Ultrasonography for quantitative assessment of knee joint effusions-useful tool for objective evaluation of rehabilitation progress?

PURPOSE: We sought to externally validate ultrasonography (US) for quantification of suprapatellar effusion size to improve diagnosis and individualised rehabilitation strategies in knee rehabilitation after anterior cruciate ligament reconstruction (ACLR) surgery. METHODS: US was performed on 35 patients as part of the ongoing CAMOPED study. Data were collected in ACLR and post surgery in defined intervals up to one year post-operation. The palpatory assessment was graded using the International Knee Documentation Committee (oIKDC). RESULTS: In a total of 164 sonographies, a strong correlation between palpatory and US effusion (r = 0.83, p < 0.01) with lower deviations in US quantification compared to palpatory quantification Y = 1.15 + 0.15* x was seen. Threshold values could be determined for the detection of effusions by palpation and for the differentiation between mild and moderate/severe effusions (effusion depth: 2.6 mm and resp. 5.8 mm, respectively). CONCLUSIONS: As demonstrated in this multicenter study, the size of suprapatellar effusions can be easily quantified with high accuracy using standardised bedside ultrasound. Especially in moderate to severe effusions, US provides a practical and reliable tool for outcome measurement superior to palpatory assessment with the goal of optimising individual recommendations during the rehabilitation course. Furthermore, for the first time, it has been possible to define sonographic threshold values for the detection of effusion and differentiation of mild vs. moderate/severe effusion by means of palpation.

Human Parvovirus B19 (B19V) Up-regulates CXCR4 Surface Expression of Circulating Angiogenic Cells: Implications for Cardiac Ischemia in B19V Cardiomyopathy.

Background: Human parvovirus B19 (B19V) infection and damage of circulating angiogenic cells (CAC) results in dysfunctional endogenous vascular repair (DEVR) with secondary end-organ damage. Trafficking of CAC is regulated by SDF-1α and the respective receptor CXCR4. We thus tested the hypothesis of a deregulated CXCR4/SDF-1α axis in symptomatic B19V-cardiomyopathy. Methods: CAC were infected in vitro with B19V and transfected with B19V-components. Read-out were: CXCR4-expression and migratory capacity at increasing doses of SDF-1α. In 31 patients with chronic B19V-cardiomyopathy compared to 20 controls read-outs were from blood: migratory capacity, CXCR4 expression on CAC, serum SDF-1α; from cardiac biopsies: SDF-1α mRNA, HIF-1α mRNA, microvascular density, resident cardiac stem cells (CSC), transcardiac gradients of CAC. Results: In vitro B19V-infected CAC showed up-regulation of surface CXCR4 with increased migratory capacity further enhanced by elevated SDF-1α concentrations. Overexpression of the B19V capsid protein VP2 was associated with this effect. Chronic B19V-cardiomyopathy patients showed increased numbers of ischaemia mobilised CAC but DEVR as well as diminished numbers of CAC after transcardiac passage. Cardiac microvascular density and CSC were significantly reduced in B19V-cardiomyopathy. Conclusions: We thus conclude that B19V infection has a direct VP2-mediated negative impact on trafficking of CAC in the presence of impaired cardiac regeneration.

Impaired Endothelial Regeneration Through Human Parvovirus B19-Infected Circulating Angiogenic Cells in Patients With Cardiomyopathy.

Human parvovirus B19 (B19V) is a common pathogen in microvascular disease and cardiomyopathy, owing to infection of endothelial cells. B19V replication, however, is almost restricted to erythroid progenitor cells (ErPCs). Endothelial regeneration attributable to bone marrow-derived circulating angiogenic cells (CACs) is a prerequisite for organ function. Because of many similarities of ErPCs and CACs, we hypothesized that B19V is a perpetrator of impaired endogenous endothelial regeneration. B19V DNA and messenger RNA from endomyocardial biopsy specimens, bone marrow specimens, and circulating progenitor cells were quantified by polymerase chain reaction analysis. The highest B19V DNA concentrations were found in CD34(+)KDR(+) cells from 17 patients with chronic B19V-associated cardiomyopathy. B19V replication intermediates could be detected in nearly half of the patients. Furthermore, chronic B19V infection was associated with impaired endothelial regenerative capacity. B19V infection of CACs in vitro resulted in expression of transcripts encoding B19V proteins. The capsid protein VP1 was identified as a novel inducer of apoptosis, as were nonstructural proteins. Inhibition studies identified so-called death receptor signaling with activation of caspase-8 and caspase-10 to be responsible for apoptosis induction. B19V causally impaired endothelial regeneration with spreading of B19V in CACs in an animal model in vivo. We thus conclude that B19V infection and damage to CACs result in dysfunctional endogenous vascular repair, supporting the emergence of primary bone marrow disease with secondary end-organ damage.

