Incidence of thrombotic and bleeding complications during cardiac catheterization in children: comparison of high-dose vs. low-dose heparin protocols.

BACKGROUND: During cardiac catheterization (CC) in children, unfractionated heparin (UFH) is used for primary prophylaxis of thrombotic events (TE). However, the optimal UFH dose to minimize TE and bleeding in children has yet to be established. OBJECTIVES: To (i) objectively assess the incidence of TE and bleeding during pediatric CC using clinical assessment and ultrasound; and (ii) compare a high-dose vs. low-dose UFH protocol for thromboprophylaxis. METHODS: A randomized controlled trial (RCT) comparing high-dose UFH (100 units kg(-1) bolus, followed by 20 units kg h(-1) continuous infusion) vs. low-dose UFH (50 units kg(-1) bolus) during CC. Outcome assessment was by clinical examination and vascular ultrasound, performed by blinded examiners before and within 48 h after CC. Children with no consent for randomization were followed in a cohort receiving standard-of-care UFH (parallel-cohort RCT). RESULTS: A total of 227 children were included; 137 were randomized and 90 followed in the cohort study. The overall incidence of TE was 4.6% and bleeding 6.6%. The RCT was stopped early for futility as there were no differences between the high-dose and the low-dose UFH in TE (5% vs. 3%; risk ratios [RR] 1.5, 95% confidence interval [CI] 0.3; 9) and bleeding (7% vs. 12%, RR 0.6, 95% CI 0.2; 2). There were also no differences when RCT and cohort study populations were combined. CONCLUSIONS: The incidences of TE and bleeding during CC in children were low. There were no differences between the high-dose and the low-dose UFH protocols studied. Although Heparin Anticoagulation Randomized Trial in Cardiac Catheterization (HEARTCAT) was not designed as non-inferiority trial, low-dose UFH (50 units kg(-1) bolus) appears sufficient for thromboprophylaxis during CC.

Evidence of carotid atherosclerosis in orthopantomograms and the risk for future cardiovascular events.

BACKGROUND: Evidence of carotid atherosclerosis can be detected in 3 to 5% of orthopantomogram (OPG) investigations. The clinical impact of these findings is unknown. We investigated the association of OPG findings of carotid atherosclerosis with the occurrence of future cardiovascular adverse events. PATIENTS AND METHODS: We randomly selected 411 of 1268 participants with pre-existent cardiovascular disease from the prospective Inflammation in Carotid Arteries Risk for Arthrosclerosis Study (ICARAS) and assessed their OPGs for the presence of calcified atherosclerotic lesions or indirect signs of atherosclerosis, such as surgical clips or intravascular stents. The degree of carotid stenosis was measured by duplex ultrasound investigations. Patients were then followed for median 39 months (interquartile range 33 to 44 months) for the occurrence of major adverse cardiovascular events (MACE) including myocardial infarction, coronary revascularisation, stroke and death. RESULTS: We found no statistically significant association between the presence of carotid atherosclerosis detected on OPGs and the presence of a significant carotid stenosis (left carotid artery kappa=0.08; right carotid artery kappa=0.12), or the degree of carotid stenosis (P=0.20). Furthermore, the presence of OPG signs of carotid atherosclerosis was not statistically significant associated with future MACE (adjusted hazard ratio 0.92, 95% confidence interval 0.59 to 1.42; P=0.70). CONCLUSIONS: Evidence of carotid plaque revealed by OPGs in patients with previously known cardiovascular disease is no useful prognostic marker for MACE. Detection of carotid atherosclerosis by OPGs in these patients therefore has no clinical consequence.

Renal artery stenosis predicts adverse cardiovascular and renal outcome in patients with peripheral artery disease.

