High Incidence Of Vascular Disease Research Articles

Effect of metformin on fibrinolysis in type 2 diabetes mellitus: an explorative study

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of vascular disease which can cause significant morbidity and mortality. The risk of cardiovascular mortality in T2DM patients is observed to be more compared to the age-matched subjects. This is attributed to depression of the fibrinolytic system which maintains patency of blood vessels. Endogenous inhibitors such as plasminogen activator inhibitor-1 (PAI-1) inhibit the activation of plasminogen and thus prevent the degradation of fibrinogen. In T2DM there is increased levels of PAI-1. Such a state of altered fibrinolysis is attributed to insulin resistance. A previous study done at our institute demonstrated higher euglobulin lysis time (ELT) in T2DM patients than controls, suggesting altered fibrinolytic activity in the former group. D-dimer is a degradation product of fibrin. Its presence indicates a state of hypercoagulability. In a study by Nwose et al rise in D-dimer levels were observed in diabetics, especially with cardiovascular complications as compared to controls indicating D-dimer could be a useful marker for predicting the complications in T2DM.

Clinical and Molecular Variables Associated with Atherosclerotic Vascular Disease in Myelodysplastic Syndromes

BACKGROUNDHealthy adults with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of death from vascular disease. CHIP-associated genetic mutations such as ASXL1, TET2 and DNMT3A have been linked to the pathogenesis of atherosclerosis (Jaiswal et al, 2017). MDS and CHIP share common genetics events; in fact, certain MDS cases are believed to arise from preexisting clonal hematopoiesis. A recent SEER study demonstrated that 60 months from diagnosis, patients (pts) with low-risk MDS are at higher risk of death from cardiovascular causes than from MDS itself (Brunner et al, 2017). As the relationship between vascular disease and clonal hematopoiesis is delineated, management of vascular disease in patients with MDS is becoming increasingly important. Here we performed a retrospective analysis of MDS pts from Roswell Park to evaluate whether MDS-related factors such as morphologic subtype, treatment, cytopenias, iron status, blast percentage and karyotype modify atherosclerosis risk when molecular events are taken into account. METHODSOver the past decade, 850 pts were diagnosed with MDS were seen and treated at Roswell Park. For the purpose of this study, 192 pts with a confirmed diagnosis of MDS seen between 2012- 2017 were investigated for cardiac events, blood counts, iron or inflammatory status as ferritin, MDS-related morphology, molecular profile and treatment. Cases were comprehensively annotated for the presence of vascular events, (defined as imaging or procedure verified coronary artery disease, cerebrovascular accident, or peripheral vascular disease) by review of the medical record. Conventional karyotype information was present in 98% of the cohort and NGS based multi-gene sequencing results through FoundationOne Heme was evaluated in 30% of the cohort. Numeric variables were summarized using simple descriptive statistics. A logistic regression model was used to investigate the association between vascular events and a set of explanatory variables for multivariate analysis. RESULTSThe median age at diagnosis for this cohort is 69 (range: 21-91) years; 60% were male and 57% had MDS with excess blasts. By IPSS-R, 25% had very low/low risk MDS, 22% had intermediate risk MDS and 46% had high risk MDS. The most common karyotypic abnormalities were normal (42%), complex (17%), trisomy 8 (10%) and del 7/7q (10%). Of the 59 patients with molecular data, the most common recurrent somatic mutations were in ASXL1 (47%), TET2 (30%), SRSF2 (27%), RAS pathway (22%) SF3B1 (22%), RUNX1 (20%) and TP53 (17%). The overall incidence of vascular events in this cohort was 27%.Vascular disease was noted at similar frequencies for pts with low grade and high grade MDS (based on subtype of MDS), 23% vs. 30% (p=0.33) respectively. Women with MDS were significantly less likely to develop to vascular events than were men, 16% vs. 34% (p=0.007) and the mean age of pts with vascular disease was significantly higher, 71 vs. 65 years (p=0.005). Traditional risk factors such as hypertension and hyperlipidemia were more prevalent in MDS pts with vascular disease. Baseline hemoglobin, transfusion requirements and blast % levels were comparable in MDS patients with or without vascular disease. MDS pts with vascular disease had higher median ferritin levels, 432 vs. 301 ng/ml (p=0.093). When stratified by the IPSS-R, pts with very low risk MDS had a non-significant lower incidence of cardiac events, 14% vs. 25% (p=0.30), compared to other groups. Treatment with erythropoietin, lenalidomide or hypomethylating agents was not associated with vascular events. MDS pts with mutations in ASXL1 and SRSF2 had a higher incidence of vascular disease, 43% vs. 13% (p=0.01) and 38% vs 20% (p=0.18) respectively. On multivariable analysis, older age and male gender were most strongly predictive for vascular events. CONCLUSIONHere we retrospectively examined the potential factors associated with cardiovascular events in MDS pts treated at our institute over a 5-year time span. Male gender and older age were positively associated. Treatment regimen (erythropoietin injections or lenalidomide) and IPSS-R were not associated with an increased risk for vascular events. Factors independent of traditional cardiac risk factors, such as somatic mutations in ASXL1, iron overload and/or an inflammatory milieu i.e, ferritin, may contribute to atherosclerotic vascular disease in pts with MDS. [Display omitted] DisclosuresBaron:Pfizer Pharmaceuticals: Other: Previously served as a consult on the Advisory Boards (May 2017).. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Griffiths:Pfizer, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Alexion Inc.: Honoraria, Research Funding. Thota:Incyte: Speakers Bureau.