Cardiac migration of endogenous mesenchymal stromal cells in patients with inflammatory cardiomyopathy.

Introduction. Mesenchymal stromal cells (MSC) have immunomodulatory features. The aim of this study was to investigate the migration and homing potential of endogenous circulating MSC in virus negative inflammatory cardiomyopathy (CMi). Methods. In 29 patients with (n = 23) or without (n = 6) CMi undergoing endomyocardial biopsies (EMB), transcardiac gradients (TCGs) of circulating MSC were measured by flow cytometry from blood simultaneously sampled from aorta and coronary sinus. The presence of MSC in EMB, cardiac inflammation, and SDF-1α mRNA expression were detected via immunohistochemistry and real-time PCR. Results. MSC defined as CD45(-)CD34(-)CD11b(-)CD73(+)CD90(+) cells accounted for 0.010 [0.0025-0.048]%/peripheral mononuclear cell (PMNC) and as CD45(-)CD34(-)CD11b(-)CD73(+)CD105(+) cells for 0.019 [0.0026-0.067]%/PMNC, both with similar counts in patients with or without cardiac inflammation. There was a 29.9% (P < 0.01) transcardiac reduction of circulating MSC in patients with CMi, correlating with the extent of cardiac inflammation (P < 0.05, multivariate analysis). A strong correlation was found between the TCG of circulating MSC and numbers of MSC (CD45(-)CD34(-)CD90(+)CD105(+)) in EMB (r = -0.73, P < 0.005). SDF-1α was the strongest predictor for increased MSC in EMB (P < 0.005, multivariate analysis). Conclusions. Endogenous MSC continuously migrate to the heart in patients with CMi triggered by cardiac inflammation.

A Novel Sensor-Based Application for Home-Based Rehabilitation Can Objectively Measure Postoperative Outcomes following Anterior Cruciate Ligament Reconstruction.

In order to successfully implement individualized patient rehabilitation and home-based rehabilitation programs, the rehabilitation process should be objectifiable, monitorable and comprehensible. For this purpose, objective measurements are required in addition to subjective measurement tools. Thus, the aim of this prospective, single-center clinical trial is the clinical validation of an objective, digital medical device (DMD) during the rehabilitation after anterior cruciate ligament reconstruction (ACLR) with regards to an internationally accepted measurement tool. Sixty-seven patients planned for primary ACLR (70:30% male-female, aged 25 years [21-32], IKDC-SKF 47 [31-60], Tegner Activity Scale 6 [4-7], Lysholm Score 57 [42-72]) were included and received physical therapy and the DMD after surgery. For clinical validation, combined measures of range of motion (ROM), coordination, strength and agility were assessed using the DMD in addition to patient-reported outcome measures (PROMs) at three and six months after ACLR. Significant correlations were detected for ROM (rs = 0.36-0.46, p < 0.025) and strength/agility via the single-leg vertical jump (rs = 0.43, p = 0.011) and side hop test (rs = 0.37, p = 0.042), as well as for coordination via the Y-Balance test (rs = 0.58, p ≤ 0.0001) regarding the IKDC-SKF at three months. Additionally, DMD test results for coordination, strength and agility (Y-Balance test (rs = 0.50, p = 0.008), side hop test (rs = 0.54, p = 0.004) and single-leg vertical jump (rs = 0.44, p = 0.018)) correlate significantly with the IKDC-SKF at six months. No adverse events related to the use of the sensor-based application were reported. These findings confirm the clinical validity of a DMD to objectively quantify knee joint function for the first time. This will have further implications for clinical and therapeutic decision making, quality control and monitoring of rehabilitation measures as well as scientific research.