BACKGROUND: Patients with symptomatic peripheral artery disease (PAD) are considered cardiovascular high-risk patients. Our aim was to investigate whether incidental renal artery stenosis (RAS) increases the risk for adverse cardiovascular and renal outcomes in these patients. MATERIALS AND METHODS: We prospectively enrolled 487 consecutive patients admitted for revascularization of symptomatic PAD and performed a renal overview angiogram categorizing RAS as absent (0-29%), moderate (30-59%) and severe (>or= 60%) respectively. Clinical follow-up was for median 15 months (IQR 12-22) for the occurrence of major adverse events [MAE: composite of death, myocardial infarction (MI), stroke, percutaneous coronary intervention, coronary bypass surgery, amputation and kidney failure]. Glomerular filtration rates (GFR) were obtained at 12 months to quantify the course of renal function. RESULTS: A severe RAS was found in 76 patients (15.6%). Overall MAE occurred in 121 patients (24.8%), the composite endpoint of MI, stroke, amputation and death occurred in 101 patients (20.7%). Patients with a severe RAS had a 1.87-fold increased adjusted risk for MAE (95% CI 1.12-3.12, P = 0.017), a 2.51-fold increased adjusted risk for occurrence of the composite endpoint of MI, stroke, amputation and death (95% CI 1.45-4.34, P = 0.001) and a 2.93-fold increased risk for death (95% CI 1.41-6.08, P = 0.004), compared to those of patients without RAS respectively. We observed a significant association between the decrease of GFR over the 12-month follow-up period and the severity of RAS by multivariable analysis (P = 0.044). CONCLUSION: Severe RAS in patients with symptomatic PAD is an independent predictor of major adverse cardiovascular events, adverse renal outcome and mortality.

Influence and interaction of diabetes and lipoprotein (a) serum levels on mortality of patients with peripheral artery disease.

BACKGROUND: Diabetes mellitus is a risk factor for early complications and mortality in patients with peripheral artery disease. Lipoprotein (a) [Lp(a)] is also suggested to be a marker of increased cardiovascular risk. We investigated the association and interaction between diabetes mellitus, lipoprotein(a) and mortality in high risk patients with peripheral artery disease (PAD). METHODS: We studied 700 consecutive patients [median age 73 years, interquartile range (IQR) 62-80, 393 male (56%)] with PAD from a registry database. Atherothrombotic risk factors (diabetes, smoking, hyperlipidaemia, arterial hypertension) and Lp(a) serum levels were recorded. We used stratified multivariate Cox proportional hazard analyses to assess the mortality risk at a given patient's age with respect to the presence of diabetes and Lp(a) serum levels (in tertiles). RESULTS: Patients with Lp(a) levels above 36 mg dL(-1) (highest tertile) and insulin-dependent type II diabetes had a 3.01-fold increased adjusted risk for death (95% confidence interval 1.28-6.64, P = 0.011) compared to patients without diabetes or patients with non-insulin-dependent type II diabetes. In patients with Lp(a) serum levels below 36 mg dL(-1) (lower and middle tertile), diabetes mellitus was not associated with an increased risk for death. CONCLUSION: Insulin-dependent type II diabetes mellitus seems to be associated with an increased risk for mortality in PAD patients with Lp(a) serum levels above 36 mg dL(-1). PAD patients with non-insulin-dependent type II diabetes, and patients with diabetes and Lp(a) levels below 36 mg dL(-1) showed survival rates comparable to PAD patients without diabetes.

Haem oxygenase-1 genotype and cardiovascular adverse events in patients with peripheral artery disease.

BACKGROUND: A functional GT dinucleotide length polymorphism in the haem oxygenase-1 (HO-1) gene promoter is thought to be involved in the pathogenesis of cardiovascular disease. Short (< 25) (GT)n repeats are suggested to facilitate enhanced HO-1 up-regulation in response to injury and confer potent anti-inflammatory and antioxidative effects. MATERIALS AND METHODS: We investigated the association between the HO-1 GT-polymorphism and cardiovascular outcome in 472 patients with advanced peripheral artery disease. Cardiovascular risk profile and DNA samples for determination of the HO-1 genotype (carrier vs. noncarrier of a short (GT)n repeat allele) were obtained at baseline, and patients were followed for median 21 months for the occurrence of coronary events (myocardial infarction, percutaneous coronary interventions and coronary artery bypass graft), cerebrovascular events (stroke or carotid revascularization) and all-cause mortality. RESULTS: Coronary events occurred in 48 patients (9%), cerebrovascular events in 40 patients (9%) and 59 patients (13%) died. In total, 173 major adverse cardiovascular events (MACE) occurred in 133 patients (28%). Carriers of the short (GT)n repeat allele had a 0.46-fold reduced adjusted hazard ratio for coronary events (P = 0.016) as compared to noncarriers. No significant difference was found for cerebrovascular events, mortality and overall MACE. CONCLUSION: Apparently, the HO-1 genotype exerts potentially protective effects against coronary adverse events in patients with peripheral artery disease. Homozygous and heterozygous carriers of < 25 (GT)n repeats had lower rates of myocardial infarction, percutaneous coronary interventions and coronary bypass operations compared to patients with longer (GT)n repeats.

