Observation of the radiative decay of the 229Th nuclear clock isomer.

The radionuclide thorium-229 features an isomer with an exceptionally low excitation energy that enables direct laser manipulation of nuclear states. It constitutes one of the leading candidates for use in next-generation optical clocks1-3. This nuclear clock will be a unique tool for precise tests of fundamental physics4-9. Whereas indirect experimental evidence for the existence of such an extraordinary nuclear state is substantially older10, the proof of existence has been delivered only recently by observing the isomer's electron conversion decay11. The isomer's excitation energy, nuclear spin and electromagnetic moments, the electron conversion lifetime and a refined energy of the isomer have been measured12-16. In spite of recent progress, the isomer's radiative decay, a key ingredient for the development of a nuclear clock, remained unobserved. Here, we report the detection of the radiative decay of this low-energy isomer in thorium-229 (229mTh). By performing vacuum-ultraviolet spectroscopy of 229mTh incorporated into large-bandgap CaF2 and MgF2 crystals at the ISOLDE facility at CERN, photons of 8.338(24) eV are measured, in agreement with recent measurements14-16 and the uncertainty is decreased by a factor of seven. The half-life of 229mTh embedded in MgF2 is determined to be 670(102) s. The observation of the radiative decay in a large-bandgap crystal has important consequences for the design of a future nuclear clock and the improved uncertainty of the energy eases the search for direct laser excitation of the atomic nucleus.

Using the Lower Limit of Normal Instead of the Conventional Cutoff Values to Define Predictors of Pulmonary Function Impairment in Subjects With Chronic Heart Failure.

BACKGROUND: Using the newer lower limit of normal criterion instead of the conventional cutoff values to define pulmonary function abnormalities may result in different predictors of pulmonary function impairment in patients with heart failure. Therefore, we assessed predictors of pulmonary function impairment in subjects with chronic heart failure according to the lower limit of normal in comparison with conventional cutoff values. METHODS: In this prospective cross-sectional study, 164 chronic heart failure subjects (age 68 ± 10 y, 78% men, 88% New York Heart Association class I-II) with left ventricular ejection fraction <40% underwent pulmonary function tests. Predictors of pulmonary function impairment were assessed using the lower limit of normal and conventional cutoff values (ie, 80% predicted value and the fixed ratio of FEV1/FVC <0.7). RESULTS: The lower limit of normal criterion identified an extra independent predictor of diffusion impairment compared with the 80% predicted value; in addition to body mass index, pack-years, and alveolar volume, female sex also turned out to be an independent predictor. A smoking history of ≥10 pack-years was a significant predictor of diffusion impairment and airway obstruction using the lower limit of normal criterion but not using the conventional cutoff values. However, lowering the cutoff points of conventional criteria to match the more stringent lower limit of normal and thus avoid overdiagnosis of diffusion impairment and airway obstruction in the elderly produced similar results as the lower limit of normal. CONCLUSIONS: The lower limit of normal identifies more predictors of diffusion impairment and airway obstruction compared with conventional cutoff values in subjects with chronic heart failure with left ventricular systolic dysfunction. However, lowering the conventional cutoff points yielded similar results as the lower limit of normal. (ClinicalTrials.gov registration NCT01429376.).

Serial pulmonary function tests to diagnose COPD in chronic heart failure.

BACKGROUND: It is unknown whether serial pulmonary function tests are necessary for the correct diagnosis of chronic obstructive pulmonary disease (COPD) in patients with stable non-congested chronic heart failure (CHF). The aim of this study was to determine the prevalence of COPD in outpatients with stable CHF without pulmonary congestion using initial as well as confirmatory spirometry three months after treatment for COPD. METHODS: Spirometry was performed in 187 outpatients with stable CHF without pulmonary congestion on chest radiograph who had a left ventricular ejection fraction < 40% (mean age 69 ± 10 years, 78% men). COPD was defined according to the Global Initiative for Chronic Obstructive Lung Disease guidelines. The diagnosis of COPD was confirmed three months after treatment with tiotropium in newly diagnosed COPD patients. RESULTS: Using a three month follow-up spirometry to confirm initial diagnosis of de novo COPD did not change COPD prevalence significantly: 32.6% initially versus 32.1% after three months of follow-up. Only 1 of 25 (4%) patients with newly diagnosed COPD was not reproducibly obstructed at follow-up. COPD was greatly under- (19%) and overdiagnosed (32%). CONCLUSIONS: Spirometry should be used under stable and euvolemic conditions to decrease the burden of undiagnosed or overdiagnosed COPD in patients with CHF. Under these conditions, a confirmatory spirometry is unnecessary, as it does not change a newly established diagnosis of COPD in the vast majority of patients with CHF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01429376.