Matrix Metalloproteinase-1 Gene Polymorphism Associated with Ultrasound-Assessed Carotid Thickness among Older Adults.

Background and Aim Due to the high incidence of vascular diseases, it is necessary to identify new circulating or structural markers for predicting risk for chronic diseases. Some studies suggest that MMP1 gene polymorphisms are associated with the enzyme expression levels in situ (e.g., in atherosclerotic plaques). Objectives Thus, the study of this polymorphism may help understanding the pathophysiology of coronary disease. Methods We performed cross-sectional clinical and laboratory evaluations (including measurement of intima-media thickness of carotid arteries) and genotyping of the MMP1 SNP rs495366 (A/G) in 366 elderly people. Results No significant differences between genotypes were noted for biochemical, metabolic, inflammatory, or clinical variables except for a significant difference in intima-media thickness for the left carotid artery and a trend toward significance for the right counterpart. Conclusion Carriers of the allele associated with lower MMP1 expression (allele A) presented greater carotid thickness. We suggest that the phenomenon can be explained by impaired remodeling of the arterial wall (poor degradation of collagen fibers in this scenario), yielding carotid wall thickening and a greater intrinsic risk for cerebrovascular events.

Monocyte-Derived Procoagulant Microvesicles Induced by High Glucose Can Be Attenuated by the Antioxidant N-Acetyl-L-Cysteine, Partly Through the P38/MAPK Pathway.

Microvesicles (MVs) are small membrane vesicles that are derived from many different cell types by a process of exocytic budding of the plasma membrane. MVs may be associated with a higher incidence of vascular disease in diabetic patients, but the mechanism of this association is unclear. Diabetic patients also show hypercoagulability and platelet hyperaggregability. In this study, we investigated the generation and activity of high glucose (HG)-induced MVs from monocytes to elucidate the potential mechanism of such MVs in diabetes. HG-induced MV generation from THP-1 monocytes before and after N-acetyl-L-cysteine (NAC) treatment was examined by enzyme-linked immunosorbent assay. MV activity was measured by spectrophotometry. Apoptosis and generation of reactive oxidative species (ROS) from THP-1 cells were detected by flow cytometry. Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and P38/MAPK pathway components were also analyzed in treated monocytes. MVs were generated from THP-1 cells after 20 hr of exposure to HG (4.6-fold higher than untreated control cells), which was concomitant with a 3.3-fold increase in apoptosis (P < 0.01). The procoagulant activity (PCA) of the generated MVs was increased significantly by 4.1-fold (P < 0.01) relative to untreated cells. ROS levels peaked 2 hr after HG exposure. The frequency of MVs was greatly decreased after NAC treatment (P < 0.01). Both the ERK/MAPK and P38/MAPK pathway were activated after HG stimulation, whereas treatment with a P38 inhibitor decreased MV generation by 66% compared to untreated control. The generation of monocyte-derived MVs induced by HG was associated with PCA, concomitant with apoptosis and ROS generation. The P38/MAPK pathway was partly involved in this process as evidenced by the reduction in MV generation following treatment with a P38 inhibitor. Our results could provide insights into novel mechanisms of thrombogenicity in an HG state.