Effects of intravenous prostaglandin E1 on arterial compliance: a randomized controlled trial.

BACKGROUND: Prostanoids are in widespread use for the treatment of critical limb ischemia and are suggested to improve arterial compliance. However, dose- and time-dependency of these drug effects are indeterminate. We investigated the influence of intravenous application of prostanoids on arterial compliance parameters in patients with critical limb ischemia due to peripheral artery disease (PAD). PATIENTS AND METHODS: We included 82 consecutive patients with PAD Fontaine stage III and IV in a patient-blinded, randomized controlled trial. Patients were randomly assigned to either single dose intravenous treatment with 40 microg (n = 29) or 60 microg (n = 27) of Alprostadil (PGE1) in 250 ml 0.9% saline over 2 hours, or 250 ml 0.9% saline solution as a placebo group (n = 26). Large and small artery compliance was measured by peripheral pulse contour analysis at baseline, at one hour during intravenous infusion of Alprostadil, immediately after and 24 hours after the end of the infusion. For study purposes the patients received Alprostadil only once during the observation period of 2 days. RESULTS: Large artery compliance, blood pressure, heart rate and cardiac output were unaffected by PGE1 administration irrespectively of drug-dosage or time interval. Small artery compliance increased at 1 hour during intravenous application of Alprostadil (40 microg Alprostadil p = 0.001; 60 microg Alprostadil p < 0.0001) compared to placebo and increased median +47% (IQR +5% to +100%) after administration of 40 microg Alprostadil and median +32% (IQR -11% to +88%) after 60 microg Alprostadil (p = 0.5). Immediately after the end of Alprostadil infusion small artery compliance decreased to baseline levels. CONCLUSIONS: Prostaglandin E1 causes a significant improvement of small artery compliance during the time of intravenous application. However, this effect rapidly diminishes after the end of administration and no dose-dependency between 40 microg and 60 microg Alprostadil is observed.

Long-term follow-up after percutaneous transluminal angioplasty of the distal abdominal aorta.

Aortoiliac disease can be either treated with surgery-endarterectomy for localized aortic disease or with bypass graft placement for more extensive aortoiliac disease--or with percutaneous transluminal angioplasty (PTA), which has become an established method. Long term results of surgery are well documented in literature, but long term results of distal aortic PTA are scarce, furthermore angiographic follow-up is very uncommon. We report about a patient with isolated aorta abdominalis stenosis due to atherosclerotic disease who underwent PTA in 1982 and had an angiographic follow-up four and twenty years later, thus we demonstrate that patency can be obtained even after twenty years.

Reduction in renal function after renal arteriography and after renal artery angioplasty.

OBJECTIVE: To investigate the incidence and risk factors for renal function deterioration after renal angiography and angioplasty or stenting. METHODS: A retrospective study of 85 consecutive patients undergoing selective renal artery arteriography (n = 53) or renal artery angioplasty % (PTRA) stenting (n = 32) for renal artery stenosis. Multivariate logistic regression analysis was used to determine independent predictors of deterioration of renal function, defined as an increase of serum creatinine by at least one third within 24 h. RESULTS: Deterioration of renal function occurred in 13 patients (15%), [8/53 (15%) after angiography and 5/32 (16%) after PTRA/stenting]. Only pre-existing renal impairment (se-creatinine > or = 177 mumol/l) (Odds ratio: 40; 95% confidence interval 1.2-72, p = 0.02) and administered dosage of contrast agent (more than 225 ml) (OR 67; 95% CI 11.8-100, p = 0.02) were independently associated with renal function deterioration. CONCLUSION: Transient renal dysfunction after renal artery angiography or PTRA/stenting occurs in about 15% of patients, but persistent renal failure is uncommon. Pre-existing renal impairment and amount of contrast agent are independent risk factors. Endovascular treatment of renal artery stenosis is not associated with a higher risk of renal deterioration compared to selective renal angiography.

