High-density lipoprotein cholesterol, C-reactive protein, and prevalence and severity of coronary artery disease in 5641 consecutive patients undergoing coronary angiography.

BACKGROUND: Although high-density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP) are well-established predictors for future cardiovascular events, little information is available regarding their correlation with the prevalence and severity of angiographically evaluated coronary artery disease (CAD). MATERIAL AND METHODS: Five thousand six hundred forty-one consecutive patients undergoing coronary angiography for the evaluation of CAD were analysed. Cardiovascular risk factors were assessed by routine blood chemistry and questionnaire. CAD severity was graded by visual estimation of lumen diameter stenosis with significant stenoses defined as lumen diameter reduction of >or= 70%. Coronary angiograms were graded as one-, two- or three-vessel disease, as nonsignificant CAD (lumen irregularities < 70%) or non-CAD. RESULTS: HDL-C (60.3 +/- 18.5 vs. 51.9 +/- 15.3 mg dL(-1); P < 0.001) was higher and CRP was lower (0.65 +/- 1.68 vs. 1.02 +/- 2.38 mg dL(-1); P < 0.001) in non-CAD (n = 1517) compared to overall CAD patients (n = 4124). CAD patients were older (65.2 +/- 10.5 years vs. 59.9 +/- 11.4 years), more often diabetics (19.2% vs. 10.6%) and hypertensives (79.2% vs. 66.0%) and included more smokers (18.8% vs. 16.5%) (all P < 0.005). Low-density lipoprotein cholesterol (124.5 +/- 38.3 vs. 126.0 +/- 36.3 mg dL(-1); P = NS) was similar in overall CAD and non-CAD patients with more statin users (43.4% vs. 27.9%; P < 0.001) among CAD patients. Comparing non-CAD with different CAD severities using analysis of variance, results did not change substantially. In a multivariate analysis, HDL-C and CRP remained independently associated with the prevalence of CAD. In addition, HDL-C is also a potent predictor for the severity of CAD. CONCLUSIONS: In this large consecutive patient cohort, HDL-C and CRP are independently associated with the prevalence of CAD. In this analysis, HDL-C is an even stronger predictor for CAD than some other major classical risk factors.

Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men.

OBJECTIVES: The aim of this study was to determine whether the combination of lipid-lowering therapy and vitamin E supplementation improves peripheral endothelial function and whether it is more effective than lipid-lowering therapy alone. BACKGROUND: Endothelium-dependent vasodilation is impaired in coronary and peripheral arteries of patients with hypercholesterolemia. Coronary endothelial function has been shown to improve under lipid-lowering and antioxidant therapy, but the effect of additive vitamin E supplementation in the brachial artery is unknown. METHODS: Seven patients with hypercholesterolemia (mean+/-SD; age 51+/-10 yr) were studied. Endothelium-dependent, flow-mediated dilation (FMD) and endothelium-independent nitroglycerin-induced dilation (NMD) were assessed in the brachial artery using high resolution ultrasound 1) at baseline (BL I), 2) after 8 weeks of simvastatin (20 mg) and vitamin E (300 IU) therapy (Comb I), 3) after withdrawal of vitamin E for 4 weeks (Statin), 4) after therapy as in #2 for 4 weeks (Comb II) and 5) after withdrawal of both drugs for 4 weeks (BL II). RESULTS: Combined simvastatin and vitamin E therapy reduced total cholesterol (Comb I vs. BL I: 276+/-22 vs. 190+/-14 mg/dl, p < 0.0001) and low-density lipoprotein (LDL)-C (197+/-22 vs. 106+/-22 mg/dl, p < 0.00001), augmented alpha tocopherol levels normalized to LDL (12.2+/-4.1 vs. 4.9+/-0.9 microg alpha-T/100 mg% LDL-C, p < 0.01) and resulted in significant improvements in FMD (16.4+/-4.7 vs. 4.9+/-2.5%, p < 0.001) as well as NMD (17.9+/-4.3 vs. 11.2+/-2.8%, p < 0.01). The ratio of FMD to NMD (0.92+/-0.17 vs. 0.46+/-0.24%, p < 0.05) also increased under combination therapy, indicating a greater improvement of FMD than that of NMD. After withdrawal of vitamin E, both FMD (Comb I vs. Statin: 16.4+/-4.7 vs. 7.9+/-4.7%, p < 0.01) and NMD (17.9+/-4.3 vs. 10.9+/-4.5%, p < 0.05) decreased significantly such that simvastatin alone only tended to improve FMD and did not change NMD. Results under combination therapy (Comb II vs. BL II) were reproducible. CONCLUSIONS: Combined vitamin E and simvastatin therapy leads to an improvement of FMD and NMD in the brachial artery of patients with hypercholesterolemia. The improvement of FMD is more pronounced after combination therapy than after lipid-lowering therapy alone, similar to previous findings in the coronary circulation.