Effect of Hyperketonemia (Acetoacetate) on Nuclear Factor-κB and p38 Mitogen-Activated Protein Kinase Activation Mediated Intercellular Adhesion Molecule 1 Upregulation in Endothelial Cells

Hyperketonemia is a pathological condition observed in patients with type 1 diabetes and ketosis-prone diabetes (KPD), which results in increased blood levels of acetoacetate (AA) and β-hydroxybutyrate (BHB). Frequent episodes of hyperketonemia are associated with a higher incidence of vascular disease. We examined the hypothesis that hyperketonemia activates the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that regulate intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were cultured with AA (0-8 mM) or BHB (0-10 mM) for 0-24 hr. Western blotting was used to determine NF-κB activation in whole-cell lysates. ICAM-1 expression was measured using flow cytometry. RESULTS show a 2.4-fold increase in NF-κB activation in cells treated with 8 mM AA compared to the control. BHB had little or no effect on NF-κB activation. Pretreatment with a reactive oxygen species (ROS) inhibitor [N-acetyl-l-cysteine (NAC)] reduced NF-κB to near-control levels. The expression of AA-induced ICAM-1 was significantly reduced when cells were pretreated with either NAC or p38 MAPK inhibitor. These results suggest that NF-κB and p38 MAPK mediate upregulation of ICAM-1 expression in endothelial cells exposed to elevated levels of AA, which may contribute to the development of vascular disease in diabetes.

Hyperketonemia induces upregulation of LFA-1 in monocytes, which is mediated by ROS and P38 MAPK activation

Type 1 diabetic patients have hyperketonemia, elevated levels of pro-inflammatory and oxidative stress markers, and a higher incidence of vascular disease. This study examines the hypothesis that hyperketonemia increases reactive oxygen species (ROS) and is in part responsible for increased expression of adhesion molecules in monocytes. THP-1 monocytes were treated with acetoacetate (AA) or β-hydroxybutyrate (BHB) (0-10mmol/L) for 24h. Results show that AA, but not BHB, increases ROS production in monocytes. Pretreatment of monocytes with N-acetylcysteine (NAC) inhibited AA-induced ROS production. AA treatment induced upregulation of LFA-1 and pretreatment of monocytes with NAC or an inhibitor to p38 MAPK inhibited this upregulation in monocytes. This suggests that physiological concentrations of AA can contribute to increased ROS and activation of p38 MAPK, which may be responsible for AA-induced upregulation of LFA-1 in monocytes. Thus, hyperketonemia contributes to the risk for cardiovascular disease in type 1 diabetes.

Treatment of diabetic vasculopathy: an overview

Correspondence: Sayeeda Rahman Department of Clinical Sciences, School of Medical Sciences, University of Bradford, Bradford BD7 1DP, United Kingdom Tel +44 12 7423 6283 Email srahman6@bradford.ac.uk Abstract: Type 2 diabetes is a chronic, degenerative, and noncommunicable disease, and is associated with a high prevalence of cardiovascular morbidity and mortality. The complications of diabetic vasculopathy are commonly grouped into microvascular and macrovascular complications. In diabetes, macrovascular complications are the commonest cause of morbidity and mortality and are responsible for a high incidence of vascular diseases. The aim of this review to provide an overview of current treatment modalities for diabetic vasculopathy and highlight the importance of effective control of blood glucose, blood lipids, and blood pressure, as well as reduction of blood hypercoagulability, in lowering the macrovascular complications of diabetic vasculopathy. A literature review was conducted to retrieve the relevant information using the PubMed, Science Direct, and Google Scholar databases, reports, and books. People with type 2 diabetes are at markedly increased risk for cardiovascular disease and mortality. The initiators of vasculopathy that ultimately develop into long-term diabetic complications can be avoided by a healthy lifestyle and pharmacological intervention. Clinical trials have shown that effective control of blood glucose, blood lipids, blood pressure, and blood hypercoagulability can reduce macrovascular complications in patients with type 2 diabetes. Type 2 diabetes is responsible for premature mortality, predominantly through atherosclerotic vascular disease. Lifestyle modification and pharmacotherapy should be used to prevent or delay development of type 2 diabetes, including adverse cardiovascular outcomes. A multidisciplinary approach involving patients, health professionals, and diabetic educators should be used to combat the type 2 diabetes epidemic and its associated cardiovascular complications.

