Abstract only Detection of the vasculotropic parvovirus B19 (B19V) in endomyocardial biopsies (EMB) is strongly associated with endothelial dysfunction and coronary vasospasms mimicking acute ...myocardial infarction. B19V replicates primarily in erythroblasts in bone marrow (BM). Endothelial progenitors (EPC) mobilised from BM participate in endothelial cell (EC) regeneration. We, therefore, tested the hypothesis of a systemic EC damage with a direct influence of B19V on EPC and endothelial regeneration. Circulating apoptotic mature endothelial cells (CMAEC; CD45 − CD146 + vWF + Ann + ) and CD45 dim CD34 + KDR + -EPC were quantified from blood by FACS analysis. In 12 patients with B19V (>500 copies/ μ g DNA) in EMB, numbers of CMAEC (27±12.8/ μ l) were 6fold higher compared to 9 healthy controls (p<0.05). There were no transcoronary gradients (TCG) of CMAEC, in contrast (p<0.05) to patients with troponin T negative acute coronary syndromes (n=11; +150%; p<0.05), pointing to a systemically induced EC damage. EPC were significantly higher in patients with B19V compared to controls (0.24±0.1%/PMNC vs. 0.008±0.001%/PMNC; p<0.05). In contrast, EPC-function (CFU-Hill) was reduced in these patients (p<0.05). There was a strong trend towards a negative TCG (−33%±40%, p=0.051) of EPC. Intracardiac SDF-1 α mRNA was 4.6-fold (p<0.05) and CXCR4 mRNA was twofold (p<0.05) increased in B19V+-patients compared to controls, further supporting the hypothesis of a continuous homing. In a second study, CD34 + KDR + -EPC of these patients (n=7) were magnetically separated from BM and blood and B19V DNA with qPCR compared to 5 controls. Compared to controls, only patients had B19V DNA in BM and blood (21399±10378 vs. 16±12 copies/ug DNA in CD34 − , p<0.05) and documenting replication intermediates of B19V, mRNA was detected in CD34 + KDR + -EPC (4 – 1435 copies cDNA/ μ g DNA) in BM and blood. Indeed, in one patient with highest copy numbers of B19V mRNA in CD34 + KDR + in blood, B19V mRNA was detected in EMB. Thus, for the first time we present a virally-induced systemic endothelial damage and B19V infection in EPC with replication intermediates. Continuous circulation of BM-derived, B19V-infected EPC could contribute to impaired endothelial regeneration.
Abstract 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 ≥ 60 and < 80 s or INR ≥ 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
1 Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany, 2 Division of Clinical Immunology and Allergy, University of Florence, Florence, Italy
...Submitted 1 November 2006
; accepted in final form 9 January 2007
Regulatory T cells (T reg ) migrate into allografts and induce tolerance of the graft. Immunosuppressive T reg are found among CD4 + CD25 ++ T cells and specifically express the forkhead/winged transcription factor FOXP3. We hypothesized that activated T cells and T reg might modulate the ongoing inflammation of the cardiac allograft (CA) and that the chronic inflammatory environment might influence the balance between these distinct cell types. We therefore quantified levels of activated T cells and CD4 + CD25 ++ T reg in the cardiac and systemic circulation in heart transplant recipients. To determine the influence of the allograft passage on these cells, transcardiac gradients were evaluated in CA recipients ( n = 22) compared with controls ( n = 18). Systemic levels of circulating T reg were significantly lower in CA recipients (8.9 ± 1.3 µl) compared with controls (15.8 ± 1.6 µl; P = 0.002). Similarly, the proportion of T reg related to the total leukocyte number was significantly lower in CA recipients ( P < 0.01). In contrast, systemic levels of circulating activated CD4 + T cells and of circulating plasmacytoid dendritic cells were similar in both groups. In transplant patients, numbers of T reg significantly decreased during transcardiac passage (3.0 ± 0.3 to 2.4 ± 0.3% of CD4 + T cells, P < 0.01), and FOXP3 + T cells invaded into the allograft. In contrast, numbers of activated CD4 + T cells increased during passage through the allograft, even in the presence of effective immunosuppression. In conclusion, numbers of circulating immunosuppressive T reg are reduced in transplant recipients. Recruitment of T reg into the cardiac allograft during transcoronary passage may induce graft tolerance during subclinical inflammation potentially influencing allograft vasculopathy.
