Hans G. Schneider

Association of high-sensitivity C-reactive protein with de novo major depression

BACKGROUND Although there is cross-sectional evidence that changes in the immune system contribute to the pathophysiology of depression, longitudinal data capable of elucidating cause and effect relationships are lacking. AIMS We aimed to determine whether subclinical systemic inflammation, as measured by serum high-sensitivity C-reactive protein (hsCRP) concentration, is associated with an increased risk of de novo major depressive disorder. METHOD Major depressive disorder was diagnosed using a clinical interview (SCID-I/NP). This is a retrospective cohort study; from a population-based sample of 1494 randomly selected women recruited at baseline during the period 1994-7, 822 were followed for a decade and provided measures of both exposure and outcome. Of these women, 644 (aged 20-84 years) had no prior history of depression at baseline and were eligible for analysis. RESULTS During 5827 person-years of follow-up, 48 cases of de novo major depressive disorder were identified. The hazard ratio (HR) for depression increased by 44% for each standard deviation increase in log-transformed hsCRP (ln-hsCRP) (HR = 1.44, 95% CI 1.04-1.99), after adjusting for weight, smoking and use of non-steroidal anti-inflammatory drugs. Further adjustment for other lifestyle factors, medications and comorbidity failed to explain the observed increased risk for depression. CONCLUSIONS Serum hsCRP is an independent risk marker for de novo major depressive disorder in women. This supports an aetiological role for inflammatory activity in the pathophysiology of depression.

Seasonal Periodicity of Serum Vitamin D and Parathyroid Hormone, Bone Resorption, and Fractures: The Geelong Osteoporosis Study

In this population‐based study, seasonal periodicity was seen with reduced serum vitamin D, increased serum PTH, and increased bone resorption in winter. This was associated with an increased proportion of falls resulting in fracture and an increased risk of wrist and hip fractures.

Relation of Peripheral Collagen Markers to Death and Hospitalization in Patients With Heart Failure and Preserved Ejection Fraction Results of the I-PRESERVE Collagen Substudy

Background— Heart failure with preserved ejection fraction (HFPEF) is a common and increasing public health problem. Myocardial fibrosis is a key pathological feature of HFPEF. Peripheral collagen markers may reflect this excess fibrosis; however, the relation of these markers to prognosis in patients with HFPEF has not as yet been determined. Methods and Results— This substudy of the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial measured plasma levels of procollagen type I amino-terminal peptide, procollagen type III amino-terminal peptide, and osteopontin in 334 patients with HFPEF. Measurements were performed at baseline and 6 months after randomization to placebo or irbesartan 300 mg/day. The relation of baseline collagen markers to the I-PRESERVE primary end point (all-cause death and hospitalization for prespecified cardiovascular causes) was evaluated by single and multivariable analysis. Similar evaluations were performed for all-cause death alone as well as heart failure events (death or hospitalization because of heart failure). Increased plasma levels of collagen markers at baseline were associated with increased frequency of the study primary end point for all collagen markers. For each 10-&mgr;g/L increase in procollagen type I amino-terminal peptide, the hazard ratio (HR) for the primary end point was 1.09 (95% CI, 1.052 to 1.13; P<0.0001); for each 10-&mgr;g/L increase in procollagen type III amino-terminal peptide procollagen type I amino-terminal peptide, the HR was 2.47 (95% CI, 0.97 to 6.33; P=0.059); and for each 10-nmol/L increase in osteopontin, the HR was 1.084 (95% CI, 1.026 to 1.15; P=0.004). No variable remained significant as an independent predictor when introduced into a multivariable model. Both treatment groups tended to reduce collagen markers, with the reduction significantly greater for placebo versus irbesartan for procollagen type III amino-terminal peptide only (P=0.0185). Conclusions— Increased peripheral collagen turnover markers were not independently associated with increased mortality and cardiovascular hospitalization in an HFPEF population on multivariable analysis but were associated on single-variable analysis. These findings provide some support to the hypothesis that pathological fibrosis in the heart, and possibly the peripheral vasculature, may be contributory to adverse clinical outcomes in patients with HFPEF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Meta-analysis: Effect of B-Type Natriuretic Peptide Testing on Clinical Outcomes in Patients With Acute Dyspnea in the Emergency Setting