Hyperketonemia increases monocyte adhesion to endothelial cells and is mediated by LFA-1 expression in monocytes and ICAM-1 expression in endothelial cells

Frequent episodes of hyperketonemia are associated with a higher incidence of vascular disease. The objective of this study was to examine the hypothesis that hyperketonemia increases monocyte-endothelial cell (EC) adhesion and the development of vascular disease in diabetes. Human U937 and THP-1 monocyte cell lines and human umbilical vein endothelial cells (HUVECs) were cultured with acetoacetate (AA) (0-10 mM) or β-hydroxybutyrate (BHB) (0-10 mM) for 24 h prior to evaluating adhesion and adhesion molecule expression. The results demonstrate a significant (P < 0.01) increase in both U937 and THP-1 adhesion to HUVEC monolayers treated with 4 mM AA compared with control. Equal concentrations of BHB resulted in similar increases in monocyte-EC adhesion. Similarly, treatments of AA or BHB to isolated monocytes from human blood also show increases in adhesion to endothelial cells. intercellular adhesion molecule-1 (ICAM-1) was significantly increased on the surface of HUVECs and an increase in total protein expression with AA treatment compared with control. The expression level of lymphocyte function-associated antigen-1 (LFA-1) was increased in monocytes treated with AA, and LFA-1 affinity was altered from low to high affinity following treatment with both AA and BHB. Monocyte adhesion could be blocked when cells were preincubated with an antibody to ICAM-1 or LFA-1. Results also show a significant increase in IL-8 and MCP-1 secretion in monocytes and HUVECs treated with 0-10 mM AA. These results suggest that hyperketonemia can induce monocyte adhesion to endothelial cells and that it is mediated via increased ICAM-1 expression in endothelial cells and increased expression and affinity of LFA-1 in monocytes.

Sustained Delivery of Nitric Oxide from Poly(ethylene glycol) Hydrogels Enhances Endothelialization in a Rat Carotid Balloon Injury Model

The continuing high incidence of vascular disease is leading to a greater need for interventional therapies and vascular prostheses. Nitric oxide (NO), which has been heavily investigated in recent years as an important biological mediator, is presented in this work as a sustained localized therapeutic for vascular disorders, specifically in the prevention of restenosis. NO-releasing PEG hydrogels were applied to the outer surfaces of carotid arteries following balloon denudation in a rat animal model. NO was allowed to diffuse into the vessel, and intimal thickening, as assessed after 2 and 28 days, was almost fully eliminated, showing an approximate 90% decrease. Meanwhile, endothelial cell migration and proliferation into the damaged vessel sections were observed. These results signify that these materials are suitable to prevent intimal hyperplasia and induce endothelialization in vivo, making these NO-releasing hydrogels an ideal candidate for incorporation into blood-contacting devices for the prevention of restenosis.

