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Contains fulltext : 291245.pdf (Publisher’s version ) (Open Access) Hypertension is an important risk factor for cardiovascular disease. In the Netherlands, there are approximately 2.8 million people with hypertension. Despite treatment recommendations including lifestyle changes and antihypertensive drugs, most patients do not meet guideline-recommended blood pressure (BP) targets. In order to improve BP control and lower the risk of subsequent cardiovascular events, renal sympathetic denervation (RDN) has been introduced and studied as a non-pharmacological approach. While early data on the efficacy of RDN showed conflicting results, improvements in treatment protocols and study design resulted in robust new evidence supporting the potential of the technology to improve patient care in hypertensive subjects. Recently, 5 randomised sham-controlled trials demonstrated the safety and efficacy of the technology. Modelling studies have further shown that RDN is cost-effective in the Dutch healthcare setting. Given the undisputable disease burden along with the shortcomings of current therapeutic options, we postulate a new, clearly framed indication for RDN as an adjunct in the treatment of hypertension. The present consensus statement summarises current guideline-recommended BP targets, proposed workup and treatment for hypertension, and position of RDN for those patients with primary hypertension who do not meet guideline-recommended BP targets (see central illustration). 01 januari 2023

Aim To evaluate the distribution of a generic diastolic pressure ratio (dPR) after angiographically successful percutaneous coronary intervention (PCI) and to assess its association with the 2‑year incidence of target vessel failure (TVF), defined as a composite of cardiac mortality, target vessel revascularisation, target vessel myocardial infarction and stent thrombosis. Methods The dPR SEARCH study is a post hoc analysis of the prospective single-centre FFR-SEARCH registry, in which physiological assessment was performed after angiographically successful PCI in a total of 1000 patients, using a dedicated microcatheter. dPR was calculated offline with recently validated software in a subset of 735 patients. Results Mean post-PCI dPR was 0.95 ± 0.06. Post-PCI dPR was ≤ 0.89 in 15.2% of the patients. The cumulative incidence of TVF at 2‑year follow-up was 9.4% in patients with a final post-PCI dPR ≤ 0.89 as compared to 6.1% in patients with a post-PCI dPR > 0.89 (adjusted hazard ratio [HR] for dPR ≤ 0.89: 1.53; 95% CI 0.74–3.13; p = 0.249). dPR ≤ 0.89 was associated with significantly higher cardiac mortality at 2 years; adjusted HR 2.40; 95% CI 1.01–5.68; p = 0.047. Conclusions In a real-world setting, despite optimal angiographic PCI results, 15.2% of the patients had a final post-PCI dPR of ≤ 0.89, which was associated with a higher incidence of TVF and a significantly higher cardiac mortality rate.

Background Angiography-Based Vessel FFR (vFFR) demonstrated a strong correlation with invasive fractional flow reserve (FFR) in both a pre- and post-percutaneous coronary intervention (PCI) setting. However, the role of vFFR and its correlation with post-PCI FFR in chronic coronary occlusion (CTO) has not been evaluated yet. We sought to investigate the diagnostic performance of post-PCI vFFR with post-PCI FFR as a reference in patients undergoing successful CTO PCI. Methods Between March 2016 and September 2019, a total of 80 patients from the FFR-SEARCH and FFR REACT studies underwent successful CTO recanalization [1,2]). A total of 50 patients (median age 66 (IQR: 56–74) years, 76% were male) were eligible for the analysis. Median FFR was 0.89 (IQR: 0.84–0.94) while median vFFR was 0.91 (IQR: 0.85–0.94). Suboptimal physiological results, defined as FFR and vFFR Conclusion vFFR shows a good agreement with FFR and a high diagnostic accuracy for FFR ≤0.90 in patients undergoing successful PCI of a CTO lesion. Funding Acknowledgement Type of funding sources: None.

Background Patients with acute myocardial infarction (AMI) frequently experience recurrent atherothrombotic events, largely attributable to non-culprit lesions with high-risk characteristics. Statins can halt the progression of coronary atherosclerosis, and addition of protein convertase subtilisin/kexin type 9-inhibitors (PCSK9i) results in incremental low-density lipoprotein cholesterol (LDL-C) lowering and atheroma regression. Purpose We sought to examine the interrelation between baseline imaging characteristics, on-treatment LDL-C levels, and changes in coronary atherosclerosis as assessed by serial, multi-modality intracoronary imaging in patients with AMI. Methods This is a post hoc analysis from the PACMAN-AMI randomized trial. Patients were randomly allocated to biweekly alirocumab 150 mg vs. placebo on top of high-intensity statin initiated within 24h of presentation with AMI, and underwent serial imaging of the two non-infarct-related arteries at baseline and after 52 weeks. The primary endpoint was percent atheroma volume (PAV) by intravascular ultrasound (IVUS). Powered secondary endpoints were maximal lipid core burden index (maxLCBI4mm) by near-infrared spectroscopy (NIRS) and minimum fibrous cap thickness (FCTmin) by optical coherence tomography (OCT). Results Of 300 randomized patients (mean age 58.5±9.8 years, 18.7% women, baseline LDL-C 3.94±0.87 mmol/L), IVUS was serially performed in 265 patients (537 arteries). LDL-C levels decreased to 1.92±0.79 mmol/L with placebo and 0.61±0.61 mmol/L with alirocumab (p Conclusion In this study of intensive LDL-C lowering treatment initiated in the acute AMI setting, more favorable plaque changes were observed in patients with lower on-treatment LDL-C levels and in lesions with more adverse baseline plaque characteristics. Whether AMI patients with high-risk plaque features might derive greater clinical benefit from early initiation of intensive LDL-C-lowering therapies requires further investigation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi, Regeneron

