Indications for an early invasive strategy in NSTE-ACS patients.

An early invasive strategy in patients who have acute coronary syndrome without ST-elevation (NSTE-ACS) can improve clinical outcome in high-risk subgroups. According to the current guidelines of the European Society of Cardiology (ESC), the majority of NSTE-ACS patients are classified as "high-risk". We propose to prioritise patients with a global registry of acute coronary events (GRACE) risk score >140 over patients with isolated troponin rise or electrocardiographic changes and a GRACE risk score <140. We also acknowledge that same-day transfer for all patients at a high risk is not necessary in the Netherlands since the majority of Dutch cardiology departments are equipped with a catheterisation laboratory where diagnostic coronary angiography is routinely performed in NSTE-ACS patients. Therefore, same-day transfer should be restricted to true high-risk patients (in addition to those NSTE-ACS patients with very high-risk (VHR) criteria) in centres without coronary angiography capabilities.

Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention or after acute coronary syndrome : Practical lessons from a review.

To prevent recurrent ischaemic events, dual antiplatelet therapy (DAPT) is the standard of care after percutaneous coronary intervention and in the treatment of acute coronary syndrome. Recent evidence supports an adjusted DAPT duration in selected patients.The current paper aims to encourage cardiologists to actively search for patients benefiting from either shorter or prolonged duration DAPT and proposes an algorithm to identify patients who are likely to benefit from such an alternative strategy.Individualised DAPT duration should be considered in high-risk anatomic and/or clinical subgroups or in patients at increased haemorrhagic risk with low ischaemic risk. Both thrombotic and haemorrhagic risk should be assessed in all patients. In patients undergoing percutaneous coronary intervention, the interventional cardiologist could advise on the minimal duration of DAPT. However, in contrast to the minimum duration of DAPT for stent thrombosis prevention, longer duration DAPT is aimed at prevention of spontaneous myocardial infarction, and not at stent thrombosis, and thus the key to success is to treat the patient's overall thrombotic risk.The advice on the duration of DAPT must be documented in the patient's records and communicated with the treating physician and general practitioner. DAPT duration should be reassessed at least on a yearly basis.

On- versus off-hour care for patients with non-ST-segment elevation myocardial infarction in Germany : Exemplary results within the chest pain unit concept.

AIM: The aim of this study was to analyze differences in the timing of invasive management of patients with high-risk acute coronary syndrome without persistent ST-segment elevation (hr-NSTE-ACS) or myocardial infarction without persistent ST-segment elevation (NSTEMI) between on- and off-hours in a German chest pain unit (CPU). PATIENTS AND METHODS: We retrospectively enrolled 160 NSTEMI patients in the study, who were admitted to two German CPUs in 2013. Patients presenting on weekdays between 8 a.m. and 6 p.m. were compared with patients presenting during off-hours. Data analysis included time intervals from admission to invasive management (goals: for hr-NSTE-ACS, <2 h; for NSTEMI, <24 h) and the resulting guideline adherence. RESULTS: Guideline-adherent timing of an invasive strategy did not differ significantly between the on-hour (6.5 h [3.0-22.0 h], 79.9 %) and off-hour groups (10.5 h [2.0-20.0 h], 75.3 %; p = 0.94), without additional significant differences between admissions during off-hours Monday to Thursday and weekends (10.0 h [2.0-19.0 h], 75.6 % vs. 7.5 h [2.0-20.0 h], 76.2 %; p = 0.96). CONCLUSION: Our exemplary experience in two different German CPUs demonstrates adequate timing of coronary catheterization in over 75 % of cases, irrespective of admission during on- or off-hours. Nationwide validation of our findings by the German CPU registry is mandatory.

Guideline-conforming timing of invasive management in troponin-positive or high-risk ACS without persistent ST-segment elevation in German chest pain units. Urban university maximum care vs. rural regional primary care.