Endothelial progenitor cell trafficking in human immunodeficiency virus-infected persons

Human immunodeficiency virus (HIV)-infected people exhibit a high incidence of vascular diseases. Since in the general population the high cardiovascular risk has been associated with an impaired endothelial cell function, we investigated circulating endothelial progenitor cells in HIV-positive patients. We evaluated circulating colony-forming unit-endothelial cell (CFU-EC) and endothelial colony-forming cell (ECFC) progenitors in 14 antiviral therapy-naive HIV-positive patients, in comparison with 15 normal controls. CFU-EC and ECFC derived from peripheral blood mononuclear cells from HIV-infected and HIV-uninfected individuals were recovered and evaluated for HIV genome presence by PCR. Vascular endothelial growth factor (VEGF) and apolipoprotein B mRNA-editing enzyme catalytic polypeptide like (APOBEC) subunits expression were evaluated in infected colonies by real-time PCR. We found that circulating CFU-EC but not ECFC were significantly reduced in HIV-positive patients and that proviral HIV DNA was detectable only in CFU-EC but not in ECFC. Furthermore, the expression of APOBEC subunits was significantly lower in CFU-EC than in circulating monocytes. Accordingly, the CFU-EC displayed a high content of proviral DNA copies, suggesting that these cells have a high sensitivity to the HIV infection. Although HIV does not affect the 'true endothelial progenitor' compartment, it infects and strongly depletes circulating endothelial progenitors with hematopoietic signature. We unravel a novel pathogenetic mechanism by which HIV infection might cause vascular diseases.

Hypertriglyceridaemic waist phenotype criteria and prevalent metabolic triad in women

To assess the metabolic profile and the prevalence of the metabolic triad (i.e. hyperinsulinaemia, hyperapobetalipoproteinaemia, and decreased low-density lipoprotein particle size) in women characterized by the hypertriglyceridaemic waist (HTGW) phenotype and to identify cut-off values for triglycerides and waist circumference, effectively discriminating women with the metabolic triad. Two hundred and twenty-eight female subjects without any history of vascular disease or diabetes mellitus attending an Outpatient Lipid Clinic setting at the University Hospital of Ioannina, Greece were studied. Currently available HTGW criteria for women were unable to detect any significant differences in the metabolic profile either in the pre- or post-menopausal women, and proved similar in terms of sensitivity and specificity in identifying women with the metabolic triad. A cut-off value of 1.26 mmol/L for triglycerides and 84.5 cm for waist circumference were determined by Receiver-operating Curve evaluation. Women with both triglycerides and waist circumference above these thresholds had four-fold higher odds of presenting with the metabolic triad compared with women with non-HTGW phenotype. A HTGW phenotype definition of 1.26 mmol/L for triglycerides and 84.5 cm for waist circumference may effectively identify Mediterranean women with the atherogenic metabolic triad. Whether these criteria are also associated with a higher incidence of vascular disease and/or new-onset diabetes in women remains to be investigated.

Soluble CD40 Ligand Predicts Ischemic Stroke and Myocardial Infarction in Patients With Nonvalvular Atrial Fibrillation

Atrial fibrillation (AF) is associated with a high incidence of vascular disease that may be related to a prothrombotic and inflammatory state. Soluble CD40 ligand (sCD40L), which stems essentially from platelet activation, possesses inflammatory and prothrombotic properties. The aim of the study was to assess whether sCD40L is a predictor of stroke or myocardial infarction (MI) in patients with nonvalvular AF. Plasma levels of sCD40L were measured in 231 patients (177 [77%] had permanent or persistent AF, and 54 [23%] had paroxysmal AF). Patients were followed for a mean period of 27.8+/-8.8 months, and cardiovascular events such as fatal and nonfatal stroke and MI were recorded. AF population was divided in 2 groups according to sCD40L level above or below the median (4.76 ng/mL). The 2 patients' groups had similar distribution of cardiovascular risk factors, age, gender, medications, or serum C-reactive protein levels. During the follow-up period, vascular events occurred in 6 (2 nonfatal MI and 4 nonfatal ischemic strokes) of 116 patients with low levels of sCD40L (5.1%) and in 29 (11 fatal and 3 nonfatal MI; 3 fatal and 12 nonfatal ischemic strokes) of 115 patients with high levels (25.2%) (log-rank test: P<0.001). Using the COX proportional Hazards model, patients with sCD40L above the median were 4.63 times more likely to experience a vascular event (95% C.I.: 1.92 to 11.20). This study shows that enhanced soluble CD40L level is a predictor of vascular events in patients with nonvalvular AF, thus suggesting that enhanced platelet activation may play a role in its clinical progression.

