Diastolic dysfunction in heart failure with preserved systolic function: need for objective evidence:results from the CHARM Echocardiographic Substudy-CHARMES.

OBJECTIVES: We tested the hypothesis that diastolic dysfunction (DD) was an important predictor of cardiovascular (CV) death or heart failure (HF) hospitalization in a subset of patients (ejection fraction [EF] >40%) in the CHARM-Preserved study. BACKGROUND: More than 40% of hospitalized patients with HF have preserved systolic function (HF-PSF), suggesting that DD may be responsible for the clinical manifestations of HF. METHODS: Patients underwent Doppler echocardiographic examination that included assessment of pulmonary venous flow or determination of plasma NT-pro-brain natriuretic peptide > or months after randomization to candesartan or placebo. The patients were classified into 1 of 4 diastolic function groups: normal, relaxation abnormality (mild dysfunction), pseudonormal (moderate dysfunction), and restrictive (severe dysfunction). RESULTS: There were 312 patients in the study, mean age was 66 +/- 11 years, EF was 50 +/- 10%, and 34% were women. The median follow-up was 18.7 months. Diastolic dysfunction was found in 67% of classified patients (n = 293), and moderate and severe DD were identified in 44%. Moderate and severe DD had a poor outcome compared with normal and mild DD (18% vs. 5%, p < 0.01). Diastolic dysfunction, age, diabetes, previous HF, and atrial fibrillation were univariate predictors of outcome. In multivariate analysis, moderate (hazard ratio [HR] 3.7, 95% confidence interval [CI] 1.2 to 11.1) and severe DD (HR 5.7, 95% CI 1.4 to 24.0) remained the only independent predictors (p = 0.003). CONCLUSIONS: Objective evidence of DD was found in two-thirds of HF-PSF patients. Moderate and severe DD, which were found in less than one-half of the patients, were important predictors of adverse outcome. The results demonstrate the prognostic significance and need for objective evidence of DD in HF-PSF patients.     

燃煤烟道蜂窝净化剂除氟效果的研究

针对中国燃煤污染氟中毒分布范围广病情严重的特点，在民用炉灶烟道内装入蜂窝状净化剂除氟措施的可行性进行了初步的探讨。其中对蜂窝状净化剂的材料配比、孔径大小、长度、吸附容量、安装方法的堵塞问题进行了较详细的实验。在现场进行了除氟效果的验证、实验结果表明，烟道内装入蜂窝状净化剂除氟效率为８９．１％，同时对煤烟中的ＳＯ２也有一定的去除效果，除硫率为５３．６％。此项措施与改炉改灶措施结合推广运用，将有助于燃煤氟硫污染问题的解决。     

Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseline characteristics of patients in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme

AIMS: To describe the clinical characteristics and contemporary treatment of a broad spectrum of patients with chronic heart failure (CHF) randomised in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme, consisting of three component studies comparing placebo to candesartan. METHODS AND RESULTS: CHARM Alternative, CHARM Added and CHARM Preserved enrolled 2028 low left ventricular ejection fraction (LVEF) ACE inhibitor intolerant patients, 2548 low LVEF ACE inhibitor treated patients and 3025 preserved LVEF patients, respectively. Patients in CHARM Preserved were more often female. The proportion of women in CHARM Preserved was 40% compared to 32% in CHARM Alternative and 21% in CHARM Added. Patients in CHARM Preserved were also more often hypertensive than in the other two trials (64% vs. 50% and 48%, respectively). Symptoms and signs (with the exception of a third heart sound) were similar in all three patient groups. Beta-blockers were used in over half of patients in all three groups. Digoxin and spironolactone were used less frequently and calcium antagonists more frequently in CHARM Preserved. Spironolactone was used most frequently in CHARM Alternative, i.e. in ACE inhibitor intolerant patients. CONCLUSIONS: The CHARM Programme provides the largest and most detailed comparison to date of patients low- and preserved-LVEF CHF. It also describes the causes of ACE-inhibitor intolerance in a large cohort of patients and the other treatment which these patients receive.     

Inhibition of proliferation and induction of apoptosis in juvenile myelomonocytic leukemic cells by the granulocyte-macrophage colony- stimulating factor analogue E21R

Juvenile myelomonocytic leukemia (JMML) is a malignancy that almost inevitably leads to death before adulthood. Chemotherapy has given disappointing results and a substantial number of patients relapse after bone marrow transplantation. A salient feature of this disease is that the JMML cells produce granulocyte-macrophage colony-stimulating factor (GM-CSF) spontaneously and survive and proliferate without exogeneous GM-CSF. Furthermore, JMML cells are hypersensitive to GM-CSF with addition of this cytokine leading to enhanced proliferation. We have recently generated a human GM-CSF analogue, E21R, that acts as a complete and selective GM-CSF receptor antagonist. We have now tested this molecule as a potential new agent to control the leukemic cell load in JMML with particular emphasis on its role in JMML cell survival. We found that E21R inhibited the spontaneous growth of JMML cells in vitro and caused their apoptosis in a dose- and time-dependent manner in seven of seven cases. In contrast, neither a neutralizing anti-GM-CSF monoclonal antibody (MoAb) nor a selective interleukin-1 (IL-1) receptor antagonist affected JMML cell survival. Furthermore, the apoptotic effect of E21R was seen even in the presence of interleukin-1 beta and tumor necrosis factor-alpha, which have also been implicated in the pathogenesis of JMML. The inhibitory effects of E21R on JMML cell growth and viability offer a novel approach to therapy in this lethal childhood leukemia.     

