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The PROTECT AF (Watchman Left Atrial Appendage Closure Technology for Embolic Protection in Patients With Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the Watchman LAA Closure Device In Patients With Atrial Fibrillation Versus Long-Term Warfarin Therapy) trials revealed

Objectives The purpose of this study was to assess the safety and efficacy of left atrial appendage (LAA) closure in nonvalvular atrial fibrillation (AF) patients ineligible for warfarin therapy. Background The PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) trial demonstrated that LAA closure with the Watchman device (Boston Scientific, Natick, Massachusetts) was noninferior to warfarin therapy. However, the PROTECT AF trial only included patients who were candidates for warfarin, and even patients randomly assigned to the LAA closure arm received concomitant warfarin for 6 weeks after Watchman implantation. Methods A multicenter, prospective, nonrandomized study was conducted of LAA closure with the Watchman device in 150 patients with nonvalvular AF and CHADS 2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score ≥1, who were considered ineligible for warfarin. The primary efficacy endpoint was the combined events of ischemic stroke, hemorrhagic stroke, systemic embolism, and cardiovascular/unexplained death. Results The mean CHADS 2 score and CHA 2 DS 2 -VASc (CHADS 2 score plus 2 points for age ≥75 years and 1 point for vascular disease, age 65 to 74 years, or female sex) score were 2.8 ± 1.2 and 4.4 ± 1.7, respectively. History of hemorrhagic/bleeding tendencies (93%) was the most common reason for warfarin ineligibility. Mean duration of follow-up was 14.4 ± 8.6 months. Serious procedure- or device-related safety events occurred in 8.7% of patients (13 of 150 patients). All-cause stroke or systemic embolism occurred in 4 patients (2.3% per year): ischemic stroke in 3 patients (1.7% per year) and hemorrhagic stroke in 1 patient (0.6% per year). This ischemic stroke rate was less than that expected (7.3% per year) based on the CHADS 2 scores of the patient cohort. Conclusions LAA closure with the Watchman device can be safely performed without a warfarin transition, and is a reasonable alternative to consider for patients at high risk for stroke but with contraindications to systemic oral anticoagulation. (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology [ASAP]; NCT00851578)

Objectives This study sought to assess the safety and efficacy of paclitaxel-coated balloon (PCB) angioplasty in an international, multicenter, prospective, large-scale registry study. Background In small randomized trials, PCB angioplasty was superior to uncoated balloon angioplasty for treatment of bare-metal stent (BMS) and drug-eluting stent (DES) restenosis. Methods Patients treated with SeQuent Please PCBs were included. The primary outcome measure was the clinically driven target lesion revascularization (TLR) rate at 9 months. Results At 75 centers, 2,095 patients with 2,234 lesions were included. The TLR rate was 5.2% after 9.4 months. Definite vessel thrombosis occurred in 0.1%. PCB angioplasty was performed in 1,523 patients (72.7%) with DES or BMS restenosis and 572 patients (27.3%) with de novo lesions. The TLR rate was significantly lower in patients with PCB angioplasty for BMS restenosis compared with DES restenosis (3.8% vs. 9.6%, p Conclusions PCB angioplasty in an all-comers, prospective, multicenter registry was safe and confirmed in a large population the low TLR rates seen in randomized clinical trials. PCB angioplasty was more effective in BMS restenosis compared with DES restenosis, with no difference regarding the type of DES.

This study was designed to analyze the effect of iNOS on mitochondrial creatine kinase (mi-CK) expression and exercise capacity in chronic heart failure (CHF).The molecular mechanisms underlying exercise intolerance in CHF are still unclear. Expression of inducible nitric oxide synthase (iNOS) and reduced phosphocreatine resynthesis have been described in skeletal muscle of patients with CHF. However, it is unknown whether these phenomena are causally related to each other and to exercise tolerance.Thirty-eight patients with CHF and 8 healthy controls (C) underwent bicycle ergospirometry and biopsy of the vastus lateralis muscle. Expression of iNOS was quantified by immunohistochemistry and reverse-transcriptase polymerase chain reaction, mi-CK by Western-blot. Intracellular presence of NO was confirmed by immunohistochemical quantification of nitrotyrosine (NT). To corroborate clinical findings, L6 rat skeletal myoblasts were incubated with sodium nitroprusside (SNP).Expression of iNOS was significantly increased in CHF (4.0+/-2.8 vs. 0.8+/-0.7% iNOS positive tissue area, p0.001 vs. C) and inversely correlated to maximal oxygen uptake (r=-0.65, p0.001). Intracellular NO-accumulation was confirmed by increased NT levels (13.5+/-8.5 vs. 2.0+/-1.7% NT-positive tissue area, p0.001 vs. C). Mi-CK was decreased in CHF (0.84+/-0.36 vs. 1.57+/-0.60, p0.001 vs. C). The inverse correlation seen between iNOS and mi-CK expression in patients (r=-0.68, p0.001) was reproduced in incubation experiments with SNP.Increased expression of iNOS in skeletal muscle of patients with CHF was inversely correlated with mi-CK expression and exercise capacity. Cell experiments confirmed a causal relationship via NO. These findings extend our knowledge of the pathophysiology of exercise intolerance in CHF.