The role of dialysis in contrast-induced nephropathy: doubts and certainties

Over past years, there has been a progressive increase in percutaneous endovascular procedures in patients with chronic renal disease, owing to the high incidence of vascular disease, particularly coronary artery disease, in this population. The use of contrast media may further worsen renal function in such patients, in some cases even accelerating the progression towards end-stage renal failure, and may increase patient morbidity and mortality. In this review, we discuss the role of dialysis in preventing contrast-induced nephropathy as well as present indications to its use in patients already on dialysis treatment undergoing diagnostic or therapeutic procedures with contrast medium injection.

Dimethylthetin treatment causes diffuse alveolar lung damage: A pilot study in a sheep model of Continuous Ambulatory Peritoneal Dialysis (CAPD)

Total plasma homocysteine (Hcy) concentration correlates with risk of vascular disease. Over 80% of chronic renal failure patients have elevated plasma Hcy and a 10–20 times higher incidence of vascular disease. Glycine betaine lowers plasma Hcy through methylation catalysed by betaine-homocysteine methyltransferase (BHMT). Dimethylthetin (DMT), a synthetic glycine betaine analogue, is a more effective BHMT substrate. DMT is therefore a potential therapeutic agent for reducing plasma Hcy in humans and may be particularly useful in renal failure patients receiving dialysis because of chronic betaine depletion as a result of treatment. We aimed to determine whether the addition of DMT to dialysis fluid lowered plasma Hcy concentrations in a Continuous Ambulatory Peritoneal Dialysis sheep model using animals that were either in acute renal failure ( n = 3 ) or had normal renal function ( n = 1 ). Sub-acute exposure to DMT was toxic to all four animals, which died with total lung consolidation and collapse and Diffuse Alveolar Damage within 48 h of beginning treatment. Adverse side effects were observed after 4–8 doses. DMT was not detected in pre-dialysis plasma samples and the final concentration at death was 0.5–7.8 mmol/L, depending on the number of doses each animal was exposed to. Abnormalities were not observed in animals supplied standard dialysis fluid, or fluid with added glycine betaine. Toxicity associated with DMT treatment raises concerns for its use in further studies. However, sub-acute administration of DMT to sheep may provide a useful model of acute alveolar damage.

Increased Plasma HB-EGF Associated with Obesity and Coronary Artery Disease

The mechanism by which the obese subjects are more associated with vascular disease remains unclear. We reported that the adipose tissues produce and secrete many bioactive molecules, conceptualized as adipocytokines. Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), produced locally by vascular macrophages and smooth muscle cells, has been suggested to induce the migration and proliferation of vascular smooth muscle cells. The current study reveals that (1) HB-EGF mRNA is abundantly expressed in human adipose tissue, (2) HB-EGF mRNA increases in the fat tissues of obese mice, (3) plasma HB-EGF levels increase in parallel with fat accumulation in human, and (4) the subjects with coronary artery disease have higher plasma HB-EGF levels, associated with fat accumulation. These results suggest that increased plasma HB-EGF derived from the accumulated fat contributes to the higher incidence of vascular disease in obesity, proposing HB-EGF as an adipocytokine directly linking adipovascular axis.