Effects of vitamin E on chronic and acute endothelial dysfunction in smokers.

OBJECTIVES: The aims of this study were to determine whether chronic or acute impairment of flow mediated vasodilation (FMD) in the brachial artery of smokers can be restored or preserved by the antioxidant vitamin E. BACKGROUND: Transient impairment of endothelial function after heavy cigarette smoking and chronic endothelial dysfunction in smokers result at least in part from increased oxidative stress. METHODS: We studied 22 healthy male smokers (mean +/- SD, 23 +/- 9 cigarettes per day) randomly assigned to receive either 600 IU vitamin E per day (n = 11, age 28 +/- 6 years) or placebo (n = 11, age 27 +/- 6 years) for four weeks and 11 age-matched healthy male nonsmokers. Flow mediated vasodilation and endothelium-independent, nitroglycerin-induced dilation were assessed in the brachial artery using high resolution ultrasound (7.5 MHz) at baseline and after therapy. Subjects stopped smoking 2 h before the ultrasound examinations. At the end of the treatment period, a third scan was obtained 20 min after smoking a cigarette (0.6 mg nicotine, 7 mg tar) to estimate transient impairment of FMD. RESULTS: Flow mediated vasodilation at baseline was abnormal in the vitamin E (5.3 +/- 3.8, p < 0.01) and in the placebo group (6.4 +/- 3.5, p < 0.05) compared with nonsmoking controls (11.6 +/- 4.7). Using a two-way repeated measures analysis of variance (ANOVA) to examine the effects of vitamin E on FMD, we found no effect for the grouping factor (p = 0.5834) in the ANOVA over time but a highly significant difference with respect to time (p = 0.0065). The interaction of the time factor and the grouping factor also proved to be significant (p = 0.0318). Flow mediated vasodilation values remained similar after treatment for four weeks in both groups but declined faster after smoking a cigarette in subjects taking placebo compared with those receiving vitamin E (p values from successive differences for the time/group factor: 0.0001/0.0017). The transient attenuation of FMD (calculated as the percent change in FMD) was related to the improvement of the antioxidant status, estimated as percent changes in thiobarbituric acid-reactive substances (r = -0.67, p = 0.0024). Nitroglycerin-induced dilation did not differ between study groups at baseline or after therapy. CONCLUSIONS: These results demonstrate that oral supplementation of vitamin E can attenuate transient impairment of endothelial function after heavy smoking due to an improvement of the oxidative status but cannot restore chronic endothelial dysfunction within four weeks in healthy male smokers.

Increased intimal apoptosis in coronary atherosclerotic vessel segments lacking compensatory enlargement.

OBJECTIVES: In a histopathologic study, we assessed the balance of cell proliferation and apoptosis by counting the number of apoptotic and proliferating cell nuclear antigen-positive cells in freshly harvested atherectomy specimens from 34 patients. BACKGROUND: Remodeling of human coronary arteries is an adaptive process that alters vascular lumen size. METHODS: Intravascular ultrasound was performed prior to atherectomy. Total vessel area (area within the external elastic lamina [EEL]), lumen area and plaque area were measured at the region of interest (ROI), and at a proximal and distal reference segment, utilizing the formula Delta(%)=100x(ROI-reference segment)/reference segment. Positive arterial remodeling (R+) resulting in luminal expansion was defined as DeltaEEL >10%. Absence of remodeling (0 < DeltaEEL <10%) and constrictive arterial remodeling (DeltaEEL <0) were considered as neutral remodeling (R0) and negative remodeling (R-), respectively. RESULTS: In R- lesions, apoptotic indices (APO) were significantly elevated (17.17 +/- 2.19%) compared with R+ lesions (4.89 +/- 1.7%; p = 0.0007). In a rabbit iliac percutaneous transluminal coronary angioplasty model intimal apoptosis was increased four weeks after balloon angioplasty injury (APO 8.8 +/- 0.03%) compared with contralateral untreated segments (APO 3.0 +/- 0.04%, n = 6). Lesions with an EEL/intimal area <3.0 showed significantly more intimal apoptosis than untreated lesions (p = 0.02). CONCLUSIONS: The data indicate that constrictive remodeling of atherosclerotic coronary lesions is associated with increased apoptosis of intimal cells. We speculate that increased apoptosis is due to extensive plaque healing after episodes of symptomatic or asymptomatic plaque rupture.