Background Cardiac allograft vasculopathy (CAV) is still the main drawback of heart transplantation (HTx) and percutaneous coronary intervention (PCI) is a palliative measure because of the high incidence of PCI failure. The bioresorbable scaffolds (BRS) could represent a potential novel therapeutic tool for the treatment of coronary obstructions in CAV. Purpose To investigates the effects of BRS implantation in CAV patients in a Nationwide prospective study. Methods Multicentre, single-arm, prospective, open-label study that included patients affected by advanced CAV treated with PCI and second-generation ABSORB BRS. The primary endpoint was the incidence of 12-month angiographic in-segment scaffold restenosis (ISSR). Secondary endpoints were the composite of cardiac death, myocardial infarction, and target lesion revascularisation at 12-and 36-month follow-up and the incidence of ISSR at 36 months. A paired analysis of intravascular ultrasound (IVUS) and optical coherence tomography (OCT) at baseline and follow-up was also performed. Results Between 2015–2017 35 HTx patients were enrolled and treated on 44 coronary lesions with 51 BRS. The primary endpoint occurred in 13.5% of the lesions (5/37), with a cumulative ISSR rate up to 3 years of 16.2% (6/37).Angiographic lumen loss was 0.40±0.62mm at 12 months and 0.53±0.57mm at 36 months. Overall survival was 91.4% and 74.3%, and MACEs 14.2% and 31.4% at 12 and 36 months, respectively. At the paired intracoronary imaging analysis a significant increase of the vessel external elastic membrane area in the treated segment of the BRS was described at the OCT, while some progression of CAV was detected proximally at the IVUS assessment. Conclusions BRS in CAV was feasible and safe, with an ISSR incidence similar to drug-eluting stents. For the first time, a positive remodeling was observed in HTx patients after PCI. Vessel enlargement and the lack of metallic stents may allow repeated PCI avoiding the vessel shrinkage caused by the addition of multiple metal layers, being CAV a complex clinical scenario with a high incidence of MACEs, mainly driven by PCI failure. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Partial funding by Abbott Vascular Italy

Although there is robust evidence that revascularisation of non-culprit vessels should be pursued in patients presenting with an acute coronary syndrome (ACS) and multivessel coronary artery disease (MVD), the optimal timing of complete revascularisation remains disputed. In this systematic review and meta-analysis our results suggest that outcomes are comparable for immediate and staged complete revascularisation in patients with ACS and MVD. However, evidence from randomised controlled trials remains scarce and cautious interpretation of these results is recommended. More non-biased evidence is necessary to aid future decision making on the optimal timing of complete revascularisation. ispartof: NETHERLANDS HEART JOURNAL vol:30 issue:10 pages:449-456 ispartof: location:Netherlands status: published

Hypertension is an important risk factor for cardiovascular disease. In the Netherlands, there are approximately 2.8 million people with hypertension. Despite treatment recommendations including lifestyle changes and antihypertensive drugs, most patients do not meet guideline-recommended blood pressure (BP) targets. In order to improve BP control and lower the risk of subsequent cardiovascular events, renal sympathetic denervation (RDN) has been introduced and studied as a non-pharmacological approach. While early data on the efficacy of RDN showed conflicting results, improvements in treatment protocols and study design resulted in robust new evidence supporting the potential of the technology to improve patient care in hypertensive subjects. Recently, 5 randomised sham-controlled trials demonstrated the safety and efficacy of the technology. Modelling studies have further shown that RDN is cost-effective in the Dutch healthcare setting. Given the undisputable disease burden along with the shortcomings of current therapeutic options, we postulate a new, clearly framed indication for RDN as an adjunct in the treatment of hypertension. The present consensus statement summarises current guideline-recommended BP targets, proposed workup and treatment for hypertension, and position of RDN for those patients with primary hypertension who do not meet guideline-recommended BP targets (see central illustration).

Introduction and objectives: Patients with a low post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) are at a higher risk for future adverse cardiac events. The objective of the current study was to assess specific patient and procedural predictors of post-PCI FFR. Methods: The FFR-SEARCH study is a prospective single-center registry of 1000 consecutive all-comer patients who underwent FFR measurements after an angiographically successful PCI with a dedicated microcatheter. Mixed effects models were used to search for independent predictors of post-PCI FFR. Results: The mean post-PCI distal coronary pressure divided by the aortic pressure (Pd/Pa) was 0.96 ± 0.04 and the mean post-PCI FFR, 0.91 ± 0.07. After adjusting for the independent predictors of post-PCI FFR, the left anterior descending coronary artery as the measured vessel was the strongest predictor of post-PCI FFR (adjusted β = -0.063; 95%CI, -0.070 to -0.056; P 2 for the complete model was 53%. Conclusions: Multiple independent patient and vessel related predictors of postprocedural FFR were identified, including sex, the left anterior descending coronary artery as the measured vessel, and postprocedural minimum lumen diameter.

