Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure

OBJECTIVES: This study was designed to determine whether therapy with vasodilators and diuretics, designed to normalize loading conditions in decompensated heart failure (HF), reduces neurohormonal activation in the short term. BACKGROUND; Elevated vasoactive neurohormone levels in chronic HF have adverse prognostic impact and may be targeted by specific therapies. METHODS: Endothelin-1, catecholamines, renin, aldosterone, angiotensin and atrial natriuretic peptides (ANP, N-ANP and BNP) were measured in 34 patients with advanced HF before and after hemodynamically guided therapy with vasodilators and diuretics. The therapy was designed to reduce filling pressures and systemic vascular resistance (SVR) without inotropic therapy. Blood was drawn before therapy (A), after initial diuretic and nitroprusside therapy to optimize hemodynamics (B, mean 1.4 days) and after transition to an oral regimen designed to maintain improved hemodynamics (C, mean 3.4 days). RESULTS: Mean pulmonary wedge pressure fell from 31 to 18 mm Hg, right atrial pressure from 15 to 8 mm Hg, and SVR from 1,780 to 1,109 dynes/s/cm(-5). Cardiac index increased from 1.7 to 2.6 l/min/m(2) without intravenous inotropic agents (all p < or = 0.05). Average endothelin levels declined by 30%, from 7.7 to 5.5 pg/ml, and remained low at time point C, 5.2 pg/ml (p < 0.01). Norepinephrine was 858 at time A, 817 at time B, and fell by time C to 608 pg/ml (p < or = 0.05). The mean plasma BNP level fell by 26% after only 1.4 days and by 53% at time C (p < 0.001). CONCLUSIONS: Neurohormonal activation rapidly decreases after short-term therapy tailored to decrease severely elevated filling pressures and SVR without inotropic agents. Therapy designed to address neurohormonal activation should include therapy to improve severe resting hemodynamic compromise.     

Association between plasma chromogranin A concentration and long-term mortality after myocardial infarction

PURPOSE: Chromogranin A, a polypeptide that is distributed throughout the neuroendocrine system, may be a marker of neuroendocrine activation. We sought to assess the long-term prognostic value of circulating levels of chromogranin A after myocardial infarction. METHODS: We studied 119 patients (88 [74%] male; median age, 70 years [interquartile range, 62 to 75 years]) with documented myocardial infarction. Chromogranin A levels in plasma were determined by radioimmunoassay from samples obtained 3 days after the onset of symptoms. RESULTS: During a median follow-up of 10.8 years, 56 patients (47%) died. The median concentration of chromogranin A in plasma was 24 ng/mL (interquartile range, 18 to 36 ng/mL). Plasma chromogranin A levels were associated with increased long-term mortality (hazard ratio [HR] = 1.17 per 10-ng/mL increase; 95% confidence interval [CI]: 1.06 to 1.28) in models that adjusted for age, clinical heart failure during the initial hospitalization, and use of thrombolytic therapy. As a dichotomous variable (cutoff, 24 ng/mL), an elevated chromogranin A level was also associated with mortality in univariate analysis (HR = 2.6; 95% CI: 1.4 to 4.8), but this relation was no longer significant after adjustment for age (HR = 1.4; 95% CI: 0.8 to 2.7). CONCLUSION: Plasma levels of chromogranin A are related to long-term mortality after myocardial infarction, perhaps because they reflect neuroendocrine activation.     

Contribution of peripheral versus central EP1 prostaglandin receptors to inflammatory pain

Few studies on transcranial brain sonography have been performed in hereditary and non-hereditary ataxias. The objective of the present study was to report transcranial brain sonography findings in a sample of clinically and molecularly proven Machado-Joseph disease patients and to compare these data against those of an age- and gender-matched control group. A cross-sectional study on transcranial brain sonography was conducted in 30 Machado-Joseph disease patients. Transcranial brain sonography was performed by an experienced sonographer blinded to the clinical, genetic, and neuroimaging data. The results were compared with those of a control group of 44 healthy subjects matched for age and gender. The sonographic findings were also correlated with clinical features and genetic data in Machado-Joseph disease group. A significantly higher frequency of substantia nigra and lenticular nucleus hyperechogenicity was found in the Machado-Joseph disease group compared to an age- and gender-matched healthy control group (p < 0.001). The substantia nigra echogenic area proved to be the best predictor for differentiating cases from controls. Third and lateral ventricles were significantly larger in the Machado-Joseph disease patients than in the control subjects. No significant correlations were found between transcranial brain sonography findings and Machado-Joseph disease demographic/clinical data. Transcranial brain sonography findings in Machado-Joseph disease patients differed significantly to those in age- and gender-matched controls. Substantia nigra hyperechogenicity occurred frequently in Machado-Joseph disease patients and was found to be the best predictor for differentiating cases from controls. Additionally, this data describes the occurrence of brain atrophy in Machado-Joseph disease group.     