Clinical outcome and prognostic factors for ischaemic ulcers treated with PTA in lower limbs.

OBJECTIVE: To analyse the clinical outcome of patients with ischaemic ulcers (Fontaine stage IV) undergoing percutaneous transluminal angioplasty (PTA). METHODS AND DESIGN: Retrospective cohort study of 40 patients (21 males) treated between January 1998 and December 1998. Cardiovascular risk factors, co-morbid, baseline laboratory, angiographic data and technical success were recorded. Patients were followed for a median of 20 (inter quartile range (IQR) 8-26) months. RESULTS: Cumulative ulcer healing rates at 3, 6, 12, and 24 months were 15, 40, 54 and 81%, respectively. The median time to healing was 5 (IQR 2-7) months. Cumulative restenosis at 1, 3, 6 and 12 months was 3, 10, 29 and 52%, respectively. Nine patients (22%) suffered ulcer reappearance. Lipoprotein (a) serum levels > 30 mg/dl (HR 0.2, 95% CI 0.05-1.0, p = 0.05) and diabetes mellitus (HR 0.2, 95% CI 0.5-0.7, p = 0.01) were associated with delayed ulcer healing. CONCLUSION: PTA leads to ulcer healing in the majority of patients. Elevated lipoprotein (a) levels > 30 mg/dl and diabetes mellitus are independently associated with ulcer persistence.

Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with restenosis after percutaneous transluminal angioplasty.

PURPOSE: To determine if an association exists between postdilation restenosis and heme oxygenase-1 (HO-1), which is induced by balloon injury and inhibits neointimal formation through the action of endogenous carbon monoxide. A dinucleotide repeat in the promoter region of the HO-1 gene shows a length polymorphism that modulates the level of gene transcription. METHODS: This cohort study included 96 consecutive patients (64 men; median age 69 years, interquartile range 60-75) who underwent successful balloon dilation in the femoropopliteal segment. Six-month patency was evaluated using oscillography, ankle-brachial index, and duplex sonography. The association of patency and the length of (GT) repeats in the HO-1 gene promoter was assessed in univariate and multivariate analyses. RESULTS: Restenosis was found in 23 (24%) patients within the first 6 months. Patients with short (<25 GT) dinucleotide repeats in the HO-1 gene promoter on either allele had restenosis significantly less often than patients with longer (> or = 25 GT) dinucleotide repeats (p = 0.01). Multivariate analysis revealed a significantly reduced risk for restenosis in these patients compared to patients without the short allele (odds ratio 0.2, 95% Cl 0.06 to 0.70, p = 0.007). CONCLUSIONS: Genetic risk factors for restenosis after percutaneous transluminal angioplasty have not been investigated. In this patient population, short repeat alleles of the heme oxygenase-1 gene promoter polymorphism were associated with reduced postdilation restenosis at 6 months. Upregulation of HO-1 may be an important protective factor after balloon angioplasty by inhibition of vascular smooth muscle cell proliferation.

Restenosis after percutaneous transluminal angioplasty in the femoropopliteal segment: the role of inflammation.

PURPOSE: To determine the value of baseline C-reactive protein (CPR), fibrinogen, and white blood cell (WBC) counts in predicting 1-year patency after percutaneous transluminal angioplasty (PTA) in the femoropopliteal segment. METHODS: In a retrospective cohort study, 168 consecutive patients (103 men; median age 70 years, interquartile range 61-77) who underwent successful PTA of the femoral and/or popliteal arteries were analyzed. Twelve-month patency was evaluated using oscillography, ankle brachial index, duplex sonography, and angiography. The predictive value of inflammatory markers was assessed in a multivariate model controlling for cardiovascular risk factors, technical success, and hemodynamic factors. RESULTS: Transient WBC elevation was found 6 hours after PTA, but this returned to baseline after 24 hours. Fibrinogen was elevated at 24 hours. Duplex scanning disclosed restenosis in 66 (39%) patients within the first 12 months after PTA. Only residual postdilation stenosis (> or = 30%) in the target segment (odds ratio 3.6, p=0.001) and baseline CRP levels (odds ratio 4.2, p=0.02) were independent predictors of outcome; neither WBC counts nor fibrinogen levels at any time point was associated with restenosis. CONCLUSIONS: Primary technical success and postinterventional hemodynamic flow at the dilated segment seem to be more important for intermediate-term patency than atherogenic risk factors. The predictive value of preprocedural serum CRP levels on restenosis should be further investigated.