AIM: This study aimed to analyze guideline adherence in the timing of invasive management for myocardial infarction without persistent ST-segment elevation (NSTEMI) in two exemplary German centers, comparing an urban university maximum care facility and a rural regional primary care facility. METHODS: All patients diagnosed as having NSTEMI during 2013 were retrospectively enrolled in two centers: (1) site I, a maximum care center in an urban university setting, and (b) site II, a primary care center in a rural regional care setting. Data acquisition included time intervals from admission to invasive management, risk criteria, rate of intervention, and medical therapy. RESULTS: The median time from admission to coronary angiography was 12.0 h (site I) or 17.5 h (site II; p = 0.17). Guideline-adherent timing was achieved in 88.1 % (site I) or 82.9 % (site II; p = 0.18) of cases. Intervention rates were high in both sites (site I-75.5 % vs. site II-75.3 %; p = 0.85). Adherence to recommendations of medical therapy was high and comparable between the two sites. CONCLUSION: In NSTEMI or high-risk acute coronary syndromes without persistent ST-segment elevation, guideline-adherent timing of invasive management was achieved in about 85 % of cases, and was comparable between urban maximum and rural primary care settings. Validation by the German Chest Pain Unit Registry including outcome analysis is required.

Cardiac shockwave therapy in patients with chronic refractory angina pectoris.

BACKGROUND: Cardiac shockwave therapy (CSWT) might improve symptoms and decrease ischaemia burden by stimulating collateral growth in chronic ischaemic myocardium. This prospective study was performed to evaluate the feasibility and safety of CSWT. METHODS: We included 33 patients (mean age 70 ± 7 years, mean left ventricular ejection fraction 55 ± 12 %) with end-stage coronary artery disease, chronic angina pectoris and reversible ischaemia on myocardial scintigraphy. CSWT was applied to the ischaemic zones (3-7 spots/session, 100 impulses/spot, 0.09 mJ/mm(2)) in an echocardiography-guided and ECG-triggered fashion. The protocol included a total of 9 treatment sessions (3 treatment sessions within 1 week at baseline, and after 1 and 2 months). Clinical assessment was performed using exercise testing, angina score (CCS class), nitrate use, myocardial scintigraphy, and cardiac magnetic resonance (CMR) 1 and 4 months after the last treatment session. RESULTS: One and 4 months after CSWT, sublingual nitrate use decreased from 10/week to 2/week (p < 0.01) and the angina symptoms diminished from CCS class III to CCS class II (p < 0.01). This clinical improvement was accompanied by an improved myocardial uptake on stress myocardial scintigraphy (54.2 ± 7.7 % to 56.4 ± 9.4 %, p = 0.016) and by increased exercise tolerance at 4-month follow-up (from 7.4 ± 2.8 to 8.8 ± 3.6 min p = 0.015). No clinically relevant side effects were observed. CONCLUSION: CSWT improved symptoms and reduced ischaemia burden in patients with end-stage coronary artery disease without relevant side effects. The study provides a solid basis for a randomised multicentre trial to establish CSWT as a new treatment option in end-stage coronary artery disease.

Treatment variation in stent choice in patients with stable or unstable coronary artery disease.

AIM: Variations in treatment are the result of differences in demographic and clinical factors (e.g. anatomy), but physician and hospital factors may also contribute to treatment variation. The choice of treatment is considered important since it could lead to differences in long-term outcomes. This study explores the associations with stent choice: i.e. drug-eluting stent (DES) versus bare-metal stents (BMS) for Dutch patients diagnosed with stable or unstable coronary artery disease (CAD). METHODS & RESULTS: Associations with treatment decisions were based on a prospective cohort of 692 patients with stable or unstable CAD. Of those patients, 442 patients were treated with BMS or DES. Multiple logistic regression analyses were performed to identify variables associated with stent choice. Bivariate analyses showed that NYHA class, number of diseased vessels, previous percutaneous coronary intervention, smoking, diabetes, and the treating hospital were associated with stent type. After correcting for other associations the treating hospital remained significantly associated with stent type in the stable CAD population. CONCLUSIONS: This study showed that several factors were associated with stent choice. While patients generally appear to receive the most optimal stent given their clinical characteristics, stent choice seems partially determined by the treating hospital, which may lead to differences in long-term outcomes.

Infective endocarditis on ICU: risk factors, outcome and long-term follow-up.

