Prognostic markers of all-cause mortality in patients with atrial fibrillation: data from the prospective long-term registry of the German Atrial Fibrillation NETwork (AFNET).

AIMS: Atrial fibrillation (AF) is associated with a high risk of cardiovascular and non-cardiovascular death, even on anticoagulation. It is controversial, which conditions-including concomitant diseases and AF itself-contribute to this mortality. To further clarify these questions, major determinants of long-term mortality and their contribution to death were quantified in an unselected cohort of AF patients. METHODS AND RESULTS: We established a large nationwide registry comprising 8833 AF-patients with a median follow-up of 6.5 years (45 345 patient-years) and central adjudication of adverse events. Baseline characteristics of the patients were evaluated as predictors of mortality using Cox regression and C-indices for determination of predictive power. Annualized mortality was highest in the first year (6.2%) and remained high thereafter (5.2% in men and 5.5% in women). Thirty-eight percent of all deaths were cardiovascular, mainly due to heart failure or sudden death. Sex-specific age was the strongest predictor of mortality, followed by concomitant cardiovascular and non-cardiovascular conditions. These factors accounted for 25% of the total mortality beyond age and sex and for 84% of the mortality differences between AF types. Thus, the electrical phenotype of the disease at baseline contributed only marginally to prediction of mortality. CONCLUSION: Mortality is high in AF patients and arises primarily from heart failure, peripheral artery disease, chronic obstructive lung disease, chronic kidney disease, and diabetes mellitus, which, therefore, should be targeted to lower mortality. Parameters related to the electrical manifestation of AF did not have an independent impact on long-term mortality in our representative cohort.

Association of echocardiographic atrial size and atrial fibrosis in a sequential model of congestive heart failure and atrial fibrillation.

BACKGROUND: Cardioversion (CV) success of atrial fibrillation (AF) inversely correlates to the size of the left atrium (LA). Atrial fibrillation and its most important risk factor, congestive heart failure (CHF), both induce atrial structural enlargement and fibrosis. To investigate the effect of AF and CHF on atrial dilatation and fibrosis, and to estimate whether echocardiographically determined atrial size may be used as a marker for atrial fibrosis. METHODS: In six dogs, pacemakers were implanted followed by HIS bundle ablation. After 4 weeks of rapid ventricular stimulation (185 bpm) for CHF induction, additional rapid atrial stimulation (500 bpm) was maintained for 7 weeks to induce AF. Serial determinations of echocardiographic atrial size were performed. Seven dogs with sinus rhythm served as histological controls. Postmortem tissue was obtained to determine the degree and composition of atrial fibrosis. RESULTS: While the ejection fraction of the AF/CHF dogs decreased significantly from 57+/-5% to 19+/-7% (P<.01), an increased degree of atrial fibrosis was found (right atrium [RA], 4.9+/-2.0% to 19.9+/-5.4%; LA, 4.4+/-1.6% to 22.2+/-3.2%; P<.01), accompanied by a significant increase of atrial volumes (LA: 21+/-4 to 44+/-4 mm3; P<.01; RA: 10+/-3 to 18+/-6 mm3; P<.05) and LA diameters (34+/-4 to 43+/-2 mm, P<.05). Atrial fibrosis and size significantly correlated. CONCLUSIONS: Atrial fibrillation/CHF leads to a significant atrial fibrosis and dilation. The increased echocardiographic size correlates to the degree of atrial fibrosis and may be used as clinical marker for atrial fibrosis. The fibrosis accompanying atrial dilatation may also explain why LA size, as determined by echocardiography, is a strong predictor of CV success.

Efficacy of transesophageal defibrillation in ventricular fibrillation of long duration.