BACKGROUND AND OBJECTIVES: Imagery rescripting is an effective treatment strategy for trauma related disorders, but its underlying mechanisms are still largely unknown. The aim of the present study was to test whether a) imagery (versus writing) is essential in the process of rescripting, and b) rescripting affects emotional memories on an implicit level.METHODS: Healthy participants were subjected to an experimental trauma ('trauma film'), and randomly allocated to four conditions: recall of film + Imagery Rescripting (ImRs), recall of film + Writing Rescripting (WRs), recall only (ImRE), or no recall + no manipulation (NM). Next, participants recorded intrusion frequency and distress during one week, after which they executed a visual interference task (VIT) including neutral and trauma film stills, to access implicit emotional memory.RESULTS: Main findings were that ImRs and WRs resulted in fewer intrusions than NM, with no differences between both rescripting conditions. We did not find an effect on intrusion distress and the VIT.LIMITATIONS: Stills in the VIT were distracted from all four film scenes, whereas rescripting was done on one scene only, possibly obscuring the effect. Also, an analogue sample was used, which may limit generalizability to clinical samples.CONCLUSIONS: We replicated previous effects of ImRs on intrusion development. Furthermore, no superior effect of imagery as key modality for rescripting was found; writing seems a viable alternative. Measures for implicit emotional memory such as the VIT may have to be applied relatively soon after the experimental session (e.g., same day as the experimental session).

The design, realization and operation of a prototype or “demonstrator” version of an active target and time projection chamber (ACTAR TPC) for experiments in nuclear physics is presented in detail. The heart of the detection system features a micromegas gas amplifier coupled to a high-density pixelated pad plane with square pad sizes of 2 × 2 mm 2 . The detector has been thoroughly tested with several different gas mixtures over a wide range of pressures and using a variety of sources of ionizing radiation including laser light, an α -particle source and heavy-ion beams of 24Mg and 58Ni accelerated to energies of 4.0 MeV/u. Results from these tests and characterization of the detector response over a wide range of operating conditions will be described. These developments have served as the basis for the design of a larger detection system that is presently under construction.

Hypertension is a major risk factor for ischaemic heart disease and stroke. Despite the availability of numerous pharmacological treatment options, blood pressure (BP) targets are often not achieved. The inability to reach BP levels below 140/90 mmHg despite the use of three or more antihypertensive drugs is defined as resistant hypertension (RH). The etiology for RH is multifactorial. First, BP should be appropriately measured. In order to improve BP control, lifestyle modification should be recommended, adherence should be carefully assessed to exclude pseudo-resistance, and efforts should be made to exclude secondary causes of hypertension before initiating new drugs or considering device-based treatment strategies. This short review will highlight several aspects of RH management along with a focus on several new treatment options. act available.

Acute withdrawal of calcium channel blockers can lead to the so-called calcium channel blocker withdrawal phenomenon, in particular, when high dosages are used. In the case presented, inadequate drug substitution led to this phenomenon which resulted in a serious course of events. Careful monitoring the process of drug substitution with respect to equal therapeutic dosages is therefore a necessity, especially in vulnerable patients.

Background Polarization-sensitive (PS-) optical frequency domain imaging (OFDI) measures polarization properties of tissue together with conventional cross-sectional OFDI images of subsurface microstructure. PS-OFDI offers refined insight into plaque morphology and composition, which are implicated in the pathogenesis of acute coronary syndromes (ACS). Purpose This first-in-human pilot study of intravascular polarimetry aimed to investigate birefringence and depolarization features of coronary plaques in patients and to examine the relationship of these features with established structural characteristics available to conventional OFDI and with clinical presentation. Methods 30 patients undergoing PS-OFDI (acute coronary syndrome; ACS, n=12 and stable angina pectoris; SAP, n=18) participated in this study. 342 cross-sectional images evenly distributed along all imaged coronary arteries were classified into one of seven plaque categories according to conventional OFDI. Polarization features averaged over the entire intimal area of each cross-section were compared between plaque types and with structural parameters. Further, we assessed the polarization properties in the fibrous caps of ACS and SAP culprit lesions and compared them with structural features using a generalized linear model. Results The median birefringence and depolarization showed statistically significant differences among plaque types (both p Intravascular polarimetry Conclusions Intravascular polarimetry provides quantitative metrics that help to characterize coronary arterial tissues and may offer refined insight into coronary arterial atherosclerotic lesions in patients (Figure). Quantitative assessment of plaque polarization properties by intravascular polarimetry may open new avenues for studying plaque progression and detecting high-risk patients. Acknowledgement/Funding The JSPS Overseas Research Fellowship, the Uehara Memorial Foundation, and the Japan Heart Foundation and Bayer Yakuhin