The purpose of this study was to assess the safety and efficacy of left atrial appendage (LAA) closure in nonvalvular atrial fibrillation (AF) patients ineligible for warfarin therapy.The PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) trial demonstrated that LAA closure with the Watchman device (Boston Scientific, Natick, Massachusetts) was noninferior to warfarin therapy. However, the PROTECT AF trial only included patients who were candidates for warfarin, and even patients randomly assigned to the LAA closure arm received concomitant warfarin for 6 weeks after Watchman implantation.A multicenter, prospective, nonrandomized study was conducted of LAA closure with the Watchman device in 150 patients with nonvalvular AF and CHADS₂ (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score ≥1, who were considered ineligible for warfarin. The primary efficacy endpoint was the combined events of ischemic stroke, hemorrhagic stroke, systemic embolism, and cardiovascular/unexplained death.The mean CHADS₂ score and CHA₂DS₂-VASc (CHADS₂ score plus 2 points for age ≥75 years and 1 point for vascular disease, age 65 to 74 years, or female sex) score were 2.8 ± 1.2 and 4.4 ± 1.7, respectively. History of hemorrhagic/bleeding tendencies (93%) was the most common reason for warfarin ineligibility. Mean duration of follow-up was 14.4 ± 8.6 months. Serious procedure- or device-related safety events occurred in 8.7% of patients (13 of 150 patients). All-cause stroke or systemic embolism occurred in 4 patients (2.3% per year): ischemic stroke in 3 patients (1.7% per year) and hemorrhagic stroke in 1 patient (0.6% per year). This ischemic stroke rate was less than that expected (7.3% per year) based on the CHADS₂ scores of the patient cohort.LAA closure with the Watchman device can be safely performed without a warfarin transition, and is a reasonable alternative to consider for patients at high risk for stroke but with contraindications to systemic oral anticoagulation. (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology [ASAP]; NCT00851578).

Left atrial appendage (LAA) closure is an important alternative to long term anticoagulant therapy for atrial fibrillation patients who are at high risk for stroke. As the risk of stroke and major bleeding from anticoagulation therapy increases in patients 75 years and older, we evaluated the long

This study sought to assess the safety and efficacy of paclitaxel-coated balloon (PCB) angioplasty in an international, multicenter, prospective, large-scale registry study.In small randomized trials, PCB angioplasty was superior to uncoated balloon angioplasty for treatment of bare-metal stent (BMS) and drug-eluting stent (DES) restenosis.Patients treated with SeQuent Please PCBs were included. The primary outcome measure was the clinically driven target lesion revascularization (TLR) rate at 9 months.At 75 centers, 2,095 patients with 2,234 lesions were included. The TLR rate was 5.2% after 9.4 months. Definite vessel thrombosis occurred in 0.1%. PCB angioplasty was performed in 1,523 patients (72.7%) with DES or BMS restenosis and 572 patients (27.3%) with de novo lesions. The TLR rate was significantly lower in patients with PCB angioplasty for BMS restenosis compared with DES restenosis (3.8% vs. 9.6%, p0.001). The TLR rate did not differ for PCB angioplasty of paclitaxel-eluting stent and non-paclitaxel-eluting sten restenosis (8.3% vs. 10.8%, p = 0.46). In de novo lesions (small vessels), the TLR rate was low and did not differ between PCB angioplasty with and without additional BMS implantation (p = 0.31).PCB angioplasty in an all-comers, prospective, multicenter registry was safe and confirmed in a large population the low TLR rates seen in randomized clinical trials. PCB angioplasty was more effective in BMS restenosis compared with DES restenosis, with no difference regarding the type of DES.