Sensor-based telerehabilitation system increases patient adherence after knee surgery.

OBJECTIVES: Implementing evidence-based recommendations with the option of patient-individualised and situation-specific adaptations in telerehabilitation may increase adherence with improved clinical outcome. METHODS: As part of a registry-embedded hybrid design (part 1), digital medical device (DMD)-usage in a home-based setting was analysed in a multinational registry. The DMD combines an inertial motion-sensor system with instructions for exercises and functional tests on smartphones. A prospective, single-blinded, patient-controlled, multicentre intervention study (DRKS00023857) compared implementation capacity of the DMD to standard physiotherapy (part 2). Usage patterns by health care providers (HCP) were assessed (part 3). RESULTS AND CONCLUSION: Registry raw data (10,311 measurements) were analysed from 604 DMD-users, demonstrating clinically expected rehabilitation progression post knee injuries. DMD-users performed tests for range-of-motion, coordination and strength/speed enabling insight to stage-specific rehabilitation (χ2 = 44.9, p<0.001). Intention-to-treat-analysis (part 2) revealed DMD-users to have significantly higher adherence to the rehabilitation intervention compared to the matched patient-control-group (86% [77-91] vs. 74% [68-82], p<0.05). DMD-users performed recommended exercises at home with higher intensity (p<0.05). HCP used DMD for clinical decision making. No adverse events related to the DMD were reported. Adherence to standard therapy recommendations can be increased using novel high quality DMD with high potential to improve clinical rehabilitation outcome, enabling evidence-based telerehabilitation.

Dynamic Standing Exercise using the Innowalk Device in Patients with Genetic and Acquired Motor Impairments.

OBJECTIVE: For individuals with motor impairments, dynamic standing has been proposed as an opportunity for regular daily physical activity. The aim of this study was to analyse patient characteristics, indications, intensity of usage, desired objectives and outcomes of dynamic standing in daily clinical practice in order to form the basis for research regarding this treatment option. SETTING: Data were analysed from standardized questionnaires completed prospectively before supply of a home-based medical device for dynamic standing (Innowalk; Made for Movement GmbH, Langenhagen, Germany) and at the time of individual adaptations. PARTICIPANTS: In a retrospective chart analysis, records of 46 patients (50% cerebral palsy; 50% diverse syndromes) were evaluated. INTERVENTION: The Innowalk had been prescribed for either home-based use (n = 31), in therapeutic institutions (n = 8), or other settings (n = 7). Dynamic standing was performed for 10-30 min as a single session (n = 8) or for 20-60 min 11 [4-21] weeks in 36 patients. RESULTS: Improvements were found for: passive assisted motion (79%), stimulation of intestinal functions (71%), body stability (64%), joint mobility (56%), secure means of allowing supine position (52%), and revision of abnormal motion patterns (48%). CONCLUSION: Thus, this systematic approach shows usage patterns, indications, desired goals and clinical outcome of dynamic standing in daily clinical practice and forms the basis for the design of a prospective, randomized controlled trial.

Interferon beta modulates endothelial damage in patients with cardiac persistence of human parvovirus b19 infection.

BACKGROUND: In a phase 1 study, we investigated whether interferon beta reduced endothelial damage in patients with cardiac persistence of human parvovirus B19 (B19V) infection. METHODS AND RESULTS: In vitro, B19V infected cultivated endothelial cells (ECs), which led to a reduction in their viability (P = .007). Interferon beta suppressed B19V replication by 63% (P = .008) in ECs and increased their viability (P = .021). Circulating mature apoptotic ECs (CMAECs [CD45(-)CD146(+) cells expressing von Willebrand factor and annexin V]) and circulating progenitor cells (CPCs [CD34(+)KDR(+) cells]) were quantified by flow cytometry in 9 symptomatic patients with cardiac B19V infection before and after 6 months of interferon beta therapy (16 MU) and were compared to levels in 9 healthy control subjects. Endothelial dysfunction was measured using flow-mediated dilatation of the forearm. Patients with B19V persistence had significantly higher (P = .04) levels of CMAECs than did control subjects, which normalized after treatment (mean +/- standard deviation, 0.06% +/-0.08% vs 0.01% +/- 0.006%; P = .008). Similar improvement was shown for flow-mediated dilatation (P = .04) in the treatment group only (P = .017 for the comparison with untreated patients with B19V persistence n = 5). There were significantly higher numbers of CPCs in patients with B19V persistence before therapy (mean +/- standard deviation, 0.04% +/- 0.05% vs 0.01% +/- 0.004%; P = .02; than in control subjects, which normalized after treatment (P = .03). CONCLUSION: Thus, we present (for the first time, to our knowledge) a modulation of virally induced chronic endothelial damage-specifically, EC apoptosis and endothelial regeneration.