Therapeutic decisions by number needed to treat and survival gains: a cross-sectional survey of lipid-lowering drug recommendations

Background

Previous studies suggest that lay people have difficulties with evaluating effect size in terms of number needed to treat (NNT), but theyare sensitive to effect size in terms of survival gains.

Aim

To explore whether GPs and internists are sensitive to NNT and survival gains when considering a lipid-lowering drug therapy.

Design and setting

Cross-sectional survey of primary prevention of cardiovascular disease with random allocation to different scenarios.

Method

GPs (n = 450) and internists (n = 450) were posted a vignette presenting a high-risk patient and a novel drug, ‘neostatin’. The benefit was described in terms of NNT or mean gain in disease-free survival. Each physician was randomly allocated to one version of the vignette. Outcome measures were evaluation of ‘neostatin’ on a Likert scale (0: very poor choice, 10: very good choice) and the proportion recommending ‘neostatin’.

Results

A total of 477 responses (53%) were received. Among responders to NNT scenarios, 26%, 31%, and 43% recommended ‘neostatin’ for NNT values of 34, 17, and 9 respectively. With equivalent disease-free survival gains of 9, 17, and 32 months, 40%, 49%, and 52% respectively recommended the drug. On the rating scale, mean values were 4.7, 5.0, and 5.5 across the respective NNT scenarios and 5.2, 6.2, and 6.1 across the scenarios presenting survival gains. Differences in trends between the two formats were not statistically significant. In total, 33% recommended ‘neostatin’ when presented with NNT values, compared to 47% when presented with survival gain (χ² = 9.2, P= 0.002).

Conclusion

Physicians presented with survival gains were more likely to recommend the therapy than those presented with NNT. Sensitivity to effect size was similarfor both effect formats.     

Plasma osteoprotegerin levels in the general population: relation to indices of left ventricular structure and function

Osteoprotegerin, a member of the tumor necrosis factor receptor superfamily, has pleiotropic effects on bone metabolism, endocrine function, and the immune system. Myocardial expression and circulating levels of osteoprotegerin are increased in heart failure. The relationship between osteoprotegerin levels in the general population and indices of left ventricular structure and function is unknown. Plasma osteoprotegerin levels and cardiac MRI indices of left ventricular structure and function were available in 2715 subjects (median age: 44 years; 45% male) enrolled in the Dallas Heart Study. The associations between osteoprotegerin concentration and indices of left ventricular structure and function were assessed by linear regression analysis, adjusting for possible confounders. By gender-specific linear regression analysis, higher osteoprotegerin levels were significantly associated with higher left ventricular mass, left ventricular wall thickness, left ventricular concentricity index, and lower left ventricular ejection fraction (P<0.001 for all). After adjustment for age, race, fat-free mass, fat mass, hypertension, diabetes, coronary artery disease, estimated glomerular filtration rate, hypercholesterolemia, smoking status, hormone replacement therapy, coronary artery calcium score >10, and presence of aortic plaque, osteoprotegerin remained significantly associated with each of these left ventricular indices among male subjects (P<0.05 for each). Among female subjects, higher osteoprotegerin was independently associated with higher left ventricular end-systolic volume and lower ejection fraction (P<0.0001 for each) but not with indices of left ventricular hypertrophy. These findings are compatible with the theory that osteoprotegerin may play a pathophysiological role in the development of left ventricular hypertrophy and systolic dysfunction.     