coronary circulation; chronic inflammation
Address for reprint requests and other correspondence: S. Dimmeler or A. M. Zeiher, Dept. of Internal Medicine III, Division of Cardiology, J. W. Goethe Univ., Theodor-Stern-Kai 7, 60590 Frankfurt, Germany (e-mail: dimmeler{at}em.uni-frankfurt.de )
Regulatory T cells (T sub(reg)) migrate into allografts and induce tolerance of the graft. Immunosuppressive T sub(reg) are found among CD4 super(+)CD25 super(++) T cells and specifically express the ...forkhead/winged transcription factor FOXP3. We hypothesized that activated T cells and T sub(reg) might modulate the ongoing inflammation of the cardiac allograft (CA) and that the chronic inflammatory environment might influence the balance between these distinct cell types. We therefore quantified levels of activated T cells and CD4 super(+)CD25 super(++) T sub(reg) in the cardiac and systemic circulation in heart transplant recipients. To determine the influence of the allograft passage on these cells, transcardiac gradients were evaluated in CA recipients (n = 22) compared with controls (n = 18). Systemic levels of circulating T sub(reg) were significantly lower in CA recipients (8.9 plus or minus 1.3 mu l) compared with controls (15.8 plus or minus 1.6 mu l; P = 0.002). Similarly, the proportion of T sub(reg) related to the total leukocyte number was significantly lower in CA recipients (P < 0.01). In contrast, systemic levels of circulating activated CD4 super(+) T cells and of circulating plasmacytoid dendritic cells were similar in both groups. In transplant patients, numbers of T sub(reg) significantly decreased during transcardiac passage (3.0 plus or minus 0.3 to 2.4 plus or minus 0.3% of CD4 super(+) T cells, P < 0.01), and FOXP3 super(+) T cells invaded into the allograft. In contrast, numbers of activated CD4 super(+) T cells increased during passage through the allograft, even in the presence of effective immunosuppression. In conclusion, numbers of circulating immunosuppressive T sub(reg) are reduced in transplant recipients. Recruitment of T sub(reg) into the cardiac allograft during transcoronary passage may induce graft tolerance during subclinical inflammation potentially influencing allograft vasculopathy.
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.
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.
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.
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Shear stress modulates vascular structure and function through cytoskeletal remodeling and activation of signaling cascades. Elevated vascular endothelial growth factor (VEGF) concentrations are seen ...in atherosclerotic disease and after active increase of perfusion. Levels of soluble vascular cell adhesion molecule (sVCAM-1) are increased in atherosclerotic disease without strict correlation to disease progression. In vitro, increased shear stress induces a biphasic response of sVCAM-1. No data are available on in vivo downregulation of VEGF or sVCAM-1 in humans. In 24 healthy individuals, vascular function of lower extremities was assessed by plethysmography measuring flow-mediated dilation and through intra-arterial infusion of acetylcholine and nitroglycerine. Ten healthy individuals were challenged with cycle exercise testing. Cytokines were measured from citrate plasma from cubital and femoral vein blood. Plasma concentrations of VEGF and sVCAM-1 correlated with endothelium-dependent dilation. Two hours after acetylcholine-induced shear stress, plasma concentrations of sVCAM-1 levels were reduced by 31% (p <.001) locally and 18% (p <.05) systemically. Nitroglycerine produced similar local and systemic suppression (36% and 34%; p <.0001). Immediately after exercise, concentrations of sVCAM-1 increased with a significant decrease one hour later (-9%; p <.01). VEGF increased after infusion of nitroglycerine (+35%; p <.05) and dropped after 1 h of 30-min exercising (-31%, p <.05). This is the first study to show changes of sVCAM-1 in vivo. Changes of VEGF and sVCAM-1 in humans seem time, magnitude, and substance specific. Short acting suppression of VEGF and SVCAM-1 under physiological conditions may explain exercise-induced vascular protection and the lack of correlation of these cytokines with activity of atherosclerotic disease.
Shear stress modulates vascular structure and function through cytoskeletal remodeling and activation of signaling cascades. Elevated vascular endothelial growth factor (VEGF) concentrations are seen ...in atherosclerotic disease and after active increase of perfusion. Levels of soluble vascular cell adhesion molecule (sVCAM-1) are increased in atherosclerotic disease without strict correlation to disease progression. In vitro, increased shear stress induces a biphasic response of sVCAM-1. No data are available on in vivo downregulation of VEGF or sVCAM-1 in humans. In 24 healthy individuals, vascular function of lower extremities was assessed by plethysmography measuring flow-mediated dilation and through intra-arterial infusion of acetylcholine and nitroglycerine. Ten healthy individuals were challenged with cycle exercise testing. Cytokines were measured from citrate plasma from cubital and femoral vein blood. Plasma concentrations of VEGF and sVCAM-1 correlated with endothelium-dependent dilation. Two hours after acetylcholine-induced shear stress, plasma concentrations of sVCAM-1 levels were reduced by 31% ( p < .001) locally and 18% ( p < .05) systemically. Nitroglycerine produced similar local and systemic suppression (36% and 34%; p < .0001). Immediately after exercise, concentrations of sVCAM-1 increased with a significant decrease one hour later ( m 9%; p < .01). VEGF increased after infusion of nitroglycerine (+35%; p < .05) and dropped after 1 h of 30-min exercising ( m 31%, p < .05). This is the first study to show changes of sVCAM-1 in vivo. Changes of VEGF and sVCAM-1 in humans seem time, magnitude, and substance specific. Short acting suppression of VEGF and SVCAM-1 under physiological conditions may explain exercise-induced vascular protection and the lack of correlation of these cytokines with activity of atherosclerotic disease.
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