BACKGROUND Although the accuracy of B-type natriuretic peptide (BNP) testing for diagnosing acute decompensated heart failure has been extensively evaluated, the effect of this test on clinical outcomes remains unclear. PURPOSE To investigate whether BNP testing of patients presenting with acute dyspnea in the emergency department leads to fewer admissions, shorter length of stay, and improved short-term survival compared with usual care without BNP testing. DATA SOURCES Two reviewers searched Ovid MEDLINE and EMBASE, without language restrictions, to identify pertinent studies published from January 1996 to July 2010. STUDY SELECTION Randomized, controlled trials that compared BNP testing to diagnose heart failure with routine care in patients presenting with acute dyspnea and information about 1 or more of the following outcomes: mortality, admission, or length of hospital stay. DATA EXTRACTION Two authors independently reviewed articles, extracted data, and assessed quality and risk for bias of studies. DATA SYNTHESIS Five trials conducted in 5 countries and involving 2513 patients met inclusion criteria. Study settings had differing emergency department staffing models and used various BNP testing protocols. The pooled estimate of effect of BNP testing on all-cause mortality had wide confidence bounds and was inconclusive (odds ratio, 0.96 [95% CI, 0.65 to 1.41]). Admission rates decreased in the tested group compared with the control group (odds ratio, 0.82 [CI, 0.67 to 1.01]), although this finding was not statistically significant. Length of hospital and critical care unit stay were both modestly reduced in the tested group compared with the control group, with a mean difference of -1.22 days (CI, -2.31 to -0.14 day) and -0.56 day (CI, -1.06 to -0.05 day), respectively. LIMITATION Few relevant trials were studied. Patients included in the trials and the settings in which trials were conducted were heterogeneous. CONCLUSION B-type natriuretic peptide testing in the emergency department for patients presenting with acute dyspnea decreased length hospital of stay by about 1 day and possibly reduced admission rates but did not conclusively affect hospital mortality rates. PRIMARY FUNDING SOURCE Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Desirable performance standards for HbA1c analysis – precision, accuracy and standardisation Consensus statement of the Australasian Association of Clinical Biochemists (AACB), the Australian Diabetes Society (ADS), the Royal College of Pathologists of Australasia (RCPA), Endocrine Society of Australia (ESA), and the Australian Diabetes Educators Association (ADEA)

Abstract Background: HbA1c (glycohaemoglobin) is universally used in the ongoing monitoring of all patients with diabetes. There are many % HbA1c target control rating recommendations by national, regional and international expert bodies for diabetes patients and these are variable around the world. General patient target control ratings are currently most often recommended as either <6.5% or <7.0% HbA1c, with <6.0% HbA1c stated for individual patients where clinically possible. This necessitates very precise HbA1c assays and the same patient values, irrespective of HbA1c method or area of the world. Methods: HbA1c targets recommended by major expert groups and published HbA1c assay precision (coefficient of variation, %CV) levels have been detailed. These have been compared with published biological variation levels and with calculated HbA1c error ranges at various HbA1c levels and %CV levels. In addition, these have been compared with the analytical precision necessary to differentiate between the upper limit of the normal range for HbA1c and targets recommended by expert groups for diabetes control. Results: Intralaboratory analytical CVs of <2% are necessary and are achievable on automated HPLC analysers, and are supported on grounds of both clinical need and biological variation, as well as the need to differentiate the national, regional and international target recommendations from the upper limit of the normal range (<6.0% HbA1c level). Conclusions: Routine methods with tight long-term imprecision with CVs of <2% are recommended. International HbA1c targets essentially require that all HbA1c methods be precise, and have minimal standardisation bias and minimal methodological interferences in individual patients. Clin Chem Lab Med 2007;45:1083–97.

The role of HbA1c in the diagnosis of diabetes mellitus in Australia

For many years, the diagnosis of diabetes has been made through the laboratory‐based measurement of fasting or random blood glucose levels, or using the oral glucose tolerance test. A glycated haemoglobin (HbA1c) level ≥ 6.5% (48 mmol/mol) is now also acceptable for diagnosing diabetes. Caution is needed in interpreting HbA1c test results in the presence of conditions affecting red blood cells or their survival time, such as haemoglobinopathies or anaemia.

Parathyroid hormone-related protein in hypercalcemia associated with hematological malignancy.

Hypercalcemia is an important complication in multiple myeloma as well as T-cell leukemia/lymphoma, and is moderately common in high and intermediate grade non-Hodgkins lymphoma. The underlying mechanism has been unclear because the neoplastic cells are usually present in the bone marrow, where they are in a position to produce short range effects on bone resorption which are difficult to identify. This contrasts with the situation in hypercalcemia associated with non-metastatic carcinoma, where it has been clearly demonstrated that the most common cause is release from the tumor of a humoral mediator, Parathyroid Hormone-related Protein (PTHrP). Roles have been advocated in multiple myeloma for release of a number of other cytokines with osteolytic capacity on the basis of their enhancement of osteolytic activity in cultured fetal rat bone, although a causal relationship in patients has not been established. PTHrP has more recently been implicated in the genesis of hypercalcemia in patients with hematological malignancies by the demonstration in a proportion of cases of increased circulating levels of PTHrP, comparable to those in hypercalcemia due to cancer. Immunohistochemical studies indicate neoplastic hemopoietic cells can contain PTHrP, and thus have the capacity to act in a paracrine manner to enhance local bone resorption and contribute to the development of hypercalcemia.