OBJECTIVE: To identify factors associated with short-term, intermediate and long-term outcome in patients with infective endocarditis (IE) and the need for treatment on intensive care unit (ICU). DESIGN AND SETTING: Retrospective analysis and long-term follow-up by questionnaire in the two medical ICUs of our university hospital. PATIENTS: We conducted a retrospective analysis of all consecutive patients with IE and need for ICU treatment in our department between 2002 and 2009. All patients fulfilled the modified Duke criteria for definite diagnosis of IE. MEASUREMENTS AND MAIN RESULTS: Data of 216 patients (aged 62 ± 14 years, 31 % female) were analyzed, 15.7 % of whom had prosthetic valve endocarditis. Infectious agent (IA) was identified in 74 % and surgery was performed in 57 %. 56 patients (24.9 %) died on ICU, 9 patients were sent to palliative care units and died several days later. During follow-up, another 44 patients died. Multivariate Cox-regression analysis identified the following independent risk factors: High initial SAPS II for 30d-, multiple organ failure and high maximum SAPS II for 100d- and high maximum leukocyte count for long-term mortality. Surgical intervention during ICU was an independent predictor of a better 30d outcome. CONCLUSIONS: In contrast to general IE populations, IA and the type of infected impaired valve are not main predictors of survival in critically ill IE-patients. Biomarker of acute infection and markers for severity of illness (scores and organ failure) are independent risk factors for mortality. The surgical clearance of infected valve, device or abscesses is an independent predictor of 30d outcome.

Right ventricular function in dilated cardiomyopathy and ischemic heart disease: assessment with non-invasive imaging.

BACKGROUND: Dilated cardiomyopathy and ischaemic heart disease can both lead to right ventricular (RV) dysfunction. Direct comparisons of the two entities regarding RV size and function using state-of-the-art imaging techniques have not yet been performed. We aimed to determine RV function and volume in dilated cardiomyopathy and ischaemic heart disease in relation to left ventricular (LV) systolic and diastolic function and systolic pulmonary artery pressure. METHODS AND RESULTS: A well-characterised group (cardiac magnetic resonance imaging, echocardiography, coronary angiography and endomyocardial biopsy) of 46 patients with dilated cardiomyopathy was compared with LV ejection fraction (EF)-matched patients (n = 23) with ischaemic heart disease. Volumes and EF were determined with magnetic resonance imaging, diastolic LV function and pulmonary artery pressure with echocardiography. After multivariable linear regression, four factors independently influenced RVEF (R(2) = 0.51, p < 0.001): LVEF (r = 0.54, p < 0.001), ratio of peak early and peak atrial transmitral Doppler flow velocity as measure of LV filling pressure (r = - 0.52, p < 0.001) and tricuspid regurgitation flow velocity as measure of pulmonary artery pressure (r = - 0.38, p = 0.001). RVEF was significantly worse in patients with dilated cardiomyopathy compared with ischaemic heart disease: median 48 % (interquartile range (IQR) 37-55 %) versus 56 % (IQR 48-63 %), p < 0.05. CONCLUSIONS: In patients with dilated cardiomyopathy and ischaemic heart disease, RV function is determined by LV systolic and diastolic function, the underlying cause of LV dysfunction, and pulmonary artery pressure. It was demonstrated that RV function is more impaired in dilated cardiomyopathy.

Diabetes mellitus impairs CD133+ progenitor cell function after myocardial infarction.

BACKGROUND: Circulating progenitor cells (PC) can positively influence the healing of ischaemic myocardium. Cardiovascular risk factors including diabetes mellitus (DM) may have a negative influence on both number and recruitment of PC. Recent evidence suggests that less differentiated CD133(+)PC contribute to myocardial healing and are promising candidates for therapy. Therefore, we investigated whether DM affects CD133(+)PC. METHODS: CD133(+)PC were analyzed in patients following acute myocardial infarction and successful reperfusion [acute myocardial infarction (AMI, n=45) with/without non-insulin-requiring type 2 DM (T2DM)]. Stable coronary artery disease patients (CAD, n = 45) served as stable controls. Number and phenotype of CD133(+)PC were assessed by flow cytometry. CD133(+)PC chemotaxis was assessed towards vascular endothelial growth factor, an angiogenic stimulus upregulated in AMI. The expression of anti-oxidant enzymes in CD133(+)PC was detected by reverse-transcriptase PCR. RESULTS: In non-DM patients, the number of CD133(+)PC increased on day 3 following AMI (P=0.0001). In contrast, no changes were observed in AMI patients with T2DM. Regarding the function of CD133(+)PC, an enhanced chemotactic response was observed following AMI in both non-DM (P=0.0001) and T2DM (P=0.007). However, the AMI-related functional activation was significantly weaker in diabetic patients (P=0.001). Moreover, the expression of catalase was lower in CD133(+)PC from T2DM. CONCLUSIONS: Our results show that T2DM not only limits the abundance of CD133(+)PC following AMI, but also limits their activation. This might be explained by a lower resistance of CD133(+)PC to oxidative stress. Our data provide a possible explanation for the delayed postischaemic vascular healing and myocardial recovery in DM.