The aim of this study was to assess the effects of regular physical exercise on local inflammatory parameters in the skeletal muscle of patients with chronic heart failure (CHF).Inflammatory activation with increased serum cytokine levels and expression of inducible nitric oxide synthase (iNOS) in the myocardium and peripheral skeletal muscles has been described in CHF.Twenty male patients with stable CHF (left ventricular ejection fraction 25 +/- 2%; age 54 +/- 2 years) were randomized to a training group (n = 10) or a control group (n = 10). At baseline and after six months, serum samples and vastus lateralis muscle biopsies were obtained. Serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1-beta levels were measured by enzyme-linked immunosorbent assay, local cytokine, and iNOS expression by real-time polymerase chain reaction.Exercise training improved peak oxygen uptake by 29% in the training group (from 20.3 +/- 1.0 to 26.1 +/- 1.5 ml/kg. min; p0.001 vs. control group). While serum levels of TNF-alpha, IL-6, and IL-1-beta remained unaffected by training, local skeletal muscle TNF-alpha decreased from 1.9 +/- 0.4 to 1.2 +/- 0.3 relative U (p0.05 for change vs. control group), IL-6 from 71.3 +/- 16.5 to 41.3 +/- 8.8 relative U (p0.05 vs. begin), and IL-1-beta from 2.7 +/- 1.1 to 1.4 +/- 0.6 relative U (p = 0.02 vs. control group). Exercise training also reduced local iNOS expression by 52% (from 6.3 +/- 1.2 to 3.0 +/- 1.0 relative U; p = 0.007 vs. control group).Exercise training significantly reduced the local expression of TNF-alpha, IL-1-beta, IL-6, and iNOS in the skeletal muscle of CHF patients. These local anti-inflammatory effects of exercise may attenuate the catabolic wasting process associated with the progression of CHF.

OBJECTIVES We sought to assess the role of insulin-like growth factor-I (IGF-I) in muscle wasting in chronic heart failure (CHF), serum concentrations and local muscular IGF-I expression were determined in patients with severe CHF. BACKGROUND Chronic heart failure is associated with progressive muscle atrophy, leading to cardiac cachexia. Skeletal muscle disuse and inflammatory activation with elevated cytokine levels have been implicated; however, the pathomechanism involved remains largely unknown. METHODS Serum levels of IGF-I were measured by competitive solid phase immunoassay in 47 patients with severe CHF (left ventricular ejection fraction 30%) and 15 age-matched healthy subjects (HS). Insulin-like growth factor-I and IGF-I receptor expression were assessed in vastus lateralis biopsies by real-time PCR and Western blot analysis. RESULTS Although serum IGF-I was not significantly different (175 10 ng/ml in CHF vs. 170 12 ng/ml in HS, p NS), local muscle IGF-I mRNA expression was reduced by 52% in CHF (6.7 0.4 vs. 14.0 0.9 arbitrary units in HS, p 0.001). This was accompanied by an increase in IGF-I receptor mRNA expression (86.8 5.4 in CHF vs. 23.1 1.8 arbitrary units in HS, p 0.001). Local IGF-I expression was significantly correlated with muscle cross-sectional area (R 0.75, p 0.01). Chronic heart failure patients with a body mass index of 25 kg/m 2 showed signs of peripheral growth hormone (GH) resistance, as indicated by elevated serum GH, and reduced IGF-I levels. CONCLUSIONS In CHF patients, muscle IGF-I expression is considerably reduced in the presence of normal serum IGF-I levels, possibly contributing to early loss of muscle mass. These findings are consistent with a potential role of IGF-I for skeletal muscle atrophy in CHF. (J Am Coll Cardiol 2002;39:1175– 81) © 2002 by the American College of Cardiology Foundation In recent years it has become widely accepted that the catabolic syndrome associated with advanced stages of chronic heart failure (CHF) is more than a symptom of disease progression; cardiac cachexia has been shown to be correlated with lower exercise tolerance and reduced survival (1). However, the process leading to progressive loss of muscle mass and exercise capacity, finally resulting in cardiac cachexia, is still not completely understood. Muscle wasting starts long before the clinical signs of overt cachexia become apparent. It has already been documented that noncachectic patients with CHF show reduced leg lean tissue compared with healthy subjects (HS) (2), suggesting that the factors responsible for the initiation of the catabolic process may be present at early stages of the heart failure syndrome. Until now a number of different humoral factors have been accused of being responsible for the catabolic process in CHF, among them elevated serum cytokines (3) and catecholamines (4), cortisol/dihydroepiandrosterone imbalance (5) and growth hormone (GH) resistance (5). A possible causal relationship between these factors and the catabolic syndrome was inferred based on the presumption that serum hormone levels are representative of local concentrations in target organs—most notably the skeletal muscle. However, this presumption has not been validated. In the context of the present study we focused on the GH/IGF-I axis (GH/IGF-I)—a key system involved in regulation of normal cell growth, hypertrophy and atrophy. It has been shown that, in patients with CHF, low levels of systemic IGF-I are associated with a decreased leg muscle cross-sectional area and strength (6). We therefore hypothesized that the GH/IGF-I axis may be involved in the pathogenesis of skeletal muscle catabolism and dysfunction in CHF. Insulin-like growth factor-I exerts its functions via both autocrine and paracrine pathways. In order to assess the relation between local and systemic concentrations of IGF-I and GH the serum IGF-I and GH levels were measured and compared to the local expression of IGF-I and IGF-I receptor in the quadriceps muscle and noncachectic patients with CHF and of HS.