Pulmonary function impairment in patients with chronic heart failure: lower limit of normal versus conventional cutoff values.

OBJECTIVE: To determine the prevalence of pulmonary function abnormalities in patients with chronic heart failure (HF) according to recent American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines using the lower limit of normal (LLN) compared to conventional cutoff values. BACKGROUND: Recent ATS/ERS guidelines recommend the use of the LLN instead of the conventional cutoff values to define pulmonary function impairment to avoid misclassification of patients. However, studies addressing the prevalence of pulmonary function abnormalities according to both definitions in patients with chronic HF are lacking. METHODS: In this prospective cross-sectional study, 164 chronic HF outpatients (age 68 ± 10 years, 78% men, 88% New York Heart Association class I-II) with left ventricular ejection fraction < 40% underwent spirometry and measurement of diffusing capacity. Body plethysmography was performed in patients with abnormal spirometry results. RESULTS: Diffusion impairment and airway obstruction were found in 44-58% and 26-37% of the patients, respectively, depending on the definition used (LLN versus conventional cutoff values, p < 0.05). However, restriction was infrequent, irrespective of the definition used (7% versus 5%, respectively, p > 0.05). The LLN identified fewer patients with abnormal lung function, whereas the conventional cutoff values classified more patients with diffusion impairment, airway obstruction, or a mixed category. Twenty-seven percent of patients were misclassified by the conventional cutoff values. CONCLUSION: Pulmonary function abnormalities, especially diffusion impairment and airway obstruction, were highly prevalent in patients with chronic HF. Conventional cutoff values classified more patients with diffusion impairment, airway obstruction, or a mixed category compared to the LLN.

COPD in chronic heart failure: less common than previously thought?

BACKGROUND: Using a fixed ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) < 0.70 instead of the lower limit of normal (LLN) to define chronic obstructive pulmonary disease (COPD) may lead to overdiagnosis of COPD in elderly patients with heart failure (HF) and consequently unnecessary treatment with possible adverse health effects. OBJECTIVE: The aim of this study was to determine COPD prevalence in patients with chronic HF according to two definitions of airflow obstruction. METHODS: Spirometry was performed in 187 outpatients with stable chronic HF without pulmonary congestion who had a left ventricular ejection fraction <40% (mean age 69 ± 10 years, 78% men). COPD diagnosis was confirmed 3 months after standard treatment with tiotropium in newly diagnosed COPD patients. RESULTS: COPD prevalence varied substantially between 19.8% (LLN-COPD) and 32.1% (GOLD-COPD). Twenty-three of 60 patients (38.3%) with GOLD-COPD were potentially misclassified as having COPD (FEV1/FVC < 0.7 but > LLN). In contrast to patients with LLN-COPD, potentially misclassified patients did not differ significantly from those without COPD regarding respiratory symptoms and risk factors for COPD. CONCLUSIONS: One fifth, rather than one third, of the patients with chronic HF had concomitant COPD using the LLN instead of the fixed ratio. LLN may identify clinically more important COPD than a fixed ratio of 0.7.

Bronchodilator responsiveness in patients with chronic heart failure.

OBJECTIVE: The aim of this study was to evaluate the effect of inhaled bronchodilators on pulmonary function and dyspnea in patients with chronic heart failure (HF). BACKGROUND: Conflicting data exist on whether bronchodilators may improve pulmonary function and dyspnea in patients with chronic HF. METHODS: In this retrospective observational study we analyzed data of 116 chronic HF outpatients with systolic dysfunction who underwent spirometry and Borg dyspnea measurements before and after inhalation of 400 µg salbutamol and 80 µg ipratropium. Patients with chronic obstructive pulmonary disease (COPD) or asthma were excluded. RESULTS: Bronchodilators fully reversed airway obstruction (AO) in 25 of 64 (39.1%) patients with pre-bronchodilator AO. All spirometric measurements, except for forced vital and inspiratory capacities, improved significantly post-bronchodilation. Absolute and percent improvements in forced expiratory volume in 1 s (FEV1) were more pronounced in patients with persistent AO post-bronchodilation compared to those without AO (0.19 ± 0.18 L and 8.4 ± 7.3% versus 0.11 ± 0.12 L and 4.3 ± 4.0%, p < 0.05). Significant bronchodilator responsiveness of FEV1 (>200 mL and >12%) was noted in 12.1% and was more frequent in patients with persistent AO and fully reversible AO than in those without AO (23.1% and 16.0% versus 1.9%, p < 0.05). We measured a small, albeit significant improvement in dyspnea (0.7 ± 1.2 versus 0.9 ± 1.3, p = 0.002). CONCLUSIONS: Inhaled bronchodilators may have an additional role in the management of patients with chronic HF because of their potential to improve pulmonary function, especially in those with AO. The clinical usefulness and possible adverse events of bronchodilators need to be further established.