Telbivudine Reduces Parvovirus B19-Induced Apoptosis in Circulating Angiogenic Cells.

Aims: Human parvovirus B19 (B19V) infection directly induces apoptosis and modulates CXCR4 expression of infected marrow-derived circulating angiogenic cells (CACs). This leads to dysfunctional endogenous vascular repair. Treatment for B19V-associated disease is restricted to symptomatic treatment. Telbivudine, a thymidine analogue, established in antiviral treatment for chronic hepatitis B, modulates pathways that might influence induction of apoptosis. Therefore, we tested the hypothesis of whether telbivudine influences B19V-induced apoptosis of CAC. Methods and Results: Pretreatment of two CAC-lines, early outgrowth endothelial progenitor cells (eo-EPC) and endothelial colony-forming cells (ECFC) with telbivudine before in vitro infection with B19V significantly reduced active caspase-3 protein expression (-39% and -40%, both p < 0.005). Expression of Baculoviral Inhibitor of apoptosis Repeat-Containing protein 3 (BIRC3) was significantly downregulated by in vitro B19V infection in ECFC measured by qRT-PCR. BIRC3 downregulation was abrogated with telbivudine pretreatment (p < 0.001). This was confirmed by single gene PCR (p = 0.017) and Western blot analysis. In contrast, the missing effect of B19V on angiogenic gene expression postulates a post-transcriptional modulation of CXCR4. Conclusions: We for the first time show a treatment approach to reduce B19V-induced apoptosis. Telbivudine reverses B19V-induced dysregulation of BIRC3, thus, intervening in the apoptosis pathway and protecting susceptible cells from cell death. This approach could lead to an effective B19V treatment to reduce B19V-related disease.

Effect of assisted walking-movement in patients with genetic and acquired neuromuscular disorders with the motorised Innowalk device: an international case study meta-analysis.

People with physical disabilities (PD) suffer from consequences due to lack of physical activity and consequently, are at increased risk of chronic diseases. We aimed to evaluate the ability of a motorised assistive device for dynamic standing with weight-bearing in addition to standard state-of-the-art therapy to improve clinical outcome in a meta-analysis of available studies. A total of 11 studies were identified from different European countries analysing the effect of the dynamic device Innowalk. Raw data of nine studies were pooled including a total of 31 patients observed between 2009 and 2017. Standardised questionnaires and physical outcomes were examined in this exploratory meta-analysis. We recorded patients' characteristics, duration, intensity, and location of usage as well as general clinical outcomes and improvement of passive range of motion (PROM). The analysed population consisted in 90% cases of patients younger than 18 years of age. Patients were severely disabled individuals (aged 8 (6-10) years; 58% male; 67% non-ambulatory, 86% cerebral palsy). A total of 94% used the Innowalk in a home-based or day-care setting. For nearly all individuals (94%), improvements were recorded for: walking or weight-bearing transfer (n = 13), control/strength of the trunk or head (n = 6), joint mobility (n = 14), sleep (n = 4 out of 6/67%), or muscle strength (n = 17), vital functions (n = 16), bowel function (n = 10), attention/orientation (n = 2). PROM of the hip (flexion, abduction, and adduction) significantly (p < 0.001 for multiple comparisons) increased after 1 month (p < 0.05 flexion, adduction) and further after 5 months (p < 0.05 each) in contrast (p < 0.05 each) to a control group with state-of-the-art therapy. Similarly, PROM showed a trend towards improvement in dorsal extension of the ankle (p = 0.07). In summary, this is the first report of a novel device with additional benefit to standard therapy for severe PD. These intriguing results warrant the planned prospective randomised controlled trial to prove the concept and mechanism of action of this device.