Impairment of endothelium-independent vasodilation in patients with hypercalcemia.

OBJECTIVE: Patients with primary hyperparathyroidism (PHPT) and/or hypercalcemia are at increased risk for myocardial ischemia. Whether PHPT is associated with altered endothelium-dependent dilation, vascular smooth muscle cell function, or both is unknown. This study was performed to test the hypothesis that endothelium-dependent, flow-mediated dilation (FMD) and/or endothelium-independent, nitroglycerin-induced dilation (NMD) is impaired in the preclinical phase of vascular disease in patients with PHPT. METHODS: Twenty-six PHPT patients (mean +/- SD; age 55 +/- 15 y, serum calcium 3.00 +/- 0.37 mmol/l, serum phosphate 0.79 +/- 0.21 mmol/l, iPTH 249 +/- 262 pg/ml) with no evidence of coronary artery disease (CAD) as well as 26 normocalcemic control subjects (CTL; age 51 +/- 12 y) were studied. FMD following reactive hyperemia and NMD after 0.8 mg nitroglycerin (NTG) were assessed in the brachial artery by using high resolution ultrasound (7 MHz). RESULTS: NMD was impaired in PHPT patients compared to CTL (11.9 +/- 3.9% vs. 15.6 +/- 5.7%; p = 0.012). FMD was similar in both study groups (11.6 +/- 4.6% vs. 12.6 +/- 4.9; NS). The ratio of FMD to NMD was significantly different between PHPT patients and CTL (0.98 +/- 0.19 vs 0.81 +/- 0.25, p = 0.0009). On multiple stepwise regression analysis serum calcium was independently associated with the FMD/NMD ratio (r = 0.34, p = 0.017). CONCLUSIONS: Endothelium-independent vasodilation is impaired in PHPT patients without clinical evidence of coronary artery disease compared to normocalcemic CTL, while endothelium-dependent dilation was similar in both study groups. Thus, altered arterial reactivity in the course of PHPT may predominantly involve the arterial media and not the endothelium as observed previously in patients with various stages of atherosclerosis.

Is oxidative stress causally linked to unstable angina pectoris? A study in 100 CAD patients and matched controls.

OBJECTIVE: Unstable angina pectoris often leads to acute myocardial infarction. Since lipid peroxidation is thought to be causally related to chronic and acute events in atherosclerosis and coronary artery disease, we measured lipid peroxidation products and vitamin E in 100 patients with coronary artery disease and compared them to a matched control group. METHODS: 50 consecutive patients with stable angina pectoris (SAP) and 50 consecutive patients with unstable angina pectoris (UAP) were studied and compared to 100 clinically healthy individuals. In addition to conventional lipid and lipoprotein analysis, malondialdehydes were measured as thiobarbituric acid reactive substances (TBARS). Lipid hydroperoxides were assayed with the colorimetric methylene blue method. alpha-Tocopherol was quantitated by HPLC after extraction of serum with hexane-ethanol. In the patient group conjugated dienes were also measured. RESULTS: As expected, patients had significantly higher cholesterol, triglyceride LDL-C and Lp(a) values and lower HDL-C values than controls. When patients were divided into groups with SAP and UAP respectively, peroxides and TBARS were significantly higher in the latter group as compared to patients with SAP and to controls. Conjugated dienes were also significantly higher in patients with UAP as compared to patients with SAP. Total plasma alpha-tocopherol was comparable in all three groups, whereas the alpha-tocopherol content per LDL particle was lowest in patients with UAP, followed by patients with SAP and then controls. CONCLUSION: It is concluded that lipid peroxidation parameters are increased in patients with UAP and discriminate SAP from UAP patients.

Genetic augmentation of nitric oxide synthase increases the vascular generation of VEGF.

OBJECTIVE: Vascular endothelial growth factor (VEGF) induces the release of nitric oxide (NO) from endothelial cells. There is also limited data suggesting that NO may enhance VEGF generation. METHODS: To further investigate this interaction, we examined the effect of exogenous and endogenous NO on the synthesis of VEGF by rat and human vascular smooth muscle cells (VSMC) by exposing cells to exogenous NO donors, or to genetic augmentation of eNOS or iNOS. RESULTS: NO-donors potentiated by 2-fold the generation of VEGF protein by rat or human VSMC. Similarly, rat or human VSMC transiently transfected with plasmid DNA encoding eNOS or iNOS, synthesized up to 3-fold more VEGF than those transfected with control plasmid DNA, an effect which was reversed after treatment with the NOS antagonist L-NAME. Rat VSMC stably transfected with pKeNOS plasmid, constitutively produced NO and released high concentrations of VEGF. In these cells, L-NAME significantly reduced NO synthesis and decreased VEGF generation. The VEGF protein produced by NOS-transfected VSMC was biologically active, as conditioned media harvested from these cells increased endothelial cell proliferation. CONCLUSION: These studies reveal that NO derived from NO-donors or generated by NOS within the cells, upregulates the synthesis of VEGF in vascular smooth muscle cells. Administration of NO donors, or augmentation of endogenous NO synthesis, may be an alternative approach in therapeutic angiogenesis.