Differences in Length of Stay between Coronary Bypass and Valve Procedures

Emphasis on cost reduction, national standardization of medical care, and quality improvement initiatives have led to reduced postoperative hospital stays after cardiac surgery. The present study was designed to verify the observation that valve patients have longer lengths of stay than bypass patients and to identify possible reasons. The inpatient records of 26 consecutive patients who underwent valve procedures at our institution were reviewed and compared with the records of 25 consecutive coronary bypass patients. Patients whose postoperative stays were longer than 2 weeks were considered outliers and were excluded from further review. A total of 51 records were reviewed. There were no in-hospital deaths. Five patients in the valve group and two in the bypass group were excluded because of lengths of stay exceeding 14 days. The mean length of stay for the valve procedure group was 7.7 +/- 2.1 days, vs. 5.7 +/- 1.5 days for the coronary bypass group (p = 0.001). There were no reoperative procedures in either group, and the number of emergency procedures was higher in the bypass group. Both groups were similar with respect to age and sex. The frequencies of associated pulmonary disease and malnutrition were similar. Bypass patients had a higher incidence of vascular disease and/or renal disease. Sixty percent of valve procedures were complex operations. Valve patients had a higher incidence of cardiopulmonary bypass times exceeding 3 hours and more postoperative bleeding complications. Although not statistically significant, valve procedure patients were more likely to require prolonged mechanical ventilatory and circulatory support postoperatively. The frequencies of thrombotic complications, neurological complications, and nosocomial infections were similar for both groups. Postoperatively, more valve patients had atrial fibrillation, and all of them received anticoagulation. Multivariate analysis revealed only two factors to be significant with regard to length of stay: valvular surgery and the duration of postoperative ventilatory support. Cardiac valve procedures are associated with prolonged lengths of stay compared with isolated coronary bypass procedures. Despite recent trends toward earlier operation, valve patients tended to present with advanced disease. More than half of the valve patients required complex surgical procedures. This is reflected in longer bypass times, increased bleeding complications, and more postoperative support. The proportion of valvular surgery patients should be considered when analyzing lengths of stay for cardiac surgery cohorts.

Serum paraoxonase is reduced in type 1 diabetic patients compared to non-diabetic, first degree relatives; influence on the ability of HDL to protect LDL from oxidation

Paraoxonase is a serum enzyme with an anti-oxidant function, protecting low density lipoproteins (LDL) from oxidative modifications. Diabetic patients are suggested to be at greater risk of oxidative stress, which may contribute to the significantly higher incidence of vascular disease in this population. Less efficient protection mechanisms may be one feature of the greater susceptibility to oxidation in diabetes. In this context, the present study examined the hypothesis that serum paraoxonase is reduced in type 1 (insulin-dependent) diabetic patients and that the reduction can affect the anti-oxidant capacity of HDL. Serum paraoxonase concentrations and activities were compared in type 1 patients and first degree, non-diabetic relatives with particular attention paid to the confounding effects of paraoxonase gene polymorphisms. In addition, the ability of HDL-paraoxonase to protect low density lipoproteins from oxidation was analysed in an in vitro system. Serum concentrations and enzyme activities of paraoxonase were significantly lower in type 1 patients compared to non-diabetic, first degree relatives. The differences were independent of promoter and coding region polymorphisms, which influence serum concentrations and activities of the enzyme. Overall, paraoxonase concentrations were a mean 13.3±4.5% lower ( P<0.02) in type 1 patients. Specific activities did not differ between diabetic and non-diabetic groups. The concentration ratios of LDL cholesterol:paraoxonase (1.37±0.51 vs. 1.18±0.37, P=0.003) and apolipoprotein B:paraoxonase (0.84±0.33 vs. 0.71±0.40; P=0.012) were significantly higher in diabetic patients, consistent with a reduced capacity to protect LDL from oxidation. In vitro oxidation studies showed that a significantly higher level of lipid hydroperoxides was generated in LDL in the presence of HDL, containing paraoxonase levels equivalent to those of type 1 patients, compared to HDL containing paraoxonase levels equivalent to those of control subjects (mean difference 8.1%, P<0.05). The study demonstrates that serum concentrations of the antioxidant enzyme paraoxonase are significantly lower in type 1 (insulin-dependent) diabetic patients compared to non-diabetic, first-degree relatives, independently of known gene polymorphisms. Concentrations are reduced to an extent that can affect its anti-oxidant capacity. The results are consistent with the contention that modifications to serum paraoxonase in type 1 patients can increase risk of lipoprotein oxidation and, consequently, risk of vascular disease.

Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin

Nitric oxide (NO) induces vasodilatatory, antiaggregatory, and antiproliferative effects in vitro. To delineate potential beneficial effects of NO in preventing vascular disease in vivo, we generated transgenic mice overexpressing human erythropoietin. These animals induce polyglobulia known to be associated with a high incidence of vascular disease. Despite hematocrit levels of 80%, adult transgenic mice did not develop hypertension or thromboembolism. Endothelial NO synthase levels, NO-mediated endothelium-dependent relaxation and circulating and vascular tissue NO levels were markedly increased. Administration of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) led to vasoconstriction of peripheral resistance vessels, hypertension, and death of transgenic mice, whereas wild-type siblings developed hypertension but did not show increased mortality. L-NAME-treated polyglobulic mice revealed acute left ventricular dilatation and vascular engorgement associated with pulmonary congestion and hemorrhage. In conclusion, we here unequivocally demonstrate that endothelial NO maintains normotension, prevents cardiovascular dysfunction, and critically determines survival in vivo under conditions of increased hematocrit.

An Increased Serum Level of Free Apo(a) in Renal Patients Is More Striking than that of Lp(a) and Is Influenced by Homocysteine

Lipoprotein(a) [Lp(a)] excess combined with hyperhomocysteinaemia and hyperfibrinogenaemia may contribute to the high incidence of vascular diseases in dialysis patients. This study is aimed at investigating the role of free apolipoprotein(a) [fapo(a)] in renal patients. We have been able to show that, as compared with controls (0.53 mg/l), the median serum concentrations of fapo(a) in patients with nephrotic syndrome (2.58 mg/l) and with peritoneal dialysis (3.40 mg/l) were strongly elevated (5- to 7-fold), while the fapo(a) levels in patients undergoing haemodialyis (1.02 mg/l) and after renal transplantation (0.90 mg/l) were about doubled. The observed differences in fapo(a) levels indicate that several mechanisms may increase the level of fapo(a), i.e., reduced renal clearance, enhanced hepatic synthesis, or homocysteine releasing apolipoprotein(a) from Lp(a). In the study collective, the median total homocysteine levels were significantly elevated in all patient groups, stronger in patients on haemodialysis (31.4 µmol/l) and peritoneal dialysis (31.2 µmol/l) than in patients with nephrotic syndrome (19.7 µmol/l) and after renal transplantation (19.5 µmol/l). In transplant patients with adequate renal function and without other apolipoprotein(a)-increasing factors, fapo(a) was significantly increased when total homocysteine exceeded 22 µmol/l. In conclusion, our findings let us presume that an increased fapo(a) level in renal patients possibly could be one of the reasons contributing to the high incidence of vascular diseases in these patients, because fapo(a) not covalently linked with Lp(a) is even more easily able to inhibit the fibrinolytic system than the complete Lp(a). These preliminary results have to be confirmed by further investigations.

Basal nitric oxide production is not reduced in patients with noninsulin-dependent diabetes mellitus.

Vascular disease is the leading cause of morbidity, disability and death in patients with noninsulin-dependent diabetes mellitus. Abnormalities in endothelium-derived nitric oxide (NO) have been demonstrated to be involved in the pathogenesis of vascular disease. By measuring hemodynamic responses to a NO synthase agonist or antagonist, previous studies have shown the presence of NO deficiency in patients with noninsulin-dependent diabetes mellitus, a method of assessing bioactive NO formation. However, direct biochemical evidence that this is the case, has not been produced. In vivo NO is metabolized into nitrate, an end breakdown product of NO, which can be used as an index of endogenous NO formation. To investigate further whether decreased basal synthesis of NO may be a major cause of endothelium-mediated vascular dysfunction in patients with noninsulin-dependent diabetes mellitus, the plasma nitrite/nitrate levels of 15 patients were examined and compared with 13 normal controls. The results showed that in basal conditions plasma nitrite/nitrate levels were not reduced in diabetic patients compared with normal controls (37.3 +/- 14.7 versus 29.4 +/- 8.6 mumol/l). It was concluded that in noninsulin-dependent diabetes mellitus patients, endothelium-derived basal NO formation is not impaired. This study, taken with previous observations, suggests that factors other than diminished basal NO production, such as reduced bioavailability of NO probably due to the augmented production of superoxide anion with subsequently increased inactivation of NO, contribute to the high incidence of vascular disease in patients with noninsulin-dependent diabetes mellitus.