Background: AF patients at the highest risk for embolic stroke also experience the greatest risk of hemorrhagic complications of anticoagulant use. The PROTECT AF trial revealed that LAA closure using the Watchman device was non-inferior to Warfarin for preventing stroke in AF pts with CHADS2 ≥ 1. However, these pts were treated with Warfarin post-implant until a TEE demonstrated LAA closure at 6 wks. Due to the pressing need for strategies that can prevent stroke in pts with contraindications to Warfarin, we performed a prospective study of Watchman implantation in Warfarin-contraindicated pts. Methods: Prospective registry of pts with non-valvular AF, a CHADS2 score ≥1, and a contraindication to Warfarin use. The Watchman device was implanted in standard fashion. Post-implant, patients were discharged on 6 mo of clopidogrel and life-long aspirin. Follow-up TEE was performed at 3/12 months. Results: At 4 centers, 150 pts were enrolled. The mean age was 72.5 ± 7.4 yrs. The prevalence of stroke risk factor...

OBJECTIVES The purpose of the study was to investigate if apoptosis occurs in skeletal muscle myocytes and its relation to exercise intolerance in patients with chronic heart failure (CHF). BACKGROUND Intrinsic abnormalities of skeletal muscle frequently limit exercise tolerance in CHF patients. Recently, apoptosis has been detected in cardiac myocytes of patients with CHF, suggesting that apoptosis may contribute to the reduced contractile force. The presence and regulation of apoptosis in skeletal myocytes of patients with CHF remains to be defined. METHODS Skeletal muscle biopsies (m. vastus lateralis) of 34 CHF patients (New York Heart Association functional class II–III) and eight age-matched healthy control subjects were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling for the presence of apoptosis, and by immunohistochemistry and videodensitometrical quantification for inducible nitric oxide synthase (iNOS) and Bcl-2 expression. Maximal oxygen consumption (VO2max) was determined by ergospirometry. RESULTS Apoptosis was detected in 16/34 (47%) patients with CHF and in none of the healthy subjects. Patients with apoptosis-positive skeletal muscle myocytes exhibited a significantly lower VO2max (12.0 ± 3.7 vs. 18.2 ± 4.4 ml/kg/min; p = 0.0005), a higher iNOS expression (6.8 ± 3.6 vs. 3.7 ± 2.6% iNOS-positive stained tissue area; p = 0.015) and a lower Bcl-2 expression (1.0 ± 0.3 vs. 1.4 ± 0.4% Bcl-2–positive tissue area; p = 0.03) as compared with patients with apoptosis-negative biopsies. CONCLUSIONS These results indicate that apoptosis is frequently found in skeletal muscle obtained from CHF patients, which is associated with significant impairment of functional work capacity. In skeletal muscle of these patients, iNOS and Bcl-2 are possibly involved in the regulation of apoptosis.

Objectives The objective of the study was to assess noninferiority of the polymer-free sirolimus-eluting Yukon Choice stent (Translumina GmbH, Hechingen, Germany) compared with the polymer-based Taxus Liberte stent (Boston Scientific, Natick, Massachusetts) with regard to the primary endpoint, in-stent late lumen loss, at 9 months in patients with diabetes mellitus. Background The Yukon Choice stent has been evaluated in several randomized controlled trials before, albeit to date, there has been no trial that exclusively enrolled patients with diabetes mellitus. Methods Patients with diabetes mellitus undergoing percutaneous coronary intervention for clinically significant de novo coronary artery stenosis were randomized 1:1 to receive either the polymer-free sirolimus-eluting Yukon Choice stent or the polymer-based paclitaxel-eluting Taxus Liberte stent. Results A total of 240 patients were randomized. Quantitative coronary angiography was available for 79% of patients. Mean in-stent late lumen loss was 0.63 ± 0.62 mm for the Yukon Choice stent and 0.45 ± 0.60 mm for the Taxus Liberte stent. Based on the pre-specified margin, the Yukon Choice stent failed to show noninferiority for the primary endpoint. During follow-up, there were no significant differences between groups regarding death, myocardial infarction, stent thrombosis, target lesion revascularization, target vessel revascularization, or nontarget vessel revascularization. Conclusions Compared with the Taxus Liberte stent, the polymer-free sirolimus-eluting Yukon Choice stent failed to show noninferiority with regard to the primary endpoint, in-stent late lumen loss, in patients with diabetes mellitus after 9-month follow-up. Both stents showed comparable clinical efficacy and safety. (Yukon Choice Versus Taxus Liberte in Diabetes Mellitus; NCT00368953 )