Expression of VCAM-1 in rabbit iliac arteries is associated with vasodilator dysfunction of regenerated endothelium following balloon injury.

Previous studies have demonstrated impaired endothelium-dependent vasodilation following balloon injury of the rabbit iliac artery, suggesting dysfunction of the regenerated endothelium. More recently, expression of vascular cell adhesion molecule-1 (VCAM-1) has been shown up to 4 weeks in a different injury model of the rabbit aorta, suggesting sustained inflammatory activation of endothelium following injury. The aim of the present study was to combine the examination of VCAM-1 expression, as a marker of cellular activation, and the assessment of endothelium-dependent relaxation to test the hypothesis that different forms of altered endothelial function are concurrently present in the chronic phase following experimental balloon angioplasty. New Zealand White rabbits fed either a standard (n = 7) or a 1% cholesterol (n = 8) diet, underwent balloon injury of the iliac artery 5 weeks following the initiation of the diet. Four weeks after balloon injury, control and balloon-injured arteries were harvested for in vitro studies of vascular reactivity, for morphometric analysis and for immunocytochemical staining with Rb 1/9 monoclonal antibody directed against VCAM-1 and with CD 31 monoclonal antibody for the identification of endothelial cells. The combination of balloon injury and hypercholesterolemia resulted in a marked impairment of endothelium-dependent relaxation to acetylcholine and in a pronounced intimal proliferation compared to control or either intervention alone. Control rings of rabbits fed a normal diet did not reveal positive staining for VCAM-1. Balloon-injured rings of the animals fed a normal diet showed focal areas of positive staining in the superficial cell layer overlying intimal lesions. In the group fed a high cholesterol diet, control rings and ballooned rings showed positive staining for VCAM-1 in cells overlying intimal lesions. In all groups the superficial cell layers were identified as endothelial cells by positive staining for CD 31. In conclusion, the present study shows that regenerated endothelium following mechanical arterial injury reveals expression of VCAM-1 together with impaired receptor-mediated vasodilator capacity. Thus, the expression of VCAM-1 and the impairment of endothelium-dependent relaxation may represent different features of endothelial dysfunction following balloon injury which may actively influence the proliferative lesion of restenosis after balloon angioplasty.

Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease.

Flow-mediated vasodilation (FMD) of systemic arteries, a non-invasive parameter of endothelial function, is correlated with cardiovascular risk factors. The relationship between FMD and morphologically and clinically evident coronary artery disease has not been described. This study was performed to test the hypothesis that an impairment of FMD in the brachial artery is related to the presence and/or extent and severity of coronary artery disease (CAD). We examined 74 patients with angina pectoris and 14 control subjects (age 17 36 years). Angiography revealed coronary artery disease (> or = 30% diameter stenosis) in 44 patients (CAD, age 32 67 years) and smooth coronary arteries in 30 patients (non-CAD, age 22-73 years). Vasodilation following reactive hyperemia and after sublingual nitroglycerin (NTG) was assessed in the brachial artery using B-mode high resolution ultrasound. CAD patients showed markedly impaired FMD compared to the non-CAD group (5.7 +/- 4.8 versus 12.6 +/- 6.7%, P < 0.0001) and to controls (5.7 +/- 4.8 versus 15.7 +/- 3.9%, P < 0.00001). NTG induced similar degrees of vasodilation in the CAD and non-CAD groups but less vasodilation in the CAD patients compared to controls (12.2 +/- 6.3 versus 20.4 +/- 6.9%, P < 0.01). On univariate analysis, impaired FMD in CAD patients and non-CAD patients was related to the extent of coronary disease (1-, 2- or 3-vessel disease; r = -0.67, P < 0.0001), to the maximum percent diameter stenosis in one of the major coronary vessels (r = -0.52, P < 0.0001), brachial artery diameter (r = -0.46, P < 0.0001) and plasma cholesterol level (r = -0.34, P < 0.001). On multiple stepwise regression analysis the extent of coronary disease (r = -0.51, P < 0.0001) and the baseline brachial artery diameter (r = -0.37, P < 0.0001) were independently associated with FMD in CAD and non-CAD patients. The present findings suggest that the impairment of FMD in the brachial artery, a marker of systemic endothelial function, is closely related to the angiographic extent of CAD.