Background Referral for high-risk percutaneous coronary intervention (PCI) is a progressively growing trend. Percutaneous Mechanical Circulatory Support (MCS), may protect the myocardium and reduce the risk of major adverse events. Clinical data on Left Ventricular (LV) unloading by pneumatically driven Percutaneous Left Ventricular Assist Devices (pVAD's) is currently scarce. Purpose Describe the unloading pattern produced by a pneumatically driven pulsatile pVAD on LV haemodynamics through real-time Pressure-volume (PV) analysis with a conductance catheter positioned in the left ventricle. Methods 19 patients undergoing high-risk PCI treated with MCS were monitored with PV loops and pulmonary artery catheterization throughout the intervention. Results When activated on 1:1 assist ratio, the mean output produced by the pVAD was 1.36±0.13L/min. Compared to pre-implantation, 1:1 support produced a significant reduction in End-systolic Wall Stress (ΔWSes: −11.95%, p Image 1 Conclusion High-risk PCI with pneumatic MCS may result in LV unloading and reduced myocardial oxygen consumption. Further insights will be released in the PULSE trial (Clinicaltrials.gov NCT03200990).

Intravascular polarimetry with polarization-sensitive (PS-) optical frequency domain imaging (OFDI) measures polarization properties of the coronary artery (Figure). Tissue rich in collagen and smooth muscle cells appears birefringent, while the presence of lipid causes depolarization. We aimed to

Small blood vessels (generally

Drug-eluting stents (DES) were introduced into clinical practice in 2002 in order to reduce restenosis that occurred in 15–25% of patients receiving bare-metal stents (BMS).1–3 Subsequent trials with different types of DES confirmed their efficacy in this regard.4 However, late stent thrombosis was reported as early as 2004, typically in patients discontinuing dual anti-platelet therapy.5 At the European and World Congress of Cardiology in Barcelona 2006, alarming data were presented on a worse long-term prognosis following DES implantation compared with BMS.6,7 As a result both randomized controlled trials and registry data were scrutinized to validate these concerns, bearing in mind the differential values of both types of studies.8,9 Furthermore, the worldwide discussion on the long-term safety and efficacy of DES triggered the European Society of Cardiology together with the European Association for Percutaneous Cardiovascular Interventions to organize a forum on DES. On 27 and 28 September 2007, key opinion leaders in (interventional) cardiology and representatives from industry and regulatory bodies gathered in the European Heart House with the intention to review: (i) the most recent data on the long-term efficacy (reduction of restenosis, re-intervention) and safety (late stent thrombosis, myocardial infarction, mortality) of DES and its effects on outcome (survival, event-free survival), (ii) specific indications for DES; (iii) health economical analyses currently performed with DES; (iv) the DES registration process in Europe; (v) current and possible future trial designs. The overall goal was to provide general recommendations to the medical community for the use, clinical development, and future assessment of DES. In several randomized controlled trials comparing sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES) and BMS, increased rates of death or myocardial infarction were observed at follow-up, beyond the first year,6–8,10 while no excess …

We recently reported that apolipoprotein E (ApoE)-deficient mice with a mutation in the fibrillin-1 gene (ApoE(-/-)Fbn1(C1039G+/-)) develop accelerated atherosclerosis with enhanced inflammation, atherosclerotic plaque rupture, myocardial infarction and sudden death. In the brain, fibrillin-1 functions as an attachment protein in the basement membrane, providing structural support to the blood-brain barrier (BBB). Here, we investigated whether fibrillin-1 impairment affects the permeability of the BBB proper and the blood-cerebrospinal fluid barrier (BCSFB), and whether this leads to the accelerated accumulation of lipids (xanthomas) in the brain. ApoE(-/-) (n=61) and ApoE(-/-)Fbn1(C1039G+/-) (n=73) mice were fed a Western-type diet (WD). After 14 weeks WD, a significantly higher permeability of the BBB was observed in ApoE(-/-)Fbn1(C1039G+/-) mice compared to age-matched ApoE(-/-) mice. This was accompanied by leukocyte infiltration, enhanced expression of pro-inflammatory cytokines, matrix metalloproteinases and transforming growth factor-β, and by decreased expression of tight junction proteins claudin-5 and occludin. After 20 weeks WD, 83% of ApoE(-/-)Fbn1(C1039G+/-) mice showed xanthomas in the brain, compared to 23% of their ApoE(-/-) littermates. Xanthomas were mainly located in fibrillin-1-rich regions, such as the choroid plexus and the neocortex. Our findings demonstrate that dysfunctional fibrillin-1 impairs BBB/BCSFB integrity, facilitating peripheral leukocyte infiltration, which further degrades the BBB/BCSFB. As a consequence, lipoproteins can enter the brain, resulting in accelerated formation of xanthomas.

In the framework of the German Plant Phenotyping Network (DPPN) we developed a novel PET scanner for imaging plants and crops. The observation of the carbon transport within the plant becomes possible by using 11CO2 as PET tracer. The use of the rather short living isotope C-11 asks for a scanner with high dynamic range. That means fast timing and high data rates are important features which let us choose the Philips Digital Photon Counter (DPC) as photo detector. Due to the fast photo detectors and the special crystal matrix arrangement the system will allow measurements with rather high activities. We could measure a coincidence resolution time of ∼ 250 ps FWHM between two detector elements. This opens the opportunity to employ time-of-flight information for the first time on a PET scanner of this size. This paper presents very first results from a prototype single-ring system with a FOV of 18 cm diameter and 6.5 cm axial height.

