groups, respectively. These differences were significant (P<0.05) for the 60 and 90 mg/day groups compared with placebo and for the 60 mg/day group compared with the 30 mg/day group. The times to onset of pain and termination of exercise showed similar prolongation but did not achieve statistical significance. During the one-year open label phase of the study, patients exhibited statistically significant improvements in the time to onset of ST segment depression, time to anginal pain and time to termination of exercise at a mean dose of 52.3 mg/day of nifedipine GITS. Adverse events were primarily vasodilatory in nature. This study supports the use of nifedipine GITS in patients with chronic stable angina inadequately controlled on beta-blocker alone.

Long-term outcome of patients with very long stents for treatment of diffuse coronary disease.

OBJECTIVES: The study sought to determine the 6-month clinical outcome of patients who underwent implantation of very long coronary stents to treat diffuse disease and/or long dissections and to compare the findings with those reported in the literature for patients who underwent implantation of multiple short coronary stents. BACKGROUND: New designs of flexible stents enable the implantation of long stents rather than multiple short, older design stents. The initial experience is very promising but the long-term outcome has not been described yet. METHODS: Fifty-seven consecutive patients in whom 67 long stents (>/=30 mm) were successfully deployed were included in this study. Six-month clinical and angiographic follow-up was prospectively collected. Patients with recurrent angina underwent coronary angiography without further testing. Patients who remained asymptomatic at the 6-month follow-up visit underwent positron emission tomographic imaging, and those with results suggestive of ischemia underwent coronary angiography. A combined study end point was defined as death, myocardial infarction, and the need for target vessel revascularization. RESULTS: Only 1 patient (2%) reached a study end point at hospital discharge. An additional 20 patients (total 21 patients [37%]) reached an end point by 6 months. The outcome was not influenced by the clinical presentation (stable or unstable angina) or by the indication for stenting (elective or emergency). Predictors for adverse outcome were multiple stents per narrowing (63% vs 29%, P <. 04), and stents smaller than 3.5 mm (49% vs 22%). Narrowing and stent length were not predictive of a study end point in narrowings that were successfully treated by a single long stent. CONCLUSIONS: Elective stenting provides an effective solution for patients with diffuse coronary disease provided that a single long stent (usually <40 mm) can cover the full length of the narrowing. The results are better when vessels larger than 3 mm are treated. Compared with multiple short stents, implantation of a single long stent is probably at least as effective, and the procedure is quicker and cheaper and thus should be the preferred approach.

Laparoscopic port site metastasis of an undetected primary tumor.

A 50-year-old woman presented with an adenocarcinoma at a port site of a previous laparoscopic cholecystectomy. A thorough investigation and exploratory laparotomy with excision of the tumor failed to detect its origin.

Initial and long-term results with the CrossFlex stent--data from a national registry.

The Cordis CrossFlex trade mark stent is a balloon expandable helical coil made of stainless steel. OBJECTIVE: To assess the short- and long-term safety and efficacy of this stent by conducting a multi-center national registry. METHODS: One hundred and sixteen stents were implanted in 109 patients (mean age 59 3 10 years, 95 males). The lesions were classified as type B2 or C in 56 patients (51%). Successful deployment was achieved in 103 patients (94.5%). Failure was due to damage to the stent (two patients) or inability to reach the lesion (four patients). High-pressure deployment (>14 atm) was used in 68% of cases. RESULTS: Edge dissections occurred in nine patients after high-pressure deployment and necessitated implantation of a second stent. One patient with a large acute myocardial infarction died during hospitalization. Side branch occlusion occurred in five patients (4.6%). Subacute thrombosis occurred in two patients (1.8%) during the first four weeks. During a six-month follow-up period, 18 patients (16.5%) were rehospitalized with recurrent angina. Fifteen patients had coronary angiography and 13 (12.1%) needed additional target lesion revascularization (TLR). Twelve patients required a second PTCA for in-stent restenosis, and one needed a coronary artery bypass graft operation. CONCLUSIONS: The CrossFlex coronary stent can successfully be used in complex coronary lesions, with few short-term complications and a low TLR rate. Operators should be aware of the possibility of edge dissection during high-pressure implantation.

The Cutting Balloon--a new technology?

The Cutting Balloon consists of a standard balloon dilatation catheter with four microtome-sharp blades that incise the plaque and minimize arterial wall trauma. It was used in 31 patients; nine had calcified arteries, ten had non-compliant lesions, three had in-stent restenosis and nine had aorto-ostial lesions. Seventeen lesions were predilated, 28 were post-dilated and 18 required stent implantation. The procedure was very effective in aorto-ostial lesions, non-compliant lesions that were not responsive to high-pressure balloon dilatation, and was partially successful in calcified arteries. It has a very specific niche in selected lesions.

Diffuse narrowing of coronary arteries in diabetic patients: the earliest phase of coronary artery disease.