Quality of anticoagulation with unfractionated heparin plus phenprocoumon for the prevention of thromboembolic complications in cardioversion for non-valvular atrial fibrillation. Sub-analysis from the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial.

INTRODUCTION: Anticoagulation in cardioversion for atrial fibrillation is performed using unfractionated heparin and oral anticoagulants. TEE-guided cardioversion, after achievement of therapeutic anticoagulation (1-3 days), may be an alternative to the traditional procedure (3-week anticoagulation followed by cardioversion). The quality of anticoagulation in atrial fibrillation has not been investigated in a randomised trial with TEE-guided cardioversion. We analysed respective data from the ACE trial on the quality of conventional anticoagulation, where most participating centres chose the TEE-guided approach. MATERIALS AND METHODS: In a randomised, prospective, multicentre trial, we analysed the efficacy of unfractionated heparin plus phenprocoumon in 248 patients on an intention-to-treat basis. There were 2373 evaluable anticoagulation measurements (out of 2925 measurements) and 4 categories of anticoagulation quality (under-, target, over- and severe over-anticoagulation). Of patients with evaluable measurements, 88% received short-term anticoagulation (4 weeks) in TEE-guided cardioversion. RESULTS: The median time to achieve therapeutic anticoagulation (aPTT> or =60 and <80 s or INR> or =2 and <3) was 3 days. Anticoagulation values were out of therapeutic range in 69.5% of measurements during 4- or 7-week follow-up, and never within therapeutic range in 10% of patients. Of the 15 primary endpoints observed (death, thromboembolism and major bleeding complications), only 3 were in patients with anticoagulation measurements within therapeutic range. CONCLUSIONS: In this study setting, with predominance of 4 weeks anticoagulation in TEE-guided cardioversion for atrial fibrillation, therapeutic anticoagulation was reached within 3 days using conventional anticoagulation. Despite careful dose adjustments, anticoagulation was out of therapeutic range in almost 70% of total measurements and 80% of primary endpoints.

Economic evaluation of enoxaparin for anticoagulation in early cardioversion of persisting nonvalvular atrial fibrillation: a statutory health insurance perspective from Germany.

OBJECTIVE: To estimate, from the perspective of Statutory Health Insurance (SHI, third-party payer) in Germany, the economic consequences of using the subcutaneous low-molecular-weight heparin (LMWH) enoxaparin instead of intravenous unfractionated heparin followed by oral phenprocoumon (UFH/PPC) for anticoagulation in patients undergoing transesophageal echocardiography (TEE)-guided early electrical cardioversion (ECV) of persisting nonvalvular atrial fibrillation (AF) without intracardiac clot. DESIGN AND SETTING: The incremental cost for the enoxaparin-based regimen versus the UFH/PPC-based regimen was chosen as the target variable. A decision-analytic model considering the in- and outpatient sectors was used to quantify the target variable. Resource use during in- and outpatient treatment was taken from the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial and from expert interviews with cardiologists in Germany in order to reflect the day-to-day conditions of clinical practice. Costs were given by SHI expenses for inpatient treatment and for medical services, drugs, disposables, and laboratory tests during outpatient treatment. These costs were determined by multiplying utilized resource items by the price or tariff of each item based on German healthcare regulations for the reference period of 2003/2004. According to the ACE trial, the evaluation encompassed 28 (26-30) treatment days with two consecutive phases. Phase I with 5 (3-12) days comprised diagnostics, start of anticoagulation, and ECV. Phase II with the remaining days consisted of continued anticoagulation and patient monitoring. The dosage of enoxaparin was 1 mg/kg bodyweight twice daily in treatment phase I followed by 40 mg twice daily with a bodyweight <65 kg or 60 mg twice daily with a BW > or =65 kg in treatment phase II. The daily dosages of UFH by continuous infusion and overlapping PPC were adjusted to an International Normalized Ratio of 2.0-3.0 in treatment phase I followed by 2.25mg PPC once daily in treatment phase II. Patients with any comorbidity and complication level (CCL) and those with low comorbidity and complications expected to occur in rare cases only (low-risk patients) were analyzed separately. In each base-case analysis, exclusively point estimates of all respective model parameters were applied. MAIN OUTCOME MEASURES AND RESULTS: There were savings of 339 euro and 579 euro per patient receiving the enoxaparin-based regimen versus the UFH/PPC-based regimen in the case of patients with any CCL and of low-risk patients, respectively (1 euro approximate, equals $US1.25; first quarter 2004 values). In comprehensive sensitivity analyzes, the robustness of the model and its results was shown. First, the impact of the model parameters on the target variable for each patient group was quantified in a deterministic model. Secondly, the dependency of the target variable on random variables was described for each patient group using Monte Carlo simulation. Irrespective of the patient group, the cost weight and the base rate of hospitals for inpatient ECV in phase I turned out to have the greatest impact on the savings obtained by the enoxaparin-based regimen. In the case of patients with any CCL, this impact was about 1.4-fold of that of the probability of enoxaparin patients undergoing outpatient ECV in phase I. In the case of low-risk patients, the impact of the cost weight and the base rate of hospitals for inpatient ECV in phase I was about 4.1-fold of that of the price of enoxaparin 60 mg prefilled syringes in the outpatient sector. In 79% and 93% of 10,000 simulated comparisons each versus the UFH/PPC-based regimen, there were savings obtained by the enoxaparin-based regimen in patients with any CCL and in low-risk patients, respectively. CONCLUSIONS: Results of this evaluation showed that an enoxaparin-based regimen for TEE-guided ECV of AF in patients without intracardiac clot offers SHI in Germany a considerable saving potential when used instead of an UFH/PPC-based regimen.