Survival and future need of long-term oxygen therapy for chronic obstructive pulmonary disease--gender differences

We aimed to study trends in gender-related differences in incidence, and prevalence for long-term oxygen therapy due to chronic obstructive pulmonary disease. Another aim was to study survival after onset of oxygen therapy. Prospectively followed were 5689 Swedish patients, who were prescribed oxygen therapy because of chronic obstructive pulmonary disease from 1987 to 2000. The annual incidence of women starting oxygen therapy increased more rapidly than that in men. In 2000, 7.6 per 100,000 women started treatment compared with 7.1 in men. The frequency of ever smoking in Sweden in the age group receiving oxygen, i.e. age 65-84 years, was 36.4% in women and 65.0% in men, indicating that women ran a higher risk of developing an oxygen-requiring chronic hypoxaemia. An increase in women requiring oxygen therapy is predicted due to the increase in smoking frequency in young and middle-aged women and it is estimated that about 70% of Swedish patients on oxygen in 2026 will be women, with an estimated prevalence of 61 per 100,000. In conclusion, the incidence and prevalence for long-term oxygen therapy increases more rapidly among women than in men. This is probably due to the increased frequency of smoking in women compared with men and a higher susceptibility to develop severe hypoxaemia in women. The survival is better in women with long-term oxygen therapy than in men.     

Diabetes in treated hypertension is common and carries a high cardiovascular risk: results from a 28-year follow-up

OBJECTIVE: The objective of this study was to analyse predictive factors for development of type 2 diabetes during life-long therapy for hypertension and the alleged additional cardiovascular risk this constitutes. METHODS: The study group (n = 754) comprised the hypertensive subgroup of a randomized population sample of 7500 men, aged 47-54 years, screened for cardiovascular risk factors and followed for 25-28 years. The patients were treated with thiazide diuretics and beta-adrenergic blocking drugs with the addition of hydralazin during the first decade. Calcium antagonists were substituted for hydralazin and, if needed, angiotensin-converting enzyme inhibitors were added when these drugs became available. RESULTS: A total of 148 (20.4%) treated hypertensive patients developed diabetes during 25 years, and in multivariate Cox regression analysis body mass index, serum triglycerides and treatment with beta-blockers were positively related with this complication. New-onset diabetes implied a significantly increased risk for stroke [hazard ratio (HR): 1.67; 95% confidence interval (95% CI): 1.1-2.6; P < 0.05], myocardial infarction (OR: 1.66; 95% CI: 1.1-2.5; P < 0.05) and mortality (OR: 1.42; 95% CI: 1.1-1.9; P < 0.05). The greatest risk for stroke was new-onset diabetes, followed by smoking (OR: 1.46; 95% CI: 1-2.2; P = 0.07) and the greatest risk for myocardial infarction was new-onset diabetes, followed by smoking (HR: 1.64; 95% CI: 1.1-2.4; P < 0.01). The greatest risk for mortality was smoking (HR: 1.73; 95% CI: 1.3-2.2; P < 0.005). Achieved systolic and diastolic blood pressure were not predictive of cardiovascular complications or death. The mean observation time from onset of diabetes mellitus to a first stroke was 9.1 years and to a first myocardial infarction 9.3 years. CONCLUSION: Diabetes in treated hypertensive patients is alarmingly common and carries a high risk for cardiovascular complications and mortality.     

A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years

BACKGROUND: The optimal treatment for cartilage lesions has not yet been established. The objective of this randomized trial was to compare autologous chondrocyte implantation with microfracture. This paper represents an update, with presentation of the clinical results at five years. METHODS: Eighty patients who had a single chronic symptomatic cartilage defect on the femoral condyle in a stable knee without general osteoarthritis were included in the study. Forty patients were treated with autologous chondrocyte implantation, and forty were treated with microfracture. We used the International Cartilage Repair Society, Lysholm, Short Form-36, and Tegner forms to collect clinical data, and radiographs were evaluated with use of the Kellgren and Lawrence grading system. RESULTS: At two and five years, both groups had significant clinical improvement compared with the preoperative status. At the five-year follow-up interval, there were nine failures (23%) in both groups compared with two failures of the autologous chondrocyte implantation and one failure of the microfracture treatment at two years. Younger patients did better in both groups. We did not find a correlation between histological quality and clinical outcome. However, none of the patients with the best-quality cartilage (predominantly hyaline) at the two-year mark had a later failure. One-third of the patients in both groups had radiographic evidence of early osteoarthritis at five years. CONCLUSIONS: Both methods provided satisfactory results in 77% of the patients at five years. There was no significant difference in the clinical and radiographic results between the two treatment groups and no correlation between the histological findings and the clinical outcome. One-third of the patients had early radiographic signs of osteoarthritis five years after the surgery. Further long-term follow-up is needed to determine if one method is better than the other and to study the progression of osteoarthritis.