Bone marrow cell therapy after acute myocardial infarction: the HEBE trial in perspective, first results.

During the last decennium, the role of bone marrow mononuclear cells (BMMC) has been underscored in the healing process after acute myocardial infarction (AMI). Although these cells improve left ventricular recovery after AMI in experimental studies, results from large-scale randomised trials investigating BMMC therapy in patients with AMI have shown contradictory results. To address this issue the HEBE study was designed, a multicentre, randomised trial, evaluating the effects of intracoronary infusion of BMMCs and the effects of intracoronary infusion of peripheral blood mononuclear cells after primary percutaneous coronary intervention. The primary endpoint of the HEBE trial is the change in regional myocardial function in dysfunctional segments at four months relative to baseline, based on segmental analysis as measured by magnetic resonance imaging. The results from the HEBE trial will provide detailed information about the effects of intracoronary BMMC therapy on post-infarct left ventricular recovery. In addition, further analysis of the data and material obtained may provide important mechanistic insights into the contribution of BMMCs to natural recovery from AMI as well as the response to cell therapy. This may significantly contribute to the development of improved cell-based therapies, aiming at optimising post-infarct recovery and preventing heart failure. (Neth Heart J 2008;16:436-9.).

Reversibility of platelet P2Y12 inhibition by platelet supplementation: ex vivo and in vitro comparisons of prasugrel, clopidogrel and ticagrelor.

Essentials Successful outcome of platelet transfusion depends on specific antiplatelet therapy in use. We assessed if ticagrelor, clopidogrel or prasugrel impacts on donor platelet activity ex vivo. Ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets. This might compromise the effectiveness of platelet transfusion therapy. SUMMARY: Background Platelet transfusion is the conventional approach to restore platelet function during acute bleeds or surgery, but successful outcome depends on the specific antiplatelet therapy. Notably ticagrelor is associated with inadequate recovery of platelet function after platelet transfusion. We examined whether plasma and/or platelets from ticagrelor-treated patients influence donor platelet function, in comparison with clopidogrel and prasugrel. Methods Platelet transfusion was mimicked ex vivo by mixing naïve donor platelet-rich plasma (PRP) or gel-filtered platelets (GFP) in defined proportions with PRP, plasma or GFP from cardiovascular patients receiving standard care including medication with prasugrel, clopidogrel or ticagrelor (n = 20 each). Blood was taken 4 h after the previous dose. HLA2/HLA28 haplotyping let us distinguish net (all platelet) and individual patient/donor platelet reactivity in mixtures of patient/donor platelets, measured by flow cytometry analysis of ADP-induced fibrinogen binding and CD62P expression. Results ADP responsiveness of donor platelets was dramatically reduced by even low (10%) concentrations of PRP or plasma from ticagrelor-treated patients. Clopidogrel and prasugrel were associated with more modest donor platelet inhibition. GFP from ticagrelor-treated patients but not patients receiving clopidogrel or prasugrel also suppressed donor GFP function upon mixing, suggesting the transfer of ticagrelor from patient platelets to donor platelets. This transfer did not lead to recovery of ADP responsiveness of patient's platelets. Conclusion Collectively, these observations support the concept that ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets, which might compromise the effectiveness of platelet transfusion therapy.

Inhibition of VEGF receptors causes lung cell apoptosis and emphysema.

Pulmonary emphysema, a significant global health problem, is characterized by a loss of alveolar structures. Because VEGF is a trophic factor required for the survival of endothelial cells and is abundantly expressed in the lung, we hypothesized that chronic blockade of VEGF receptors could induce alveolar cell apoptosis and emphysema. Chronic treatment of rats with the VEGF receptor blocker SU5416 led to enlargement of the air spaces, indicative of emphysema. The VEGF receptor inhibitor SU5416 induced alveolar septal cell apoptosis but did not inhibit lung cell proliferation. Viewed by angiography, SU5416-treated rat lungs showed a pruning of the pulmonary arterial tree, although we observed no lung infiltration by inflammatory cells or fibrosis. SU5416 treatment led to a decrease in lung expression of VEGF receptor 2 (VEGFR-2), phosphorylated VEGFR-2, and Akt-1 in the complex with VEGFR-2. Treatment with the caspase inhibitor Z-Asp-CH(2)-DCB prevented SU5416-induced septal cell apoptosis and emphysema development. These findings suggest that VEGF receptor signaling is required for maintenance of the alveolar structures and, further, that alveolar septal cell apoptosis contributes to the pathogenesis of emphysema.