In The Netherlands, more than 30.000 patients undergo a percutaneous coronary intervention every year, during which a coronary stent implantation will be performed in 90% of the cases. It is estimated that more than 5 million coronary stent implantations will be performed worldwide this year. While these numbers are impressive, however, coronary stents still have as a limitation the possibility of stent thrombosis. This has been and is an important stimulus for the development of both coronary stents, from a bare metal stent via a drug eluting stent to the present-day development of bio-absorbable stents, and anti-platelet drugs,from acenocoumarol to thieropyridines. The possibility of shortening the period of use of this powerful medication by developing new kinds of non-thrombogenic stents would, for example, make it possible to achieve significant reductions in subsequent bleeding during (dental) procedures.

The technological components of a multisensory-based rock stability diagnosis method are described for applications in tunnels or other subsurface openings. The test bed containing four sensors is mounted on the end effector of a robot manipulator. Articulated robotic movement of the test bed along the roof and wall periphery provides a virtually simultaneous acquisition of four pertinent, complementary signals, namely sonic/ultrasonic, thermal, visual, and fracture images, relating to rock stability. The synergistic combination of information from these signals is used to evaluate the stability conditions of the rock formation. On the technological basis further developments will be possible applying multisensory integration techniques, neural networks, clustering of fuzzy sets, or fuzzy networks.

Accumulation of macrophages, red blood cells and lipids in atherosclerotic plaques is associated with plaque rupture. It has been shown that macrophages and erythrocytes can enter the plaque also via plaque microvasculature originating from the adventitia. Furthermore, it has been reported that in advanced or ruptured human coronary lesions the microvessel density is increased and these microvessels are leaky. The leaky phenotype is characterized by poor pericyte coverage and dysfunctional inter-endothelial junctions. As angiopoietins are involved in angiogenic growth and maturation, we hypothesized that periadventitial Ang-1 or Ang-2 gene transfer would reduce atherogenesis and affect microvasculature in mouse carotid artery. To study this, atherosclerosis was induced by placing a perivascular silastic collar around the carotid artery of LDLr -/- ApoB100/100 mice fed a high cholesterol (0,15 %) diet for 3 weeks. Simultaneous to surgery adenoviral gene transfer (5μl, 5 x 107 pfu/ml) of either Ang-1, Ang-2 or LacZ as a control was applied to the carotid artery (20 mice per group). After 1 or 5 weeks follow-up on high cholesterol diet mice were sacrificed. Plaque size and microvessel density were analyzed with morphometry software (Leica Qwin) using cross-sections stained with hematoxylin and eosin or CD31 respectively. Microvessel ultrastructure was studied using electron microscopy. Ang-2 gene transfer led to significantly smaller plaque area and plaque volume 5 weeks after collar placement compared to LacZ group (2,7 fold, p In conclusion: Ang-2 over expression in mouse carotid arteries led to smaller plaque size and lower microvessel density, suggesting the involvement of angiopoietin signaling in angiogenesis of the atherosclerotic vessel wall.

The authors present a high-resolution frame-transfer charge-coupled-device (CCD) suitable for S-VHS camcorders with an additional full-resolution true electronic still picture (ESP) mode of operation. The CCD sensor is composed of an image section, an intermediate readout register, a storage section, and a second readout register. A resolution of 450 TV lines (H) is obtained in color images by applying cyan-green-yellow complementary stripe color filters on the 1187(H)*581(V) pixels. The operation of the sensor in both conventional video and ESP modes is described. Special attention is paid to the 3-D potential calculations required to obtain a design guaranteeing a high-quality picture. Experimental results are presented. >

Emotional distress has been related to clinical events in patients with coronary artery disease, but the influence of positive affect (i.e. mood states such as activity, joy and cheerfulness) has received little attention. Therefore, we wanted to investigate the role of positive affect on clinical outcome after percutaneous coronary intervention (PCI) with stent implantation in these patients.Prospective follow-up study. At baseline, patients from the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry completed measures of positive affect, depression and anxiety post-PCI. Patients with reduced positive affect scored 1 SD below the mean score.University Hospital; Thoraxcenter of the Department of Cardiology.874 patients (72% men; 62.2 +/- 10.9 years) from the RESEARCH registry. Main outcome measure. Death or myocardial infarction (MI) 2 years post-PCI.At follow-up, there were 52 clinical events (deaths n = 27, MIs n = 25). Reduced positive affect and depression/anxiety were associated with poor prognosis, but reduced positive affect was the only independent predictor of events. The incidence of death/MI in adequate versus reduced positive affect patients was 4% (29/663) vs. 11% (23/211); HR = 2.55 (95% CI 1.46-4.34, P = 0.001), adjusting for clinical variables. Reduced positive affect and diabetes were independent prognostic factors, and patients with one (HR = 2.84, 95% CI 1.58-5.10) or both (HR = 5.61, 95% CI 2.25-13.99) of these factors had a higher risk when compared with nondiabetic patients with adequate positive affect, Por = 0.003.Reduced positive affect independently predicted death/MI following stent implantation, and improved risk stratification above and beyond diabetes.