Office blood pressure underestimates ambulatory blood pressure in peripheral arterial disease in comparison to healthy controls

Patients with peripheral arterial disease (PAD) constitute a subgroup of high-risk hypertensives, but controlled studies on 24-h blood pressure (BP) and diurnal variation of BP are lacking. This study was performed in order to test the hypothesis that office BP (OBP) may underestimate 24-h BP in PAD patients in comparison to a matched control group. In all, 98 male patients (mean age 68 years) with a history of intermittent claudication and an ankle/brachial index less than 0.9, and 94 controls matched for age but without PAD or ischaemic heart disease performed 24-h recordings of ambulatory BP. A total of 59 patients had a history of hypertension and 69 were on treatment with BP-lowering drugs as compared to 17 and 23 of the control subjects, respectively. Office as well as 24-h systolic BP (SBP) were higher in patients as compared to controls (151 +/- 22 vs 140 +/- 20 mmHg, P < 0.001 and 142 +/- 14 vs 133 +/- 15 mmHg, P < 0.001, respectively), but did not differ with regard to diastolic BP. In an analysis of covariance with the continuous factors age, office SBP and the categorical factor antihypertensive treatment, 24-h SBP was higher in PAD patients compared to controls (P < 0.05). The difference between office and night SBP was lower in PAD patients with antihypertensive treatment compared to controls (P = 0.01). In conclusion, Male patients with PAD had higher systolic but not diastolic BP than age-matched control subjects. In PAD patients, 24-h SBP was higher than expected from OBP compared to controls. Night SBP was higher only in patients with antihypertensive treatment. In PAD patients, especially when on antihypertensive treatment, the severity of hypertension may be underestimated when based on OBP only.     

The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes

OBJECTIVE: To compare the effects of two antihypertensive treatment strategies for the prevention of coronary heart disease and other cardiovascular events in the large subpopulation (n=5137) with diabetes mellitus in the blood pressure-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial. METHODS: Patients had either untreated hypertension or treated hypertension. For those with type II diabetes mellitus, inclusion criteria required at least two additional risk factors. Patients were randomized to amlodipine with addition of perindopril as required (amlodipine-based) or atenolol with addition of thiazide as required (atenolol-based). Therapy was titrated to achieve a target blood pressure of less than 130/80 mmHg. RESULTS: The trial was terminated early due to significant benefits on mortality and stroke associated with the amlodipine-based regimen. In patients with diabetes mellitus, the amlodipine-based treatment reduced the incidence of the composite endpoint--total cardiovascular events and procedures--compared with the atenolol-based regimen (hazard ratio 0.86, confidence interval 0.76-0.98, P=0.026). Fatal and nonfatal strokes were reduced by 25% (P=0.017), peripheral arterial disease by 48% (P=0.004) and noncoronary revascularization procedures by 57% (P<0.001). For the other endpoints included in the composite, the endpoint differences were less clear including coronary heart disease deaths and nonfatal myocardial infarctions (the primary endpoint), which were reduced nonsignificantly by 8% (hazard ratio 0.92, confidence interval 0.74-1.15). CONCLUSION: In the large diabetic subgroup in the blood pressure-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial, the benefits of amlodipine-based treatment, compared with atenolol-based treatment, on the incidence of total cardiovascular events and procedures was significant (14% reduction) and similar to that observed in the total trial population (16% reduction).     

The role of endothelium in factor Xa regulation: the effect of plasma proteinase inhibitors and hirudin

The role of endothelium in the inhibition of human factor Xa was studied in a plasma environment. Human factor Xa can bind to and function on bovine aortic endothelium in a manner similar to that of bovine factor Xa. Approximately 70% of the bound factor Xa is subject to inhibition by plasma proteinase inhibitors, and the remaining 30% is irreversibly bound as part of a 125 Kd membrane-associated complex not subject to proteolytic degradation. The proportion reversibly bound and its rate of release do not alter with changes in calcium, citrate, heparin, or active proteinase inhibitor concentrations. The principal plasma proteinase inhibitor of human factor Xa was antithrombin III, which accounted for 60% to 65% of factor Xa released from endothelium, with alpha 1-proteinase inhibitor inactivating 20% to 25% and alpha 2- macroglobulin approximately 15%. All of the reversibly bound factor Xa was identified in complex with one of these three proteinase inhibitors. The thrombin active-site inhibitor hirudin was found to markedly accelerate the displacement of reversibly bound factor Xa from the endothelium and to associate specifically with factor Xa without a loss of activity toward chromogenic substrates, perhaps accounting for a novel mechanism of anticoagulation.