INTRODUCTION: Increasing duration of ventricular fibrillation (VF) is associated with a higher risk of ineffective resuscitation. In addition, precountershock chest compression can influence defibrillation success. Transesophageal defibrillation may increase defibrillation success because of the proximity of the esophagus to the heart. We evaluated the efficacy of transesophageal defibrillation compared with standard transthoracic defibrillation after long episodes of VF. METHODS: Defibrillation success after 10 minutes of untreated VF was evaluated in 12 sheep randomized into 2 groups: (group A) in 6 sheep, up to 3 transthoracic shocks were applied, followed by up to 3 transesophageal shocks (first shock: 150 J, second and third shocks: 200 J). (group B) In 6 sheep, 2 minutes of precountershock chest compression preceded the defibrillation shocks. Truncated biphasic shocks were delivered between a sternal and an apical patch electrode for transthoracic defibrillation and between an esophageal and a cutaneous patch electrode for transesophageal defibrillation. RESULTS: In group A with no precountershock chest compression, external defibrillation failed despite shocks with maximum energy (200 J) in all 6 sheep. Transesophageal defibrillation was successful in 3 sheep (50%). In group B with precountershock chest compression, external defibrillation failed in all 6 sheep. Transesophageal defibrillation was successful with the first shock in all 6 sheep. CONCLUSIONS: Transesophageal defibrillation may terminate VF of long duration that is refractory to standard defibrillation. Precountershock chest compression may increase transesophageal defibrillation success.

Reduced numbers of circulating endothelial progenitor cells in patients with coronary artery disease associated with long-term statin treatment.

While statin treatment may transiently mobilize endothelial progenitor cells (EPCs), the dose-dependent effects of a continuous statin therapy on EPCs in patients with chronic coronary artery disease (CAD) have not been analyzed. In 209 patients with angiographically documented CAD, 144 of which received 10-40 mg/day of statins for >8 weeks, the EPC number was determined by flow cytometry directly (CD34(+)/KDR(+), n=58) and after in vitro-culture (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled Ac-LDL (DiI-Ac-LDL(+))/lectin(+), n=209). EPC function was assessed by the formation of colony forming units (CFUs). Univariate analysis revealed that the dose of continuous statin therapy inversely correlated with the EPC number. Treatment with 40 mg/day significantly reduced EPC counts. Multivariate analysis unveiled the statin dose and extent of CAD as independent predictors of reduced EPC numbers. Conversely, obesity predicted increased counts, while CFU development was not detectable in all patients and augmented in females and smokers but not in statin-treated patients. Compared with matched controls, statin-treated patients showed significantly reduced absolute and relative EPC counts. In a prospective analysis, initiation of statin therapy significantly diminished the number of circulating and isolated EPCs after 3 but not after 1 month(s). Thus, the statin dose during chronic and continuous treatment independently predicts reduced numbers of circulating as well as isolated EPCs in patients with CAD.

Decreased plasminogen activator inhibitor and tissue metalloproteinase inhibitor expression may promote increased metalloproteinase activity with increasing duration of human atrial fibrillation.

INTRODUCTION: Atrial fibrosis has been shown to concur with the persistence of atrial fibrillation (AF) and is only incompletely reversible, thus counteracting attempts to restore and maintain sinus rhythm (SR). Besides the angiotensin system, the matrix metalloproteinases (MMP) play a major role in the pathogenesis of fibrosis. Thus, the present study investigated changes of the MMP system during the development of human AF. METHODS AND RESULTS: Right atrial appendages of 146 patients were excised during heart surgery and grouped according to rhythm (SR vs AF) and AF duration. Hydroxyproline as a surrogate for collagen content and morphometrically determined collagen content increased significantly from SR (14.3 +/- 7.7%) to chronic permanent AF (CAF) of 6-24 months (21.2 +/- 9.2%, P = 0.02), and CAF of > 60 months (25.3 +/- 4.7%, P < 0.01). From SR to paroxysmal and chronic persistent AF (CPAF) and to CAF MMP-2 and MMP-9 activity rose, while their mRNA and protein levels were not altered significantly. Plasminogen activator inhibitor (PAI), an inhibitor of a potent activator of many MMPs, was significantly decreased with increasing duration of AF. In parallel, the mRNA levels of the tissue inhibitors of MMPs TIMP-1 and -2 decreased significantly. CONCLUSION: Human atrial fibrogenesis is enhanced with increasing duration of AF: a longer AF duration is associated with elevated atrial interstitial MMP activity, but decreased PAI and TIMP expression.