Intraplaque neovascularization is linked to plaque instability and thought to be stimulated by hypoxia. However, hypoxia has not been demonstrated yet in human atherosclerosis. The hypoxia marker pimonidazole was administrated intravenously 2 hours prior to carotid endarterectomy in 6 symptomatic patients to evaluate the presence of hypoxia. Subsequent immunohistochemistry of the operatively removed atherosclerotic plaques demonstrated the presence of hypoxia, especially in the macrophage-rich center of the lesions. Notably, two hypoxic gradients were observed: hypoxia was very strong in the center of the plaque, but almost absent close to the main artery lumen and in the media. hypoxia was most intense in segments with advanced atheroma and almost absent in segments containing only diffuse intimal thickening. Hypoxia strongly correlated with CD68 immunoreactivity (ρ= 0.7, p=0.000), neovascularization (ρ= 0.6, p=0.000) and the presence of a thrombus (ρ= 0.4, p=0.009). In addition, hypoxia co-localized with expression of HIF1α and VEGF . To exclude that pimonidazole immunoreactivity in the atherosclerotic plaque was the result of surgery-induced ischemia, arterial wall segments were collected at two time-points: directly after incision of the carotid artery and directly following excision of the plaque. Pimonidazole immunoreactivity in these two pieces was not different, suggesting that hypoxia and pimonidazole adducts were already present in the plaques before surgery . To show that pimonidazole reactivity was hypoxia-specific and independent of reactive oxygen species, human THP-1 macrophages were exposed to normoxia (20% O 2 ), hypoxia (0.2% O 2 ) and/or H 2 O 2 (100 μM) in the presence of pimonidazole. Indeed, flow cytometry only showed pimonidazole-positive cells after hypoxic exposure. This is the first study proving direct evidence of the existence of hypoxia in advanced human atherosclerotic lesions, most prominently in the macrophage-rich center. Also, hypoxia was associated with the expression of HIF1α, VEGF and intraplaque microvessels, suggesting its involvement in the regulation of human intraplaque neovascularization.

Here we investigated whether platelet CD40L plays a role in atherosclerosis. Platelets were obtained from donor ApoE−/− or CD40L−/− ApoE−/− mice, activated with thrombin, neutralized by hirudin and injected intravenously into n=30 ApoE−/− recipients (3E10 7 platelets) every 5 days. Infusion of activated CD40L−/− platelets in ApoE−/− mice from age 5–17wks caused a decrease in atherosclerosis (predominantly early lesions) in the aortic arch and its major branch points (ApoE−/− platelets 2.01E10 5 ± 3.74E10 4 μm 2 vs CD40L−/−ApoE−/− platelets 1.01E10 5 ± 1.57E10 4 μm 2 ; p5 ± 1.61E10 4 μm 2 ). To induce advanced atherosclerosis, a silastic non-constrictive collar was placed around both carotid arteries in diet fed mice, and activated platelets were injected every 5 days during 5 wks. Infusion of activated CD40L−/−ApoE−/− platelets caused a 35.4% decrease in plaque volume (ApoE−/− platelets 2.08E10 8 ± 2.55E10 7 μm 3 vs CD40L−/−ApoE−/− platelets 1.36E10 8 ± 3.45E10 7 μm 3 , Sham 1.17E10 8 ± 2.71E10 7 μm 3 p

The aim of this article is to review the treatment of patients with multi-vessel coronary artery disease. Percutaneous coronary intervention (PCI) has been challenging coronary artery bypass grafting (CABG) as the gold standard of care for patients with multi-vessel disease; however, the application of PCI to these patients has been mainly limited by restenosis. Up to the late 1990s, numerous large-scale, randomized trials addressed this issue comparing CABG to PCI with balloon angioplasty or bare-metal stents. These studies demonstrated similar rates of death and myocardial infarction in both groups, while the need for revascularization remained significantly lower in the CABG group. Drug-eluting stents (DES) have dramatically reduced restenosis and repeat revascularization rates. CABG has also progressed with improvements in perioperative management, a higher use of arterial grafting, and advanced techniques with the implementation of minimally invasive and off-pump surgery as options. Therefore, the results of previous trials in the pre-DES era can no longer be extrapolated into the ''real world''. As intermediate steps preceding a fully-fledged, randomized trial, several trials have compared PCI with DES and the historical control of CABG, but the results are still inconclusive. Several dedicated randomized trials are currently ongoing to compare PCI with DES and CABG using contemporary techniques. Until the results of these randomized trials are presented, the choice for each strategy should be based on the patients' individual risk and anatomy.