Vascular endothelial growth factor synthesis in vascular smooth muscle cells is enhanced by 7-ketocholesterol and lysophosphatidylcholine independently of their effect on nitric oxide generation.

Nitric oxide (NO) generated by inducible NO synthase (iNOS) enhances vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle cells (VSMC) and both NO and modified low density lipoprotein (LDL) augment VEGF production in macrophages. Oxidized LDL (oxLDL) are known inhibitors of NO generation in the cells of vascular wall. As the relationship between VEGF, iNOS and oxLDL has not been well elucidated, we studied the effect of two main components of oxLDL, 7-ketocholesterol (7-Kchol) and lysophosphatidylcholine (LPC), on VEGF and NO synthesis in rat VSMC and on VEGF synthesis in human VSMC. Both LPC and 7-Kchol significantly augmented VEGF production in rat and human VSMC. Increase in VEGF generation was related to the activation of VEGF promoter by both 7-Kchol and LPC and enhancement of VEGF mRNA transcription. In rat, VSMC IL-1beta-induced NO generation and enhanced VEGF synthesis. 7-Kchol decreased rat iNOS promoter activity, iNOS expression and NO generation, but it did not impair IL-1beta-induced VEGF synthesis. LPC did not significantly influence IL-1beta-induced NO production in rat VSMC and VEGF synthesis was significantly enhanced by combined treatment with IL-1beta and LPC in comparison to the effect of either compound alone. The results indicate that VEGF and NO synthesis in VSMC can be modulated by oxLDL. Those interactions might have an effect on the plaque growth and might be of relevance for the physiology of vascular wall cells.

Platelet survival in patients with dilated cardiomyopathy.

Dilated cardiomyopathy is associated with thromboembolic complications, which correlate poorly, however, with a visible left ventricular thrombus. Therefore, this study was performed to assess whether an abnormality of platelet function in vivo can be detected in patients with dilated cardiomyopathy. Platelet survival was measured after autologous labeling with indium-111 oxine in 28 patients with dilated cardiomyopathy and angiographically normal coronary arteries (mean ejection fraction 21 +/- 9% [standard deviation], range 4 to 39%) and in nine patients with coronary artery disease and similar left ventricular dysfunction (mean ejection fraction 21 +/- 10%). Plasma levels of beta-thromboglobulin and platelet factor 4 were measured in patients with idiopathic cardiomyopathy (n = 15) and platelet scintigraphic images of the heart (n = 24) were obtained in subsets of both patient groups. Platelet survival was significantly and similarly shortened in patients with idiopathic and ischemic cardiomyopathy (67 +/- 34 and 55 +/- 24 h, respectively) compared to controls (209 +/- 9 h, n = 12; p less than 0.001). Of the two platelet-specific proteins, beta-thromboglobulin was increased in the patients compared with controls (42 +/- 17 versus 22 +/- 6 ng/ml, p less than 0.001). Platelet scintigraphy 24 h (n = 24) and/or 48 h (n = 9) after labeling showed a diffuse pattern of enhanced platelet uptake over the heart which varied in intensity among patients, but which was never seen in controls (n = 6). This increased platelet uptake was similar in patients with idiopathic and ischemic cardiomyopathy but did not correlate with either ejection fraction or cardiothoracic ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of beta-endorphins in silent myocardial ischemia.

The reason for the absence of pain perception in silent myocardial ischemia is unknown. A role of increased endorphinic activity in patients with silent ischemia has been postulated. To further investigate this hypothesis, 10 men with documented coronary artery disease and previous positive electrocardiographic findings during exercise without anginal pain were studied. Six healthy volunteers served as control subjects. The protocol included 2 bicycle exercise tests, the first test serving as baseline and the second performed after administration of naloxone, a specific opiate antagonist. Plasma beta-endorphin levels were measured by radioimmunoassay in both tests at rest, at peak exercise level and after recovery. All patients underwent thallium-201 scintigraphy after coronary vasodilation to provide an additional independent marker of ischemia. All patients showed stress-induced reversible perfusion abnormalities. No patient reported pain after naloxone application. Exercise duration, blood pressure and heart rate were not significantly altered by naloxone. Plasma beta-endorphin levels ranged from 18 +/- 6 pg/100 microliters (mean +/- standard deviation) at rest to 22 +/- 6 pg/100 microliters during exercise in the patient group and from 20 +/- 5 to 27 +/- 9 pg/100 microliters in the control subjects. Thus, there was no significant increase of plasma beta-endorphins during exercise or after naloxone administration, nor was there any difference observed between patients and control group. These data support the view that endorphinic activity does not play an essential role in the pathophysiology of silent myocardial ischemia.