Prolonged anticoagulation therapy adjunctive to aspirin after successful fibrinolysis: from early reduction in reocclusion to improved long-term clinical outcome.

BACKGROUND: Long-term addition of antithrombotics (clopidogrel, anticoagulants) to aspirin has improved outcome after acute coronary syndromes. Data on the impact after fibrinolysis are scarce. In Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis-2 (APRICOT-2), adjunctive moderate-intensity coumarin (median international normalized ratio 2.6) conferred a marked reduction in 3-month reocclusion and ischemic events. Given the association between reocclusion and long-term outcome, we performed long-term clinical follow-up. METHODS: Patients with thrombolysis in myocardial infarction (TIMI) 3 flow <48 hours after fibrinolysis for ST-elevation myocardial infarction were randomized to aspirin plus coumarin, with prolonged heparinization until the target international normalized ratio (2-3) was reached, or aspirin with standard heparinization. Three-month follow-up angiography (reocclusion rates 15% vs 28%) and long-term clinical follow-up (median 7.3 years, interquartile range 5.9-8.6 years) were performed. RESULTS: Patients randomized to adjunctive anticoagulation (n = 123) received coumarin for a median of 280 days (113-387 days). Survival was 94% versus 88% in patients on aspirin alone (n = 128, P = .12). Infarct-free survival was 86% versus 71% (P = .01). Thrombolysis in myocardial infarction bleeding was 4% in both groups. Patients with reocclusion had impaired survival: 80% versus 94% (P < .01). In a multivariable model without reocclusion, combination therapy independently predicted survival (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.13-1.00) and infarct-free survival (HR 0.51, 95% CI 0.28-0.95). When adjusted for reocclusion, combination therapy did not predict outcome. Reocclusion independently predicted death (HR 2.56, 95% CI 1.02-6.43) and reinfarction. CONCLUSIONS: Moderate-intensity oral anticoagulation added to aspirin improved 8-year clinical outcome after successful fibrinolysis. The beneficial effect was largely attributed to a reduction in reocclusion, which independently predicted death and reinfarction. This study provides a mechanistic rationale for prolonged adjunctive anticoagulation after fibrinolysis.

Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT)-2 Trial.

BACKGROUND: Despite the use of aspirin, reocclusion of the infarct-related artery occurs in approximately 30% of patients within the first year after successful fibrinolysis, with impaired clinical outcome. This study sought to assess the impact of a prolonged anticoagulation regimen as adjunctive to aspirin in the prevention of reocclusion and recurrent ischemic events after fibrinolysis for ST-elevation myocardial infarction. METHODS AND RESULTS: At coronary angiography <48 hours after fibrinolytic therapy, 308 patients receiving aspirin and intravenous heparin had a patent infarct-related artery (Thrombolysis In Myocardial Infarction [TIMI] grade 3 flow). They were randomly assigned to standard heparinization and continuation of aspirin alone or to a 3-month combination of aspirin with moderate-intensity coumarin, including continued heparinization until a target international normalized ratio (INR) of 2.0 to 3.0. Angiographic and clinical follow-up were assessed at 3 months. Median INR was 2.6 (25 to 75th percentiles 2.1 to 3.1). Reocclusion (< or =TIMI grade 2 flow) was observed in 15% of patients receiving aspirin and coumarin compared with 28% in those receiving aspirin alone (relative risk [RR], 0.55; 95% CI 0.33 to 0.90; P<0.02). TIMI grade 0 to 1 flow rates were 9% and 20%, respectively (RR, 0.46; 95% CI, 0.24 to 0.89; P<0.02). Survival rates free from reinfarction and revascularization were 86% and 66%, respectively (P<0.01). Bleeding (TIMI major and minor) was infrequent: 5% versus 3% (P=NS). CONCLUSIONS: As adjunctive to aspirin, a 3-month-regimen of moderate-intensity coumarin, including heparinization until the target INR is reached, markedly reduces reocclusion and recurrent events after successful fibrinolysis. This conceptual study provides a mechanistic rationale to further investigate the role of prolonged anticoagulation after fibrinolytic therapy.