The extracellular matrix is no longer seen as the static embedding in which cells reside; it has been shown to be involved in cell proliferation, migration and cell-cell interactions. Turnover of the different extracellular matrix components is an active process with multiple levels of regulation. Collagen, a major extracellular matrix constituent of the myocardium and the arterial vascular wall, is synthesized by (myo)fibroblasts in the myocardium and smooth muscle cells in the medial arterial vascular wall. Its degradation is controlled by proteinases, which include matrix metalloproteinases. This review will focus on the impact of fibrosis and especially collagen turnover on the progression of heart failure and atherosclerosis, two of the main cardiovascular pathologies. We will discuss data from human studies and animal models, with an emphasis on the effects of interventions on collagen synthesis and degradation. We conclude that there is a dynamic (dis)balance in the rate of collagen synthesis and degradation during heart failure and atherosclerosis, which makes the outcome of interventions not always predictable. Alternative approaches for intervening in collagen metabolism will be discussed as possible therapeutic intervention strategies.

Recent improvements in the clinical management of acute myocardial infarction (MI) have resulted in a dramatic decrease in mortality because of this condition. This implies that more patients enter the process of infarct healing. This is a highly complex cascade of events which, although studied for decades, is still not completely understood. An increasing number of genetically altered mice can now be studied in a mouse model of MI, to investigate the contribution of the product of the targeted gene to the infarct healing process. In this review, we will discuss the defects in infarct healing that have been observed in null mutants for plasminogen, urokinase-type plasminogen activator (u-PA), matrix metalloproteinases (MMPS), thrombospondin-2 and dishevelled-1. These studies provide new insights in the infarct healing process itself, but may also help to define new diagnostic and therapeutic targets in humans suffering from MI.

The diagnosis of an acute myocardial infarction (MI) can be cumbersome for pathologists. Even with a positive nitroblue tetrazolium (NBT) reaction, haematoxylin and eosin (HE) evaluation of the myocardial tissue can remain inconclusive. Early signs presumed diagnostic for myocardial infarction, such as hypereosinophilia, waviness, and contraction band necrosis, have to be considered non-specific and are probably reversible signs of ischaemia. Several studies implicate the complement system, and especially complement factor C9, as part of the membrane attack factor (MAC), in cardiomyocyte damage during MI. In a post-mortem study on well-documented cardiological autopsies, we evaluated the use of complement factor C9 immunostaining as a marker for the detection of very recent MI. Forty-three tissue samples from 40 patients were obtained from the left ventricular free wall only, a region that can be specifically attributed to one corresponding coronary artery. As some patients presented with MIs of various stages in that perfusion area, in total 57 observations were possible. C9 immunostaining specifically detected irreversibly damaged (=infarcted) cardiomyocytes, as is implied by the lytic activity of C9/MAC binding to cell membranes. Most interesting was the group of clinically suspected, NBT-positive MIs resulting from very recent myocardial ischaemia. In this population, where HE evaluation by (cardio-) experienced pathologists was not conclusive, C9 immunostaining clearly pointed towards myocardial infarction in 47% of the cases. In conclusion, C9 immunostaining, routinely practicable in the pathology laboratory, has an additional value in discriminating between reversible ischaemia and infarcted cardiomyocytes in very early MIs.

The role of molecular genetics in the pathophysiology of various diseases is becoming clearer and clearer. In the field of cardiovascular diseases, molecular genetic aspects have been shown to play a definite role in the aetiology of these diseases. Several molecular-genetic variations called polymorphisms, occur in the population. The genes encoding the different components of the reninangiotensin-aldosterone system (RAAS), an important system in the regulation of the function and structure of the heart and vascular wall, also display polymorphisms. For some of these polymorphisms associations with various cardiovascular and renal diseases have been described. At present, this is particularly clear for the relation between angiotensin-converting-enzyme (ACE) polymorphism and the incidence of atherosclerotic complications and diabetic nephropathy, and for the relation between so-called M235 T-variant of the angiotensinogen gene and hypertension. Future research will have to show where it is worthwhile to use these and other polymorphisms as a marker for genetic risk. In what way the different RAAS-polymorphisms relate to functional abnormalities is as yet unclear, as are the potential therapeutic implications.

Recent developments in our knowledge of the renin-angiotensin system (RAS) necessitate an update of the classical view on this system. These developments pertain to the pathways leading to formation of angiotensin II and other active metabolites, their receptors, biological functions and the presence of renin-angiotensin systems in tissues. The implications of the above new developments for the current interest in tissue renin-angiotensin systems as potential targets for drug therapy in cardiovascular disease are discussed in this review.

Not much is known about the specific pathophysiologic mechanisms of soiling. Although the causes of soiling may vary, it is mostly associated with anorectal disorders that can deform the contour of the anus and anal canal. In most cases, this disorder can be treated successfully by medical or surgical therapy. If this appropriate treatment is not available or fails, reconstruction of the contour deformity of the anus by perianal (submucosal) injection of soft tissue bulking agents may be successful. PURPOSE: The main purpose of this pilot study was to evaluate locoregional reaction and distant migration after local perianal injection of solid polydimethylsiloxane elastomer particles (Bioplastique™ implants). METHODS: Twelve Lewis rats received a local perianal injection of Bioplastique™ implants. Six of them received an additional perianal injection of gentamicin. Six weeks after injection, the rats were euthanized. RESULTS: Microscopically, the local tissue reaction was that of a quiescent foreign body reacting with encapsulation. Microscopic examinations could not reveal any migration to locoregional lymph nodes, liver, spleen, lungs, or brain. CONCLUSION: We conclude that, because of minimum local reaction and lack of evidence of distant migration, polydimethylsiloxane elastomer particle paste (Bioplastique™ implants) seems to be a potentially safe substance for local perianal injection.