Short- and long-term outcomes of Wiktor stent implantation at low versus high pressures. Austrian Wiktor Stent Study Group.

A prospective, randomized, multicenter trial was conducted to evaluate whether high-pressure postdilation of the Wiktor stent provides short- and long-term benefits compared with the conventional low-pressure implantation technique. From June 1995 through May 1996, 181 patients were randomly assigned to either low-pressure (6 to 12 atm, group A, n = 94) Wiktor stent placement or to high-pressure postdilation (> or = 13 atm, group B, n = 87) after stent deployment. All patients were followed up clinically for 7 +/- 3 months, with an angiographic follow-up in 154 patients (85%). After stent implantation, neither minimal lumen diameter (MLD) nor percent diameter stenosis (%DS) differed significantly between the 2 groups (MLD, 2.8 +/- 0.5 vs 2.9 +/- 0.5 mm; %DS, 17 +/- 8% vs 16 +/- 9% for groups A and B, respectively). However, a trend toward a larger mean lumen diameter within the stent was observed in group B (3.3 +/- 0.6 vs 3.5 +/- 0.5 mm for groups A and B, respectively; difference between means 0.14 mm, 95% confidence interval -0.01 to 0.29, p = 0.08). Angiographic follow-up revealed similar MLD and %DS in both treatment groups (MLD, 2.1 +/- 0.7 vs 2.2 +/- 0.8 mm; %DS, 31 +/- 17% vs 30 +/- 24% for groups A and B, respectively, p = NS). Acute stent thrombosis occurred in 2 patients (1%) (1 patient in each group), and subacute thrombosis in 1 patient (0.6%) in group A. There was 1 death in group A, and target lesion restenosis (> or = 50% DS) was observed in 15% of patients with no differences between the groups. In conclusion, this study demonstrated favorable short- and long-term results of Wiktor stent implantation. Despite a trend toward additional initial lumen gain by high-pressure postdilation, this did not translate into a measurable improvement in long-term outcome.

Robotic totally endoscopic coronary artery bypass: program development and learning curve issues.

BACKGROUND: The introduction of new procedures in heart surgery is a critical phase that includes learning curves and the risk of increased mortality or morbidity. Totally endoscopic coronary artery bypass grafting using robotic techniques represents such an innovative procedure. The aim of this report is to demonstrate the safe introduction of totally endoscopic coronary artery bypass grafting using a stepwise and modular approach. METHODS: From June 2001 until December 2002, 50 procedures were performed using the da Vinci telemanipulator system. After baseline training the following procedure modules were carried out in a stepwise manner: robotically assisted endoscopic left internal thoracic artery harvesting and completion of the procedure as conventional coronary artery bypass grafting, minimally invasive direct coronary artery bypass, or off-pump coronary artery bypass (n = 19), robotically assisted suturing of left internal thoracic artery to left anterior descending anastomoses during conventional coronary artery bypass grafting (n = 15), totally endoscopic coronary artery bypass grafting on the arrested heart using remote access perfusion and aortic endocclusion coronary bypass grafting (n = 15). One patient was excluded intraoperatively from a robotic procedure due to pleural adhesions. RESULTS: A significant learning curve was observed for left internal thoracic artery takedown time, y(min) = 181 - 39 x ln(x) (x = procedure number) (P <.001), and total operative time in totally endoscopic coronary artery bypass grafting, y(min) = 595 - 87 x ln(x) x = (procedure number) (P =.028). The conversion rate in totally endoscopic coronary artery bypass grafting was 2/15. Intensive care unit stay correlated significantly with total operative time (r =.427, P =.002). There was no hospital mortality. CONCLUSION: Totally endoscopic coronary artery bypass grafting can be safely implemented into a heart surgery program. Learning curves are steep for robotic left internal thoracic artery takedown and for performance of totally endoscopic coronary artery bypass grafting. Long operative times translate into prolonged intensive care unit stay in specific cases but not into increased mortality.

Therapeutic efficiency of lipoprotein(a) reduction by low-density lipoprotein immunoapheresis.