Predicting renal failure after balloon angioplasty in high-risk patients.

PURPOSE: To assess the incidence and predictors of acute renal failure after percutaneous transluminal angioplasty (PTA) in a cohort of patients with generalized atherosclerosis. METHODS: A retrospective review of 213 consecutive patients (127 men; median age 71 years, interquartile range 63-77) undergoing femoropopliteal PTA was undertaken. Renal function was measured by creatinine clearance at baseline and 24 hours after the intervention; acute renal dysfunction was defined as > or = 20% decrease of creatinine clearance. The predictive value of potential risk factors was determined in a multivariate model adjusting for comorbidities, pre-existing renal impairment, and angiographic data. RESULTS: Overall serum creatinine values and creatinine clearance remained stable within 24 hours after PTA. Acute renal dysfunction occurred in 25 (12%) patients. Two (1%) patients developed oliguria; one required transient hemodialysis and developed persistent renal failure. Pre-existing impaired renal function (OR 12.2, p < 0.0001) and contrast dosage (OR 1.1, p = 0.03) were independent predictors of acute renal failure; hypertension (OR 7.9, p = 0.06) and congestive heart failure (OR 4.5, p = 0.06) were associated factors. CONCLUSIONS: While transient acute renal dysfunction occurs in approximately 10% of patients with peripheral artery disease within 24 hours after angioplasty, persistent renal failure or end-stage renal disease is rare.

The life-shortening effect of reduced physical activity is abolished by a fat rich diet.

In female mice on a control diet (3.6% fat) reduced physical activity leads to a reduction of the average life span. So the average age at death of an inactive group is 500 +/- 166 compared to 565 +/- 175 days in an active control group. If the animals are kept on a fat rich diet (12.4% fat) this effect of physical activity restriction is no longer observable and the average age at death is 570 +/- 142 days, within the range of the control animals. The increased fat intake seems to reduce the stress or to increase the resistance to stress in the activity restricted animals. So stress is a crucial determinant of life span.

Spin trapping study of antioxidant properties of neopterin and 7,8-dihydroneopterin.

Previously, it has been shown that pteridine derivatives are capable of modulating the action of free radicals and both prooxidant and antioxidant properties have been described. However, the mechanism of manifestation of these properties is still unclear. We studied the radical scavenging properties of 7,8-dihydroneopterin and neopterin using the spin trap 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). It was found that dihydroneopterin acts generally as a radical scavenger. In the presence of dihydroneopterin the ESR signal was reduced by 30 to 90% compared to the control signal. The rate constants for the reactions of 7,8-dihydroneopterin with superoxide (10(3) M(-1) s(-1)) and peroxyl radicals (10(7) M(-1) s(-1)) were determined. Neopterin in contrast showed no reduction of the ESR signal except with superoxide radicals produced by xanthine oxidase. However, this effect was shown to be due to an inhibition of enzyme rather than to radical scavenging. Our results provide a basis for understanding previous observations of radical scavenger activity of 7,8-dihydroneopterin.

A glucose-rich diet shortens longevity of mice.

High plasma levels of glucose and insulin over long-time periods play an important role in the genesis of diabetic complications. There is evidence that the long term consumption of glucose-rich diet by rats is detrimental to insulin sensitivity. We investigated the effect of a glucose-rich diet on longevity of 70 female mice which were compared to 70 mice on a control diet. The average age of death of the control group was 568 +/- 139 days compared to 511 +/- 170 for the glucose group and the seven oldest mice of the control group died at age 890 +/- 52 days, while the seven oldest mice of the glucose group died at 833 +/- 49 days. These differences are statistically significant (P < or = 0.05). Our work shows that a life-long intake of a diet with 20% of total energy derived from glucose leads to a significant reduction of the average and maximal life-span in female mice and thus, supports previous observations of detrimental effects of high glucose intake over long periods.

The effect of reduced physical activity on longevity of mice.