Relation of Peripheral Collagen Markers to Death and Hospitalization in Patients With Heart Failure and Preserved Ejection FractionClinical Perspective

Background— Heart failure with preserved ejection fraction (HFPEF) is a common and increasing public health problem. Myocardial fibrosis is a key pathological feature of HFPEF. Peripheral collagen markers may reflect this excess fibrosis; however, the relation of these markers to prognosis in patients with HFPEF has not as yet been determined. Methods and Results— This substudy of the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial measured plasma levels of procollagen type I amino-terminal peptide, procollagen type III amino-terminal peptide, and osteopontin in 334 patients with HFPEF. Measurements were performed at baseline and 6 months after randomization to placebo or irbesartan 300 mg/day. The relation of baseline collagen markers to the I-PRESERVE primary end point (all-cause death and hospitalization for prespecified cardiovascular causes) was evaluated by single and multivariable analysis. Similar evaluations were performed for all-cause death alone as well as heart failure events (death or hospitalization because of heart failure). Increased plasma levels of collagen markers at baseline were associated with increased frequency of the study primary end point for all collagen markers. For each 10-&mgr;g/L increase in procollagen type I amino-terminal peptide, the hazard ratio (HR) for the primary end point was 1.09 (95% CI, 1.052 to 1.13; P<0.0001); for each 10-&mgr;g/L increase in procollagen type III amino-terminal peptide procollagen type I amino-terminal peptide, the HR was 2.47 (95% CI, 0.97 to 6.33; P=0.059); and for each 10-nmol/L increase in osteopontin, the HR was 1.084 (95% CI, 1.026 to 1.15; P=0.004). No variable remained significant as an independent predictor when introduced into a multivariable model. Both treatment groups tended to reduce collagen markers, with the reduction significantly greater for placebo versus irbesartan for procollagen type III amino-terminal peptide only (P=0.0185). Conclusions— Increased peripheral collagen turnover markers were not independently associated with increased mortality and cardiovascular hospitalization in an HFPEF population on multivariable analysis but were associated on single-variable analysis. These findings provide some support to the hypothesis that pathological fibrosis in the heart, and possibly the peripheral vasculature, may be contributory to adverse clinical outcomes in patients with HFPEF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Macrophage Migration Inhibitory Factor for the Early Prediction of Infarct Size

Background Early diagnosis and knowledge of infarct size is critical for the management of acute myocardial infarction (MI). We evaluated whether early elevated plasma level of macrophage migration inhibitory factor (MIF) is useful for these purposes in patients with ST‐elevation MI (STEMI). Methods and Results We first studied MIF level in plasma and the myocardium in mice and determined infarct size. MI for 15 or 60 minutes resulted in 2.5‐fold increase over control values in plasma MIF levels while MIF content in the ischemic myocardium reduced by 50% and plasma MIF levels correlated with myocardium‐at‐risk and infarct size at both time‐points (P<0.01). In patients with STEMI, we obtained admission plasma samples and measured MIF, conventional troponins (TnI, TnT), high sensitive TnI (hsTnI), creatine kinase (CK), CK‐MB, and myoglobin. Infarct size was assessed by cardiac magnetic resonance (CMR) imaging. Patients with chronic stable angina and healthy volunteers were studied as controls. Of 374 STEMI patients, 68% had elevated admission MIF levels above the highest value in healthy controls (>41.6 ng/mL), a proportion similar to hsTnI (75%) and TnI (50%), but greater than other biomarkers studied (20% to 31%, all P<0.05 versus MIF). Only admission MIF levels correlated with CMR‐derived infarct size, ventricular volumes and ejection fraction (n=42, r=0.46 to 0.77, all P<0.01) at 3 day and 3 months post‐MI. Conclusion Plasma MIF levels are elevated in a high proportion of STEMI patients at the first obtainable sample and these levels are predictive of final infarct size and the extent of cardiac remodeling.

Why did high-dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study

BACKGROUND Statins are often prescribed for prevention of atherosclerotic outcomes in patients who have chronic heart failure (CHF), if this has an ischaemic etiology. These agents may also possess additional properties, independent of effects on blood lipid levels, which may have an effect on cardiac remodeling. However, beneficial effects were not observed in the recent UNIVERSE trial. METHODS We prospectively planned a sub-study of UNIVERSE to explore relevant mechanistic effects of rosuvastatin, including effects on collagen turnover and plasma coenzyme Q10 (CoQ) levels. Additionally, CoQ levels in CHF patients receiving chronic statin therapy were measured. RESULTS CoQ levels were significantly reduced after 26 weeks of rosuvastatin statin therapy (n = 32), compared to placebo (n = 37) in CHF patients in UNIVERSE trial. Patients with CHF (n = 56) matched for age, gender and severity of disease who had been taking statins for 12 months or longer had CoQ levels of 847 ± 344 nmol/L, significantly lower than 1065.4 ± 394 nmol/L in UNIVERSE patients at baseline (p = 0.0001). Serum types I and III N-terminal procollagen peptide (PINP and PIIINP), measures of collagen turnover which can contribute to cardiac fibrosis were significantly increased in the rosuvastatin group compared to baseline in UNIVERSE patients (PINP: p = 0.03, PIIINP: p = 0.001). CONCLUSION In conclusion putative beneficial effects of statin therapy on cardiac remodeling in UNIVERSE may have been negated by increases in collagen turnover markers as well as a reduction in plasma CoQ levels in these patients with CHF.