This study was performed to investigate the effect of low-density lipoprotein (LDL) immunoapheresis on lipoprotein(a) [Lp(a)] reduction in patients with heterozygous and homozygous familial hyperlipidemia (N=16) and insufficient response to lipid-lowering agents. By desorption of approximately 5,700+/-500 mL of plasma, a mean reduction in total cholesterol of 62% (P < .001) and in LDL-cholesterol of 70% (P < .001) was achieved. Lp(a), which was elevated at study entry in seven of these patients (82.1+/-34.3 mg/dL; range, 48 to 148 mg/dL), was reduced during the initial LDL-apheresis procedure by 74.8%+/-14.1% (P < .001). Long-term apheresis treatment performed at weekly intervals resulted in an mean reduction in Lp(a) pretreatment values to 39.1+/-28.5 mg/dL (-54%; P < .001). Desorbed Lp(a) was measured at the waste of the columns for 31 apheresis treatments. Lp(a) concentration of the column waste was higher in patients with elevated serum Lp(a) pretreatment values as compared with those with Lp(a) serum values within the normal range (elevated Lp(a), 1,420+/-380 mg; without elevated Lp(a), 235+/-190 mg; P < .001). The rate of return of Lp(a) following apheresis treatment scheduled at weekly intervals was comparable to that of LDL-cholesterol.

Epoprostenol in patients with Raynaud's disease.

Prostaglandin metabolism and the clinical effect of epoprostenol (prostacyclin, PGI2) infusions were studied in thirteen patients with Raynaud's disease. Epoprostenol was infused at 5 ng/kg/min for six hours daily for two consecutive five day periods, separated by a two day interval. No beneficial effects either during or after infusion could be detected in terms of frequency of severity of attacks or on skin temperature measurement. Raynaud's patients had significantly lower serum thromboxane B2 levels than normal controls though plasma levels of thromboxane B2, 6-oxo-PGF1 and the bicyclic metabolite of PGE2 did not differ between the two groups. Platelets from Raynaud's patients had a significantly lower conversion rate of arachidonic acid into thromboxane B2 and HHT and a significantly higher rate of HETE production than platelets from controls.

Blockade of endothelium-derived relaxing factor synthesis with NG-nitro-L-arginine methyl ester leads to enhanced venous reactivity in vivo.

This study was performed to examine whether endothelium-derived relaxing factor (EDRF) influences venous tone and reactivity in vivo. The inferior vena cava and abdominal aorta were studied simultaneously under continuous haemodynamic monitoring in anaesthetised rabbits. In addition, a 20-MHz intravascular ultrasound catheter was placed in the vena cava for on-line two-dimensional imaging of vessel cross-sectional area and calculation of wall stress (T(ension) = P(mean) * r(adius)/2). This approach enabled simultaneous visualisation of both venous (CA(ven)) and aortic (CA(art)) cross-sectional area with continuous recording of vessel dimensions. Measurements were made before and after administration of NG-nitro-l-arginine methyl ester (L-NAME; 10 mg.kg i.v.), a specific inhibitor of EDRF biosynthesis. After L-NAME there was a significant increase in central venous pressure and a decrease in CA(ven). On the arterial side, L-NAME caused a significant increase in mean pressure and CA(art), resulting in a significantly augmented arterial wall stress. The venodilatation elicited by increasing doses of glyceryltrinitrate was markedly enhanced after L-NAME. Norepinephrine caused a parallel shift of the dose-response curve for CA(ven) in the presence of a lower baseline value. These results suggest that EDRF contributes substantially to the control of large capacitance veins in vivo and that L-NAME increases venous reactivity to both norepinephrine and glyceryltrinitrate.

Arterial remodelling of native human coronary arteries in patients with unstable angina pectoris: a prospective intravascular ultrasound study.

OBJECTIVE: To investigate the use of intravascular ultrasound (IVUS) in detecting the presence of arterial remodelling in patients with unstable angina. DESIGN: Prospective case study. PATIENTS: 60 of 95 consecutively admitted patients with unstable angina (41 male, 19 female), mean (SD) age 61.2 (8.1) years. INTERVENTIONS: Qualitative and quantitative coronary angiography and IVUS. MAIN OUTCOME MEASURES: Adaptive or constrictive remodelling (AR, CR) was considered present when the cross sectional area of the external elastic membrane at the lesion site was larger than the proximal cross sectional area or smaller than the distal cross sectional area, respectively. RESULTS: 22 of the 60 patients (37%) showed AR and 14 (23%) showed CR. No remodelling was seen in 24 patients (group NR). The plaque contained more thrombus and plaque rupture in group AR than in groups CR and NR (thrombus: 91% v 50% and 67%, respectively, p = 0.023; rupture: 73% v 29% and 42%, p = 0.020). AR was associated with a larger plaque cross sectional area (12.6 (SD 4.6) mm2 v 10.8 (6.3) and 9.2 (3.7) mm2, p = 0.001) and larger external elastic membrane cross sectional area (16.5 (5.8) mm2 v 13.2 (5.2) and 14.4 (3.6) mm2, p = 0.01 in group AR v groups CR and NR, respectively), while the plaque burden was larger in groups AR (74.9 (9.1)%) and CR (72.4 (16.6)%) than in group NR (66.2 (18.1)%, p = 0.005). CONCLUSIONS: IVUS is capable of detecting adaptive and constrictive remodelling of target lesions and its relation to plaque morphology in unstable angina.