Reduced physical activity leads, in female mice, to a reduction of the average and maximal life span. The average age at death of the inactive experimental group was 497 +/- 121 days (mean +/- S.D.) compared to 557 +/- 139 days in the active control group, and the six oldest inactive experimental mice died at age 732 +/- 50 days, while the six oldest active control mice died at 890 +/- 52 days. The restriction of mobility was connected with a higher growth rate and a higher body weight in spite of a significant decrease in food intake. In spite of a reduced food intake leading to a reduced whole body metabolism, the results show that mobility restriction shortens life span in female mice.

Effects of pteridines on chloramine-T-induced growth inhibition in E. coli strains: correlations with molecular structure.

Little is known about the biological significance of most pteridines, despite their ubiquitous occurrence in living cells. Seventeen different pteridines were tested for their ability to modulate the growth inhibitory effect of the disinfectant chloramine-T on three different strains of Escherichia coli bacteria. We found striking differences between the pteridine derivatives: whereas aromatic pterins with a hydroxy function at side chain atom C2' increased the growth inhibition, those with a 7,8-dihydro structure exerted a suppressive effect. These results are in excellent agreement with previously observed effects of pteridine derivatives on chloramine-T-induced luminol-dependent chemiluminescence, and together, are highly suggestive of a general interaction of these compounds with oxygen or chlorine free radicals. This interaction is likely to have biological significance and might offer an explanation for the widespread occurrence of pteridines.

The conformational flexibility of 5,6,7,8-tetrahydrobiopterin and 5,6,7,8-tetrahydroneopterin: a molecular dynamical simulation.

5,6,7,8-Tetrahydrobiopterin is an essential cofactor of diverse enzymes. Of the eight possible stereoisomers, only the 6R,1'R,2'S-configuration is biologically active. Other stereoisomers, as well as other reduced pterins such as, e.g. 5,6,7,8-tetrahydroneopterin, fail to exhibit significant cofactor activity. Different theoretical models (molecular mechanics, semi-empirical quantum chemical calculations) investigating the stereostructure of tetrahydrobiopterin have yielded diverging answers. It has been claimed on the basis of semi-empirical quantum chemical calculations that conformational properties, and thus particular features in overall shape, might be responsible for the unique biological properties of natural tetrahydrobiopterin in contrast, e.g. to 6R,1'S,2'R-5,6,7,8-tetrahydroneopterin. Molecular dynamical simulations of both molecules at realistic temperatures demonstrate, however, that they possess sufficient conformational flexibility as to render questionable any biological significance of mere conformational properties.

Effect of a high fat diet on phospholipid class distribution and fatty acid composition in rat liver.

1. Long term consumption (20 weeks) of a high fat diet (65% of the energy content as fat) rich in either saturated [30% (w/w) coconut oil] or unsaturated [30% (w/w) sunflower oil] fatty acids resulted in strikingly similar alterations in the phospholipid class distribution and fatty acid composition in the liver of male Wistar rats. 2. The effect of these two diets was compared to a control group maintained on a 2% fat diet (w/w) for the same time interval. 3. In spite of the difference in the PUFA/SFA (polyunsaturated fatty acid/saturated fatty acid) ratio between the two high fat diets (0.1, saturated fatty acid diet; 5.4, unsaturated fatty acid diet), both diets resulted in a similar PUFA/SFA ratio in liver phospholipids, a similar reduction in palmitic acid (16:0), oleic acid (18:1, n-9) and arachidonic acid (20:4, n-6) and an elevation in stearic acid (18:0), linoleic acid (18:2, n-6) and docosahexaenoic acid (22:6, n-3). 4. Further, changes in the phospholipid classes were also similarly affected by both high fat diets.

The coenzyme nicotinamide adenine dinucleotide (NADH) improves the disability of parkinsonian patients.

The coenzyme nicotinamide adenine dinucleotide (NADH) has been used in an open label trial as novel medication in 34 patients with Parkinson's disease, using an intravenous administration technique. In all patients a beneficial clinical effect was observed. 21 patients (61.7%) showed a very good (better than 30%) improvement of disability, 13 patients (38.3%) a moderate (up to 30%) improvement. Concomitant with the improvement of the disability the urine level of homovanillic acid (HVA) increased significantly in all patients (in some patients by more than a 100%). The daily "on phases" of the patients could be increased from 2 up to 9 hours in the individual patients by NADH administration.