We studied the immunoreactivity of the chymase protein in normal human myocardium and in human myocardial infarctions at various postinfarction times using immuno-histochemistry. In noninfarcted hearts chymase was mainly present in cardiomyocytes and endothelial cells. At 6 h after infarction the ischemic cardiomyocytes had lost their chymase immunoreactivity. A portion of the smooth muscle alpha-actin-expressing myofibroblasts and some of the CD-68-positive macrophages, which both appear 4-6 days after infarction, contained chymase. Chymase was also found in mast cells, which were present in the normal myocardium and the healing scar. These data show that chymase, a protein that mediates the conversion of angiotensin I to angiotensin II via a non-angiotensin-converting-enzyme-dependent pathway is present in the normal adult human myocardium and is upregulated in the healing tissue after myocardial infarction.

Current designs of the shaft sealing system for the Waste Isolation Pilot Plant (WIPP) propose using bentonite as a primary sealing component. The shaft sealing designs anticipate that compacted bentonite sealing components can perform through the 10,000-year regulatory period and beyond. To evaluate the acceptability of bentonite as a sealing material for the WIPP, this report identifies references that deal with the properties and characteristics of bentonite that may affect its behavior in the WIPP environment. This report reviews published studies that discuss using bentonite as sealing material for nuclear waste disposal, environmental restoration, toxic and chemical waste disposal, landfill liners, and applications in the petroleum industry. This report identifies the physical and chemical properties, stability and seal construction technologies of bentonite seals in shafts, especially in a saline brine environment. This report focuses on permeability, swelling pressure, strength, stiffness, longevity, and densification properties of bentonites.

Fibronectin and tenascin are matrix proteins known to be present in early experimental wound healing. As only limited data are available regarding early matrix changes in human myocardial infarction, the presence of tenascin and fibronectin was studied in human myocardial infarctions of different post-infarction times (6 h to 17 years), using immunohistochemistry. In normal myocardium, fibronectin immunostaining was found in the subendothelial space in vessels. Tenascin was not present in normal myocardium. While fibronectin was demonstrated in the ischaemic cardiomyocytes within 1 day, tenascin was found 4-6 days post-infarction and was located at the margin of the area of infarction. Tenascin expression then shifted from the margin to the centre of the area of infarction, where it could be found 2-3 weeks post-infarction. More than 4 weeks post-infarction, the scar tissue consisted of collagen fibres, with sparse (myo)fibroblasts. By that time, both tenascin and fibronectin expression had disappeared. Another interesting observation in this study was the presence of tenascin, but not fibronectin, surrounding vacuolated glycogen-rich cells, or so-called hibernating cardiomyocytes.

In this study changes in the amount and distribution of types I and III collagen mRNA and protein were investigated in the rat heart after induction of a left ventricular myocardial infarction (MI). Sham operated rats served as controls. The animals were sacrificed at different time intervals after operation. Northern blotting of cardiac RNA and hybridization with cDNA probes for types I and III procollagen revealed a 5- to 15-fold increase in the infarcted left ventricle. Type III procollagen mRNA levels were already increased at day 2 after MI, whereas type I procollagen mRNA followed this response at day 4 after MI. This increase was sustained for at least 21 days in the infarcted left ventricle for type III procollagen mRNA, whereas type 1 procollagen mRNA levels were still elevated at 90 days after MI. In the noninfarcted right ventricle a 5- to 7-fold increase was observed for both type I and type III procollagen mRNA levels, but only at day 4 after MI. In the non-infarcted septum a transient increase was observed for type I procollagen mRNA from day 7-21 (4- to 5-fold increase) and a decline to sham levels thereafter. In the septum type III procollagen mRNA levels were only elevated at 7 days after MI (4- to 5-fold increase) compared with sham operated controls. In situ hybridization with the same types I and III procollagen probes showed procollagen mRNA-producing cells in the infarcted area around necrotic cardiomyocytes, and in the interstitial cells in the non-infarcted part of the myocardium. No labeling was detected above cardiomyocytes. Combined in situ hybridization and immunohistochemistry showed that the collagen mRNA producing cells have a myofibroblast-like phenotype in the infarcted myocardium and are fibroblasts in the noninfarcted septum and right ventricle. The increase in types I and III procollagen mRNA in both infarcted and non-infarcted myocardium was followed by an increased collagen deposition, measured by computerized morphometry on sirius red-stained tissue sections as well as by the hydroxyproline assay. In the non-infarcted septum and right ventricle the collagen-positive area was maximal at day 14 (3- to 5-fold increase compared with sham operated controls) and slightly declined at day 21. In the infarcted myocardium the collagen-positive area was 57 +/- 10% at day 14 after MI. Hydroxyproline contents were significantly increased in the noninfarcted septum.(ABSTRACT TRUNCATED AT 400 WORDS)