Enoxaparin injection for the treatment of high-risk patients with non-ST elevation acute coronary syndrome.

Non-ST elevation acute coronary syndrome (NSTE-ACS) refers to a cardiovascular disorder characterized by intracoronary thrombus formation on a disrupted atherosclerotic plaque with partial or transient occlusion. Generation of thrombin resulting from exposure of collagen leads to activation of platelets and conversion offibrinogen to fibrin, thus forming a platelet-rich thrombus. The main therapeutic objective is to protect the patient from thrombotic complications, independent of the choice of antithrombotic agents. The management of NSTE myocardial infarction (MI) is constantly evolving. For primarily conservative strategy, enoxaparin has been proven superior to unfractioned heparin (UFH). With early invasive strategy providing better clinical outcome compared with conservative strategy, the effectiveness of enoxaparin in reducing death and MI rates is now being reconsidered in the era of poly-pharmacotherapy, early percutaneous coronary interventions and drug eluting stents. Bleeding complications can be minimized by avoiding cross-over from UFH to enoxaparin or vice versa, or by reducing the dosage of enoxaparin. We review the studies of enoxaparin and discuss its current role in the contemporary treatment of NSTE-ACS.

Persistent weight loss with a non-invasive novel medical device to change eating behaviour in obese individuals with high-risk cardiovascular risk profile.

In evidence-based weight-loss programs weight regain is common after an initial weight reduction. Eating slowly significantly lowers meal energy intake and hunger ratings. Despite this knowledge, obese individuals do not implement this behaviour. We, thus tested the hypothesis of changing eating behaviour with an intra-oral medical device leading to constant weight reduction in overweight and obesity. Six obese patients (6 men, age 56 ± 14, BMI 29 ± 2 kg / m2) with increased CVRF profile were included in this prospective study. All patients had been treated for obesity during the last 10 years in a single centre and had at least 3 frustrate evidence-based diets. Patients received a novel non-invasive intra-oral medical device to slow eating time. Further advice included not to count calories, to avoid any other form of diet, to take their time with their meals, and to eat whatever they liked. This device was used only during meals for the first 4 to 8 weeks for a total of 88 [20-160] hours. Follow-up period was 23 [15-38] months. During this period, patients lost 11% [5-20%] (p<0.001) of their initial weight. At 12 months, all patients had lost >5%, and 67% (4/6) achieved a >10% bodyweight loss. In the course of the study, altered eating patterns were observed. There were no complications with the medical device. Of note, all patients continued to lose weight after the initial intervention period (p<0.001) and none of them had weight regain. With this medical device, overweight and obese patients with a history of previously frustrating attempts to lose weight achieved a significant and sustained weight loss over two years. These results warrant the ongoing prospective randomised controlled trial to prove concept and mechanism of action. TRIAL REGISTRATION: German Clinical Trials Register DRKS00011357.

Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair.

BACKGROUND: The maintenance of endothelial integrity plays a critical role in preventing atherosclerotic disease progression. Endothelial progenitor cells (EPCs) were experimentally shown to incorporate into sites of neovascularization and home to sites of endothelial denudation. Circulating EPCs may thus provide an endogenous repair mechanism to counteract ongoing risk factor-induced endothelial injury and to replace dysfunctional endothelium. METHODS AND RESULTS: In 120 individuals (43 control subjects, 44 patients with stable coronary artery disease, and 33 patients with acute coronary syndromes), circulating EPCs were defined by the surface markers CD34+KDR+ and analyzed by flow cytometry. Cardiovascular events (cardiovascular death, unstable angina, myocardial infarction, PTCA, CABG, or ischemic stroke) served as outcome variables over a median follow-up period of 10 months. Patients suffering from cardiovascular events had significantly lower numbers of EPCs (P<0.05). Reduced numbers of EPCs were associated with a significantly higher incidence of cardiovascular events by Kaplan-Meier analysis (P=0.0009). By multivariate analysis, reduced EPC levels were a significant, independent predictor of poor prognosis, even after adjustment for traditional cardiovascular risk factors and disease activity (hazard ratio, 3.9; P<0.05). CONCLUSIONS: Reduced levels of circulating EPCs independently predict atherosclerotic disease progression, thus supporting an important role for endogenous vascular repair to modulate the clinical course of coronary artery disease.

Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC) study.

BACKGROUND: Asymmetric dimethylarginine (ADMA) plasma levels have been shown to be elevated in diseases related to endothelial dysfunction such as hypertension, hyperlipidemia, diabetes mellitus, and others. It has been shown that ADMA predicts cardiovascular mortality in patients who have coronary heart disease (CHD). However, the question whether ADMA is an independent risk factor for CHD still remains unresolved. METHODS: The CARDIAC study is a multicenter case-control study, designed to detect differences in ADMA plasma levels between patients with CHD and controls from the general population. We included in our analysis 131 cases and 131 controls, matched for age, sex, and body mass index. RESULTS: We found that cases had higher ADMA plasma levels than controls (0.70 micromol/L [0.59-0.87 micromol/L] vs 0.60 micromol/L [0.54-0.69 micromol/L], P < .001). To evaluate the predictive power of ADMA regarding CHD, we calculated 2 multivariate logistic regression models including laboratory parameters and traditional risk factors. The odds ratio for ADMA in the multivariate model including the laboratory characteristics was 2.59 (1.61-4.17; P < .001); the odds ratio for the multivariate model including other risk factors was 6.04 (2.56-14.25; P < .001) for the third tertile (>0.72 micromol/L) versus the first (<0.58 micromol/L). CONCLUSIONS: We conclude from the results of our study that ADMA is an independent risk factor for CHD.

Early effects on endothelial function of atorvastatin 40 mg twice daily and its withdrawal.

Combined hyperlipidemia is associated with endothelial dysfunction. Atorvastatin has lipid-lowering and pleiotropic properties, including a protective effect on endothelial function. This study investigated the short- and medium-term effects of therapy with atorvastatin and of its discontinuation on lipid lowering and endothelial function. In 33 patients with combined hyperlipidemia who had been randomized and treated for 6 weeks with 40 mg of atorvastatin twice daily (n = 23) or placebo (n = 10), fasting lipid levels and flow-mediated dilation (FMD) of the brachial artery were measured at baseline, after 12 hours, 1 week, and 6 weeks during therapy, and 36 hours after discontinuation of therapy. Thereafter, all patients received 20 mg/day of atorvastatin for another 6 weeks. In the atorvastatin group, low-density lipoprotein cholesterol was decreased by 30% and 46% after 1 and 6 weeks, respectively (p <0.0001 for the 2 comparisons). In patients who already showed an impaired FMD at the beginning of the study (n = 15), atorvastatin caused a significant improvement in FMD, from 2.6% at baseline to 4.0% and 6.3% after 1 and 6 weeks, respectively (p <0.05 and <0.001). Thirty-six hours after withdrawal of atorvastatin, the FMD in this group decreased again to 2.8% (p <0.05), whereas low-density lipoprotein cholesterol level remained unchanged. The 6 patients with normal FMD at baseline showed no improvement in FMD during therapy or any decrease after withdrawal of the drug. In conclusion, only patients with endothelial dysfunction profit from high-dose atorvastatin treatment. When the treatment is abruptly discontinued, the effect on FMD disappears in 36 hours.

Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial.

BACKGROUND: Anticoagulation in cardioversion of atrial fibrillation is currently performed with unfractionated heparin (UFH) and oral anticoagulants, with or without guidance by transesophageal echocardiography (TEE). Low-molecular-weight heparins may reduce the risk of bleeding, may obviate the need for intravenous access, and do not require frequent anticoagulation monitoring. METHODS AND RESULTS: In a randomized, prospective multicenter trial, we compared the safety and efficacy of enoxaparin administered subcutaneously with intravenous UFH followed by the oral anticoagulant phenprocoumon in 496 patients scheduled for cardioversion of atrial fibrillation of >48 hours' and < or =1 year's duration. Patients were stratified to cardioversion with (n=431) and without (n=65) guidance by TEE. The study aimed to demonstrate noninferiority of enoxaparin compared with UFH+phenprocoumon with regard to the incidence of embolic events, all-cause death, and major bleeding complications. Secondary end points included successful cardioversion, maintenance of sinus rhythm until study end, and minor bleeding complications. Of 496 randomized patients, 428 were analyzed per protocol. Enoxaparin was noninferior to UFH+phenprocoumon with regard to the incidence of the composite primary end point in a per-protocol analysis (7 of 216 patients versus 12 of 212 patients, respectively; P=0.016) and in an intention-to-treat analysis (7 of 248 patients versus 12 of 248 patients, respectively; P=0.013). There was no significant difference between the 2 groups in the number of patients reverted to sinus rhythm. CONCLUSIONS: Enoxaparin is noninferior to UFH+phenprocoumon for prevention of ischemic and embolic events, bleeding complications, and death in TEE-guided cardioversion of atrial fibrillation. Its easier application and more stable anticoagulation may make it the preferred drug for initiation of anticoagulation in this setting.

Soluble vascular endothelial growth factor, soluble VEGF receptor Flt-1 and endothelial function in healthy smokers.

OBJECTIVE: To relate levels of vascular endothelial growth factor (VEGF) and its soluble receptor, sFlt-1, with endothelial function in healthy smokers. METHODS: Plasma levels of VEGF and sFlt-1 were measured by ELISA in 22 healthy smokers and 22 matched healthy non-smoking controls, and compared to flow- (FMD) and acetylcholine-mediated (AMD) vasodilatation (endothelial-dependent) (EDV) and nitroglycerine-mediated (NMD) vasodilatation (endothelial-independent) of lower extremities were measured with plethysmography. RESULTS: Smokers and controls had similar plasma VEGF levels, but sFlt-1 levels were lower in smokers than in controls (p<0.01). AMD was lower in smokers compared to controls (p<0.05), but FMD and NMD levels were similar. Smokers and controls with high AMD (>12 ml/100 ml tissue/min) had significantly lower plasma VEGF levels (p<0.001). An inverse correlation was found in both groups, between VEGF and AMD (smokers: r=-0.6, p<0.01; controls: r=-0.71, p<0.005) and with FMD (smokers: r=-0.56, p<0.05; controls: r=-0.58, p<0.005). There were no significant correlations between sFlt-1 with VEGF levels or endothelial-dependent dilatation. CONCLUSION: In conclusion, healthy smokers demonstrate abnormal AMD, and an inverse correlation between plasma VEGF levels (but not sFlt-1) with indices of endothelial dysfunction (FMD and AMD) exists. VEGF, and not sFlt-1, may be related to the pathogenesis of endothelial dysfunction in healthy smoking individuals.