Simultaneous transesophageal cardioversion and echocardiography: feasibility and safety.

BACKGROUND: Transesophageal echocardiography (TEE) is routinely used to exclude atrial thrombus prior to cardioversion of atrial fibrillation (AF). Because the TEE probe lies adjacent to the atria, cardioversion using an electrode attached to the TEE probe should allow for immediate low-energy transesophageal cardioversion. OBJECTIVE: The purpose of this study was to evaluate a cardioversion electrode sheath that can be affixed to conventional TEE probes for simultaneous thrombus exclusion and cardioversion of AF. METHODS: A thin electrode was integrated into a latex or polyurethane sheath covering a conventional TEE probe. TEE thrombus exclusion and biphasic transesophageal cardioversion using a step-up protocol were performed during deep sedation. Esophagoscopy was performed immediately after cardioversion and after 1 week. RESULTS: TEE was performed in 27 patients. One patient showed left atrial thrombi. Transesophageal cardioversion was successful in 25 of the remaining 26 patients. Mean atrial cardioversion threshold was 63 +/- 48 J. Transesophageal cardioversion restored sinus rhythm in two patients with unsuccessful transthoracic cardioversion. Transesophageal cardioversion in deep sedation was well tolerated. Esophagoscopy revealed slight mucosal damage in three patients at the site of shock application; two of these patients showed signs of gastroesophageal reflux disease. Mucosal damage unrelated to the site of shock delivery was noted in three patients. CONCLUSION: Atrial thrombus exclusion and transesophageal cardioversion of AF via a disposable cardioversion sheath offers the opportunity to perform transesophageal cardioversion and TEE thrombus exclusion during one sedation. It may not be suitable for use in patients with gastroesophageal reflux disease. Transesophageal cardioversion may establish sinus rhythm in selected patients refractory to transthoracic cardioversion.

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.

Single-step atrial thrombus exclusion and transesophageal cardioversion in atrial fibrillation.

Atrial fibrillation (AF), the most common arrhythmia, has a major impact on both patient morbidity and healthcare economics. Hospital admissions due to AF have risen by two-thirds in the last 20 years. This is due mainly to an aging population and an increasing prevalence of chronic heart disease. Strategies for the management of AF include prevention of thromboembolism, rate control and correction of the arrhythmia. Electrical cardioversion as one component of the treatment of AF requires the absence of atrial thrombi. Transesophageal echocardiography is used routinely for exclusion of atrial thrombi prior to cardioversion in many hospitals. This review presents preliminary data on the clinical use of devices for simultaneous transesophageal echocardiography and transesophageal cardioversion.

Angiotensin II antagonist in paroxysmal atrial fibrillation (ANTIPAF) trial: rationale and study design.

BACKGROUND AND OBJECTIVE: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Recent experimental data and retrospective analyses of clinical trials suggest that increased levels of angiotensin II can induce an arrhythmogenic atrial substrate, which favours the occurrence of AF. The purpose of the ANTIPAF (Angiotensin II Antagonist in Paroxysmal Atrial Fibrillation) trial is to prove the principal concept that blockade of angiotensin II type 1 receptors with olmesartan medoxomil 40 mg/day suppresses paroxysmal AF episodes during a 12-month follow-up. The ANTIPAF trial is the first placebo-controlled trial analysing the occurrence of AF as the primary study endpoint. METHODS: Examination of the study hypothesis in a prospective, randomised, placebo-controlled, double-blind group comparison in patients with documented paroxysmal AF (total of 422 patients) stratified by beta-adrenoceptor antagonist use. The primary endpoint of the study is the percentage of days with documented episodes of paroxysmal AF identified on daily transtelephonic tele-ECG recordings. Patients will record and transmit at least one 1-minute ECG per day independent of symptoms. Furthermore, tele-ECG recordings will be transmitted in any case of symptomatic AF. The present paper summarises the rationale and design of the ANTIPAF trial.