Assessment of changes in vasomotor tone in vivo using intravascular ultrasound.

This study tested the capability of high-frequency, two-dimensional real-time intravascular ultrasound (IVUS) in the detection of dynamic changes of large vessel diameter in vivo. An IVUS-catheter (4.8 French, 20-MHz mechanical transducer) was inserted via the femoral vein, and advanced to the inferior vena cava of anesthetized rabbits (n = 7). The depth of field of the transducer allowed for visualization of the entire cross-sections of both the inferior vena cava (IVC) and the adjacent aorta. Changes in vessel diameter were induced pharmacologically using norepinephrine (NE) and glyceryltrinitrate (GTN), which were injected intravenously before and after the administration of L-NG-nitro-arginine methyl ester) L-NAME, a specific inhibitor of endothelium-derived relaxing factor (EDRF)-biosynthesis. Vasoconstriction and -dilation could be observed continuously from the two-dimensional real-time recordings of vessel cross-sections. Vessel diameters and cross-sectional areas (CA) were measured from still frames at given time intervals of drug infusion, and blood pressure and heart rate were recorded continuously. Following NE, an increase of aortic and a simultaneous decrease of venous CA were observed, while GTN elicited the opposite responses. Inhibition of EDRF was followed by an augmentation of the vascular responses. It is concluded that IVUS is capable of detecting changes in vascular dimensions in vivo. Thus in large vessels, IVUS may become a method for the direct assessment of vasomotion in vivo.

Coronary risk factors influence plaque morphology in patients with unstable angina.

BACKGROUND: The risk of plaque disruption and subsequent thrombosis in patients with unstable angina depends on the plaque type and size. DESIGN: Intravascular ultrasound (IVUS) was employed to illustrate the correlation between risk factors and plaque morphology in patients with unstable angina. METHODS: In a prospective study of 60 of 95 patients consecutively admitted with unstable angina [41 men, aged 61.2 +/- 8.1 years (mean +/- SD)], qualitative (soft and hard plaque, thrombus, calcification, eccentricity, adaptive and constrictive remodeling) and quantitative [lumen, external elastic membrane (EEM) and plaque cross-sectional area (CSA) and plaque burden] IVUS data relating to the target lesion, and proximal and distal reference segments were analyzed and correlated with risk factors. Univariate and multivariate nominal logistic regression analyses and analyses of variance were used to determine the independent predictors for IVUS morphology. RESULTS: For plaque composition univariate analysis showed a younger age (< 60 years) to be a predictor for adaptive remodeling (P = 0.019), and an older age to be a predictor for constrictive remodeling (P = 0.021). Hypercholesterolemia, smoking and sex were associated with a higher frequency of thrombus (P = 0.044, 0.038 and 0.043, respectively). Multivariate analyses revealed that only younger and older ages were independent predictors for adaptive and constrictive remodeling (P = 0.039 and P = 0.045). For plaque size, univariate and multivariate analyses demonstrated that diabetes mellitus and hypercholesterolemia were independent predictors for greater plaque (13.5 +/- 5.72 versus 10.17 +/- 4.6 mm2, P = 0.015, for diabetic versus non-diabetic patients; 12.0 +/- 5.35 versus 9.03 +/- 3.76 mm2, P = 0.010, for hypercholesterolemic versus normocholesterolemic patients) and EEM CSA (17.16 +/- 5.81 versus 14.3 +/- 5.1 mm2, P = 0.033, for diabetic versus non-diabetic patients; 16.57 +/- 5.49 versus 12.25 +/- 3.8 mm2, P = 0.001, for hypercholesterolemic versus normocholesterolemic patients) at the target lesion. Hypercholesterolemia was associated with significantly greater plaque and EEM CSA in both proximal and distal reference segments. CONCLUSIONS: Multivariate analyses indicated that age, diabetes and hypercholesterolemia are independent predictors for plaque morphology in patients with unstable angina.