Monocyte gene expression in childhood obesity is associated with obesity and complexity of atherosclerosis in adults.

Childhood obesity coincides with increased numbers of circulating classical CD14++CD16- and intermediate CD14++CD16+ monocytes. Monocytes are key players in the development and exacerbation of atherosclerosis, which prompts the question as to whether the monocytosis in childhood obesity contributes to atherogenesis over the years. Here, we dissected the monocyte gene expression profile in childhood obesity using an Illumina microarray platform on sorted monocytes of 35 obese children and 16 lean controls. Obese children displayed a distinctive monocyte gene expression profile compared to lean controls. Upon validation with quantitative PCR, we studied the association of the top 5 differentially regulated monocyte genes in childhood obesity with obesity and complexity of coronary atherosclerosis (SYNTAX score) in a cohort of 351 adults at risk for ischemic cardiovascular disease. The downregulation of monocyte IMPDH2 and TMEM134 in childhood obesity was also observed in obese adults. Moreover, downregulation of monocyte TMEM134 was associated with a higher SYNTAX atherosclerosis score in adults. In conclusion, childhood obesity entails monocyte gene expression alterations associated with obesity and enhanced complexity of coronary atherosclerosis in adults.

A dual inhibitor of platelet-derived growth factor beta-receptor and Src kinase activity potently interferes with motogenic and mitogenic responses to PDGF in vascular smooth muscle cells. A novel candidate for prevention of vascular remodeling.

PP1 has previously been described as an inhibitor of the Src-family kinases p56(Lck) and FynT. We have therefore decided to use PP1 to determine the functional role of Src in platelet-derived growth factor (PDGF)-induced proliferation and migration of human coronary artery smooth muscle cells (HCASMCs). A synthetic protocol for PP1/AGL1872 has been developed, and the inhibitory activity of PP1/AGL1872 against Src was examined. PP1/AGL1872 potently inhibited recombinant p60(c-src) in vitro and Src-dependent tyrosine phosphorylation in p60(c-srcF572)-transformed NIH3T3 cells. PP1/AGL1872 also potently inhibited PDGF-stimulated migration of HCASMCs, as determined in the modified Boyden chamber, as well as PDGF-stimulated proliferation of HCASMCs. Surprisingly, in addition to inhibition of Src kinase, PP1/AGL1872 was found to inhibit PDGF receptor kinase in cell-free assays and in various types of intact cells, including HCASMCs. PP1/AGL1872 did not inhibit phosphorylation of the vascular endothelial growth factor receptor KDR (VEGF receptor-2; kinase-insert domain containing receptor) in cell-free assays as well as in intact human coronary artery endothelial cells. In line with the insensitivity of KDR, PP1/AGL1872 had only a weak effect on vascular endothelial growth factor-stimulated migration of human coronary artery endothelial cells. On treatment of cells expressing different receptor tyrosine kinases, the activities of the epidermal growth factor receptor, fibroblast growth factor receptor-1, and insulin-like growth factor-1 receptor were resistant to PP1/AGL1872, whereas PDGF alpha-receptor was susceptible, albeit to a lesser extent than PDGF beta-receptor. These data suggest that the previously described tyrosine kinase inhibitor PP1/AGL1872 is not selective for the Src family of tyrosine kinases. It is also a potent inhibitor of the PDGF beta-receptor kinase but is not a ubiquitous tyrosine kinase inhibitor. PP1/AGL1872 inhibits migration and proliferation of HCASMCs probably by interference with 2 distinct tyrosine phosphorylation events, creating a novel and potent inhibitory principle with possible relevance for the treatment of pathological HCASMC activity, such as vascular remodeling and restenosis.

Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice.

Vascular endothelial growth factor (VEGF) is a multifunctional angiogenic growth factor that is a primary stimulant of the development and maintenance of a vascular network in embryogenesis and the vascularization of solid tumors. At the present time there are two well-characterized receptors for VEGF that are selectively expressed on endothelium. VEGF receptor 2 [VEGFR2 (KDR/Flk-1)] mediates endothelial cell mitogenesis and permeability increases, whereas the role of VEGF receptor 1 [VEGFR1 (Flt-1)] has not been clearly defined. In the present study, a monoclonal antibody, 2C3, is shown to block the interaction of VEGF with VEGFR2 but not with VEGFR1 through ELISA, receptor binding assays, and receptor activation assays. 2C3 blocks the VEGF-induced vascular permeability increase in guinea pig skin. 2C3 has potent antitumor activity, inhibiting the growth of newly injected and established human tumor xenografts in mice. These findings demonstrate the usefulness of 2C3 in dissecting the pathways that are activated by VEGF in cells that express both VEGFR1 and VEGFR2, as well as highlighting the dominant role of VEGFR2 in mediating VEGF-induced vascular permeability increase and tumor angiogenesis.

Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation.

A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 is described. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF-dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells with 50% inhibitory concentrations below 5 and 1 microM, respectively. The PDGF receptor blockers have not effect on epidermal growth factor receptor autophosphorylation; weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both; and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis. AG1296 potently inhibits signaling of human PDGF alpha- and beta-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells. These potent and selective compounds represent leads for the development of novel agents to combat tumors driven by PDGF or to inhibit PDGF action in other diseases in which PDGF plays a key role, such as restenosis.

Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus: A potential predictor for the individual capacity to develop collaterals.

BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) acts on endothelial cells and monocytes, 2 cell types that participate in the angiogenic and arteriogenic process in vivo. Thus far, it has not been possible to identify differences in individual responses to VEGF-A stimulation because of the lack of an ex vivo assay. METHODS AND RESULTS: We report a chemotaxis assay using isolated monocytes from individual diabetic patients and from healthy, age-matched volunteers. The chemotactic response of individual monocyte preparations to VEGF-A, as mediated via Flt-1, was quantitatively assessed using a modified Boyden chamber. Although the migration of monocytes from healthy volunteers could be stimulated with VEGF-A (1 ng/mL) to a median of 148.4% of the control value (25th and 75th percentiles, 136% and 170%), monocytes from diabetic patients could not be stimulated with VEGF-A (median, 91.1% of unstimulated controls; 25th and 75th percentiles, 83% and 98%; P<0.0001). In contrast, the response of monocytes to the chemoattractant formylMetLeuPhe remained intact in diabetic patients. The VEGF-A-inducible kinase activity of Flt-1, as assessed by in vitro kinase assays, remained intact in monocytes from diabetic patients. Moreover, the serum level of VEGF-A, as assessed by immunoradiometric assay, was significantly elevated in diabetic patients. CONCLUSIONS: The cellular response of monocytes to VEGF-A is attenuated in diabetic patients because of a downstream signal transduction defect. These data suggest that monocytes are important in arteriogenesis and that their ability to migrate might be critical to the arteriogenic response. Thus, we resolved a fundamental mechanism involved in the problem of impaired collateral formation in diabetic patients.

C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis.

Infiltration of monocytes into the arterial wall is an early cellular event in atherogenesis. Recent evidence shows that C-reactive protein (CRP) is deposited in the arterial intima at sites of atherogenesis. In this study, we demonstrate that CRP deposition precedes the appearance of monocytes in early atherosclerotic lesions. CRP is chemotactic for freshly isolated human blood monocytes. A specific CRP receptor is demonstrated on monocytes in vitro as well as in vivo, and blockage of the receptor by use of a monoclonal anti-receptor antibody completely abolishes CRP-induced chemotaxis. CRP may play a major role in the recruitment of monocytes during atherogenesis.

Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications.

The formation of coronary collateral vessels is a compensatory mechanism secondary to repetitive or chronic myocardial ischemia. During the past three decades the functional and prognostic benefit of such collateral vessels has been established. There are large interindividual differences in the number and extent of collateral vessels that may be explained by differences in the anatomic situation or by differences in the individual capacity to develop functional collateral vessels. Diabetes mellitus has recently been identified as one of the first negative predictors of collateral vessel formation. Novel molecular approaches have helped to improve our understanding of the process of collateral vessel formation in recent years. Besides the process of true angiogenesis, i.e. the formation of new capillaries out of preexisting ones, the formation of a collateral circulation is largely based on the growth of preexisting arterioles (collateral vessels or anastomoses) named arteriogenesis. One important feature of arteriogenesis is the infiltration of monocytes into the growing collateral vessel. Our group shows that the ability of monocytes to migrate towards a gradient of VEGF-A is severely impaired in diabetic individuals, and this impaired response seems to be secondary to a signal transduction defect within the monocyte. In this review the pathophysiology of diabetes-related monocyte dysfunction and the potential role of VEGF-A in collateral vessel formation are discussed.