Statin treatment after onset of sepsis in a murine model improves survival.

BACKGROUND: HMG-CoA-reductase inhibitors have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering. We have recently demonstrated that pretreatment with simvastatin profoundly improves survival in a cecal ligation and perforation (CLP) model of sepsis. Here, we studied whether treatment with simvastatin after onset of sepsis-induced hemodynamic alterations is beneficial and whether prolonged survival can also be achieved with other statins. METHODS AND RESULTS: Mice were rendered septic by CLP. At 6 hours after sepsis induction, when profound hemodynamic alterations were manifest, treatment with atorvastatin, fluvastatin, pravastatin, simvastatin, or placebo was initiated. Except for fluvastatin (27+/-2.3 hours), survival time was extended from 23+/-1.2 hours for placebo-treated mice to 37+/-3.6 hours for simvastatin-treated, to 40+/-4.2 hours for atorvastatin-treated, and to 39+/-3.9 hours for pravastatin-treated mice. This profound improvement is based on the preservation of cardiac function and hemodynamic status in statin-treated animals, both of which are severely impaired in untreated CLP mice. As underlying mechanisms, improved susceptibility to endothelial nitric oxide synthase stimulation and reduced endothelial adhesion of leukocytes could be demonstrated after statin treatment. CONCLUSIONS: Well established in the treatment of lipid disorders and coronary artery disease, statins harbor the additional and novel potential of effective sepsis treatment. This benefit extends to several but not all statins tested.

Association of C-reactive protein and myocardial perfusion in patients with ST-elevation acute myocardial infarction.

This study sought to evaluate the relation between C-reactive protein (CRP) on admission of patients with acute myocardial infarction (AMI) and myocardial perfusion as defined by postintervention angiographic myocardial blush grade (MBG) and their impact on subsequent mortality. The patient population comprised 191 consecutive patients with AMI undergoing PTCA within 12h of symptom onset on a native vessel. Patients were divided based on the CRP level on admission (Rolf Greiner BioChemica, Germany, cutpoint for the assay CRP: 5mg/l) into a group with elevated CRP (>or=5mg/l) and a group with normal CRP. Angiographic myocardial blush grade (MBG) after revascularization of the infarct-related artery was determined to evaluate myocardial reperfusion. Revascularization of the infarct-related artery was successful in 176 (92.6%) patients. The frequency of impaired perfusion (MBG 0-2) was higher in the elevated CRP group than in the normal CRP group (74.5% versus 59.7%, respectively, p=0.046). Elevated CRP on admission was an independent predictor of impaired myocardial perfusion (MBG 0-2, OR 1.92, 95% CI 1.02-4.01, p=0.042) in addition to age >70 years. Elevated CRP (OR 2.64, 95% CI 1.26-5.53, p=0.009) and MBG 0-2 (OR 4.58; 95% 1.73-12.20, p=0.002) were independent predictors of mortality during a 22.4+/-15.3 months follow-up in addition to heart rate on admission >100 beats/min (OR 3.07; 95% CI 1.30-7.25, p=0.009). In sequential Cox models, the predictive power of clinical data and MBG for mortality (model chi-squared 18.3) was strengthened by the inclusion of CRP levels (model chi-squared 24.3). In conclusion, there is a relation between elevated admission CRP and impaired reperfusion in the myocardium subtended to the infarct-related artery. The combination of clinical data, myocardial reperfusion levels after primary angioplasty for AMI and admission CRP increases the predictive value for subsequent survival.