Coronary arteries in diabetic patients appear to be narrower than in normal subjects, but this has not been examined systematically. To investigate this hypothesis we reviewed the data of 711 consecutive patients with angiographically 'normal coronary arteries'. Excluded were patients with valvular, myocardial or pericardial disease, and patients with hypertension or hyperlipidemia. Thirteen diabetic patients (10 men) and 22 nondiabetic persons (8 men) constituted the study and control groups, respectively. The diameters of the coronary arteries and their branches were measured and adjusted for body surface area. The sum of the proximal left anterior descending (LAD), circumflex and right coronary arteries (RCA) was calculated and defined as total coronary diameter (TCD). The sum of the distal LAD, first diagonal, first marginal and distal RCA was calculated and defined as total distal coronary diameter (dTCD). The clinical data of both groups were comparable. Adjusted TCD for body surface area was 5.4 +/- 1.1 and 6.5 +/- 1.1 mm/m2 (p < 0.05) in diabetics and nondiabetics, respectively, and adjusted dTCD was 4.9 +/- 1.2 and 6.1 +/- 1.2 mm/m2 (p = 0.01) in diabetics and normal subjects, respectively. Specific arteries and branches that were significantly smaller in diabetics included: left main coronary artery, distal LAD, first diagonal, proximal RCA, distal RCA, right ventricular branch, and posterolateral and posterior descending artery of RCA origin. Gender was not a confounding factor since the control group had a larger proportion of women and still larger arteries than the diabetic group. In conclusion, coronary arteries and their branches in diabetic patients have smaller diameters than normal subjects. This may be due to increased coronary tone, diffuse mild atherosclerosis or both.

[Percutaneous revascularization of the left main coronary artery as coronary artery bypass in high surgical risks].

Coronary artery bypass grafting is the treatment of choice for obstructive disease of the left main coronary artery. Its proximal location and easy accessibility make the left main artery an inviting target for percutaneous intervention, an approach contraindicated by the high associated risk. We describe 2 patients at high operative risk in whom the obstructed main coronary artery was successfully revascularized percutaneously. Coronary stenting and rotational ablation of calcified arteries are essential for successful outcome and minimize complications.

Long-term angiographic follow-up of coronary balloon angioplasty in patients with diabetes mellitus: a clue to the explanation of the results of the BARI study. Balloon Angioplasty Revascularization Investigation.

OBJECTIVES: We sought to compare the angiographic outcome of diabetic patients (treated with insulin or oral hypoglycemic agents) after successful coronary angioplasty with that in nondiabetic patients. The analysis included the outcome of the dilated (restenosis) and nondilated narrowings (disease progression). BACKGROUND: Recent data have confirmed that diabetes mellitus is an important risk factor for long-term adverse events. These adverse events are more common after balloon angioplasty than after bypass surgery (Bypass Angioplasty Revascularization Investigation [BARI]). METHODS: We examined retrospectively 353 coronary angiograms of 248 patients (55 diabetic, 193 nondiabetic) who were referred for diagnostic angiography >1 month after successful angioplasty (1.4 +/- 0.6 [mean +/- SD] repeat angiograms/patient). Restenosis and disease progression/regression were compared between groups by means of quantitative angiography. RESULTS: Baseline clinical and angiographic characteristics were similar in both groups. There was a nonsignificant trend for a higher restenosis rate of dilated narrowings in diabetic patients. There were no significant changes between diabetic and nondiabetic patients in the rates of progression and regression of narrowings that were not dilated during the initial angioplasty. The main difference was in the rate of appearance of new narrowings: There was a 22% increase in the number of narrowings on the follow-up angiogram in diabetic patients (38 new, 174 preexisting narrowings) compared with 12% (86 new, 734 preexisting narrowings) in nondiabetic patients (p < 0.004). Diabetes mellitus and the performance of angioplasty in the artery had an additive risk for development of new narrowings, which were identified in 15 (16.9%) of 89 arteries with and 16 (13.2%) of 121 without angioplasty in diabetic patients and in 42 (12.7%) of 331 arteries with and 38 (7.3%) of 518 without angioplasty in nondiabetic patients (p = 0.009). CONCLUSIONS: The combination of diabetes mellitus and an artery that was instrumented during balloon angioplasty is additive and increases the risk of formation of new narrowing in that artery. This finding may explain the high adverse event rates observed in diabetic patients in the angioplasty arm of the BARI study, most of whom had angioplasty performed in at least two arteries.

Initial experience with long coronary stents: the changing practice of coronary angioplasty.

The initial experience with the use of long coronary stents (> 30 mm in length) was analyzed retrospectively. Sixty-seven stents were deployed in 58 narrowings in 57 patients (34 AVE Microstents, 16 Nir stents, four Gianturco-Roubin II stents, and 13 Wallstents). Stents were implanted in 22 patients with unstable angina, 34 patients with stable angina, and one patient during direct angioplasty for acute myocardial infarction. Eighteen additional short stents were implanted to cover the entire length of the lesions so that an average of one and a half stents were deployed per patient. The length of the narrowings before stenting was 40 +/- 20 mm and the length of the stented segments was 45 +/- 20 mm. Stents were deployed for "bailout" in 23 narrowings, to improve suboptimal results of balloon angioplasty in 18 narrowings, and electively in 17 narrowings. Twenty of the 67 long stents were deployed in saphenous vein grafts. The success rate of stent implantation was 100%. One patient had a rupture of a saphenous vein graft after deployment of two long stents, with tamponade treated by emergency surgery. One patient had chest pain 18 hours after stent deployment; by the time he arrived at the catheterization laboratory the pain had subsided and the angiogram revealed a patent artery with normal flow. There were no other major complications during the hospital course and 1-month follow-up. We conclude that long coronary stents can be deployed successfully in native coronary arteries and vein grafts. They are useful for elective implantation and extremely helpful in bailout situations. The immediate results are excellent, but long-term outcome is awaited.