A double-blind, randomized, placebo-controlled multicenter clinical trial to evaluate the effects of the angiotensin II receptor blocker candesartan cilexetil on intimal hyperplasia after coronary stent implantation.

BACKGROUND: Preclinical data suggest beneficial effects of angiotensin II receptor blockers (ARBs) on neointima formation after vascular injury. Preliminary clinical data, however, revealed conflicting results. The AACHEN trial was a double-blind, randomized, placebo-controlled clinical multicenter trial to evaluate the effects of candesartan cilexetil on intimal hyperplasia after coronary stent implantation. METHODS: A total of 120 patients (61 +/- 9 years, 83% male) were randomized to receive either 32 mg candesartan cilexetil (active) or placebo starting 7 to 14 days before elective coronary stent implantation. A follow-up angiography including intravascular ultrasound assessment of the target lesion was performed 24 +/- 2 weeks after stent implantation. The primary end point was defined as the difference in neointimal area between groups as assessed by intravascular ultrasound. Secondary end points included differences in angiographic parameters (ie, restenosis rate) and incidence of major cardiac events. RESULTS: The mean stent length measured 15.0 +/- 4.9 mm in the active and 14.6 +/- 5.7 mm in the placebo group (P = .81). There was no significant difference in neointimal area between groups (2.1 +/- 1.0 vs 2.1 +/- 1.5 mm2, P = 1.00), nor were there differences in angiographic end point parameters. Major cardiac event rates were not significantly different between treatment groups (8% vs 11%, P = .75). CONCLUSIONS: High-dose candesartan cilexetil therapy in patients with symptomatic coronary artery disease undergoing coronary stent implantation does not reduce clinical event rates, restenosis rates, or neointimal proliferation after elective stent implantation.

Relation of end-diastolic wall thickness and the residual rim of viable myocardium by magnetic resonance imaging to myocardial viability assessed by fluorine-18 deoxyglucose positron emission tomography.

End-diastolic wall thickness (EDWT) and thickness of the residual non-contrast-enhanced myocardial rim have been suggested as markers for the assessment of myocardial viability by cardiovascular magnetic resonance (CMR) imaging. This study compared these parameters as derived from contrast-enhanced CMR images for the prediction of myocardial viability as determined by fluorine-18 deoxyglucose positron emission tomography (FDG-PET). Twenty-two patients with ischemic cardiomyopathy (ejection fraction 31 +/- 11%) were investigated. For contrast-enhanced CMR imaging, a standard inversion-recovery sequence was used. FDG-PET was performed using a hyperinsulinemic-euglycemic clamp. Data were analyzed with a 17-segment model. Of 146 severely dysfunctional segments, 112 were assessed as viable and 34 as nonviable by nuclear imaging. Using receiver-operator characteristic analysis, areas under the curve were 0.95 for unenhanced myocardial rim (95% confidence interval 0.92 to 0.98) and 0.86 for EDWT (95% confidence interval 0.80 to 0.93, p <0.001 vs unenhanced myocardial rim) for the prediction of viability as assessed by FDG-PET. Cutoffs of 5.4 mm for EDWT and 3.0 mm for unenhanced myocardial rim were found to optimally differentiate viability by FDG-PET. In 25 segments with divergent results, 94% of segments with an EDWT < or =5.4 mm and an unenhanced myocardial rim >3.0 mm were scored as viable by FDG-PET, whereas 57% of segments with an EDWT >5.4 mm and an unenhanced myocardial rim < or =3.0 mm were scored nonviable with the reference technique. In conclusion, unenhanced myocardial rim is superior to EDWT for the prediction of myocardial viability as determined by FDG-PET and may be clinically useful for assessment of myocardial viability in patients with ischemic cardiomyopathy and regional wall thinning.

Comparison of coronary restenosis rates in matched patients with versus without diabetes mellitus.

Diabetes mellitus (DM) is an established risk factor for stent restenosis, in part as a result of the smaller vessel dimensions and longer lesions. This study compared the magnitude of acute lumen gain and late lumen loss after elective coronary stent implantation in patients with and without DM using a matched-pair analysis. A total of 133 patients with DM and 192 coronary lesions were included in this analysis. A group of 192 lesions in 182 patients without DM were matched in a pairwise fashion, stratifying for reference diameter, minimal luminal diameter, and lesion length. The binary restenosis rate at the 5-month follow-up angiography was 25% in the DM group and 14% in the non-DM group (p <0.01). Acute angiographic lumen gain (1.47 +/- 0.41 vs 1.56 +/- 0.38 mm, p = 0.03) and late lumen loss (0.64 +/- 0.42 vs 0.55 +/- 0.36 mm, p = 0.02) were significantly different between the DM and non-DM groups. In conclusion, suboptimal acute procedural results and an exaggerated neointimal proliferation contributed by about 50% to the lower net lumen gain in the DM group. Patients with DM had a significantly higher restenosis rate even when matched for preprocedural angiographic lesion dimensions. Mechanistically, inferior procedural results, as well as exaggerated neointimal proliferation, are, quantitatively, equally important in this process.

The value of cardiopulmonary exercise testing and brain natriuretic peptide plasma levels in predicting the prognosis of patients with chronic heart failure.

BACKGROUND: A peak VO2 above 14 ml/min/kg at cardiopulmonary exercise testing and brain natriuretic peptide (BNP) levels is used to estimate survival in patients with chronic heart failure (CHF). Limited data, however, exist comparing the prognostic value of both markers simultaneously in patients with mild to moderate CHF. METHODS: We prospectively studied 85 consecutive patients (59+/-13 years, 63 men) with CHF (mean LVEF 26+/-6%). All patients underwent cardiopulmonary exercise testing with determination of peak VO2 and measurement of plasma BNP at rest. The incidence of cardiac decompensation and cardiac death was recorded in the follow-up. RESULTS: During a mean follow-up of 427+/-150 days, four deaths and ten cardiac decompensations occurred. Kaplan-Meier estimates of freedom from clinical events differed significantly for patients above and below the median BNP of 292 pg/ml and also for patients above and below a peak VO2 of 14 ml/min/kg (p<0.05 each). BNP and peak VO2 (area under the ROC 0.75 vs. 0.72) showed a comparable discrimination of CHF patients with adverse cardiac events. The prognostic information of BNP was at least as powerful as that derived from peak VO2. A BNP above 324 pg/ml was associated with a risk ratio of 8.8 for adverse cardiac events. CONCLUSIONS: In patients with mild to moderate CHF, BNP measurements appear to be an alternative to peak VO2 determined by cardiopulmonary exercise testing for the assessment of prognosis in CHF. BNP may facilitate the ambulatory management of patients with mild to moderate CHF since it is less expensive, less time-consuming, and free of procedural risk compared to exercise testing.

Multicentre evaluation of a rule-based data filter for home monitoring of implanted cardioverter defibrillators.

We developed a rule-based data filter for the automatic interpretation of data transmitted from implantable cardioverter defibrillators (ICDs). The feasibility and user acceptability of the data filter were tested in a multicentre study. Fifteen European centres analysed 10 cases each. The cases represented ICD follow-up findings, e.g. new tachycardia, battery depletion or sensing defects. The mean follow-up period was 68 days (SD 35). A questionnaire was used to collect information regarding the functionality and general concept of automatic data interpretation. A score of five or above (range 1-9) was classified as acceptable. According to the questionnaires, there was a high degree of satisfaction with the general concept of automatic data interpretation (mean 6.7, SD 1.2) and with user guidance (mean 7.1, SD 0.8). Safety (mean 7.0, SD 1.4) and accuracy (mean 6.7, SD 1.4) of the evaluation of device-related and clinical problems were regarded as high. Support in daily routine was considered to be high (mean 7.3, SD 1.1) as the system was easy to understand (mean 7.5, SD 0.9). The results indicated a high user acceptance with easy system handling.

HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis.

BACKGROUND: HMG-CoA reductase inhibitors, such as simvastatin, have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering but to date have not been used to treat severe inflammatory disease such as sepsis. We thus approached the question of whether treatment with simvastatin might improve cardiovascular function and survival in sepsis. METHODS AND RESULTS: Mice treated with simvastatin and rendered septic by cecal ligation and perforation (CLP) show a mean survival time close to 4 times the value found in untreated mice. This dramatic improvement is based on a complete preservation of cardiac function and hemodynamic status, which are severely impaired in untreated CLP mice [eg, 20 hours after CLP, cardiac output declined from 1.24+/-0.09 to 0.87+/-0.11 mL x min(-1) x g(-1) in untreated mice (P<0.005; n=12), while remaining unaltered (1.21+/-0.08 mL x min(-1) x g(-1) at baseline and 1.15+/-0.1 mL x min(-1) x g(-1) 20 hours after CLP, P=NS, n=12) in CLP mice treated with simvastatin]. Untreated CLP mice remained refractory to beta-stimulation, whereas the responsiveness to dobutamine was restored by treatment with simvastatin. Susceptibility of coronary flow to endothelial nitric oxide synthase (eNOS) stimulation by bradykinin was close to 3 times as pronounced in untreated CLP mice as in untreated sham-operated mice, indicating a high level of eNOS activation secondary to sepsis. In addition, treatment with simvastatin reversed inflammatory alterations in CLP mice, namely, increased monocyte adhesion to endothelium. CONCLUSIONS: Simvastatin, which is well established in the treatment of lipid disorders and coronary artery disease, might have the additional potential of being an effective agent in sepsis treatment.

Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury.

BACKGROUND: Chemokines expressed on atherosclerotic endothelium or deposited by activated platelets have been implicated in monocyte recruitment during atherogenesis and restenosis. Although the involvement of P-selectin in these processes is evident from studies in knockout mice, it has not been elucidated whether delivery of platelet chemokines requires P-selectin, thus serving as a P-selectin-dependent effector function. METHODS AND RESULTS: Using immunofluorescence and laminar flow assays, we found that the deposition of the platelet-derived chemokine RANTES and monocyte arrest subsequently triggered by RANTES immobilized on inflamed endothelium are more efficient after preperfusion than after static preincubation of platelets and appear to depend on interactions of platelet but not endothelial P-selectin. This was revealed by the effects of P-selectin antibodies and comparison of P-selectin-deficient and wild-type platelets. Immunohistochemistry detected a substantial luminal expression of RANTES on neointimal lesions in wire-injured carotid arteries of apolipoprotein E (apoE)-deficient mice but not of mice with a combined deficiency in apoE and P-selectin (or platelet P-selectin). As assessed by histomorphometry, treatment of apoE-deficient mice with the RANTES receptor antagonist Met-RANTES markedly reduced neointimal plaque area and macrophage infiltration. CONCLUSIONS: Our data suggest that RANTES deposition and subsequent monocyte arrest are promoted by platelet P-selectin and involved in wire-induced intimal hyperplasia, and that blocking RANTES receptors attenuates neointima formation and macrophage infiltration. This mechanism represents an important component explaining the protection against neointimal growth in P-selectin-deficient mice and may represent a novel approach to the treatment of restenosis or atherosclerosis by the administration of chemokine receptor antagonists.

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.

Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial.

BACKGROUND: Beta blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome. METHODS: In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II-IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0.35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat. FINDINGS: The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74-0.93], p=0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86-1.02], p=0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. INTERPRETATION: Our results suggest that carvedilol extends survival compared with metoprolol.