Antonín Jabor

Transpulmonary B-Type Natriuretic Peptide Uptake and Cyclic Guanosine Monophosphate Release in Heart Failure and Pulmonary Hypertension The Effects of Sildenafil

OBJECTIVES We sought to identify factors that discriminate heart failure (HF) patients with normal and elevated pulmonary vascular resistance (PVR) and to elucidate the role of cyclic guanosine monophosphate (cGMP)-dependent vasodilation. BACKGROUND Mechanisms of PVR increase in patients with chronic HF are incompletely understood. METHODS Twenty-two HF patients with high pulmonary vascular resistance (H-PVR) (>200 dyn.s.cm(-5)) were compared with 24 matched low pulmonary vascular resistance (L-PVR) patients of similar age, sex, body size, HF severity, and volume status who were undergoing invasive hemodynamic study. Pulmonary arterial (PA) and venous blood samples from a wedged PA catheter were used to calculate transpulmonary B-type natriuretic peptide (BNP) uptake and cGMP release. The H-PVR patients were re-examined 1 h after a 40-mg oral dose of sildenafil. RESULTS Although transpulmonary BNP uptake was similar (p = 0.2), cGMP release was diminished in the H-PVR patients (-1.9 vs. 27.8 nmol.min(-1); p = 0.005). Transpulmonary BNP uptake and cGMP release correlated in the L-PVR patients (R = 0.6, p = 0.004) but not in the H-PVR. The H-PVR patients also had lower PA compliance, systemic arterial compliance (by 47% and 20%, p < 0.001 and p < 0.03), and cardiac index. Sildenafil reduced PVR (-47%), systemic resistance (-24%) and heart rate (-8%), increased cardiac index (+24%), and PA compliance (+87%, all p < 0.001), with a parallel increase of cGMP release (from -5.6 to 16.5 nmol.min(-1), p = 0.047), without affecting BNP uptake or norepinephrine(PA). The PVR response was not dependent on PA wedge pressure or pulmonary hypertension reversibility with prostaglandin E(1). CONCLUSIONS The H-PVR patients have stiffening of both pulmonary and systemic arteries, preserved transpulmonary BNP uptake, but diminished cGMP release, which is reversible by the administration of sildenafil. This study provides in vivo evidence that phosphodiesterase 5A inhibition restores sensitivity of pulmonary vasculature to endogenous cGMP-dependent vasodilators.

Lipolytic Effects of B-Type Natriuretic Peptide1–32 in Adipose Tissue of Heart Failure Patients Compared With Healthy Controls

OBJECTIVES Our goal was to examine the role of B-type natriuretic peptide (BNP) in lipolysis regulation in heart failure (HF) patients. BACKGROUND Enhanced adipose tissue lipolysis can contribute to myocardial lipid overload, insulin resistance, and cachexia in advanced HF. Natriuretic peptides were recently recognized to stimulate lipolysis in healthy subjects. METHODS Ten nondiabetic HF patients (New York Heart Association functional class III, 50% nonischemic etiology) and 13 healthy subjects (control subjects) of similar age, sex, and body composition underwent a microdialysis study of subcutaneous abdominal adipose tissue. Four microdialysis probes were simultaneously perfused with 0.1 μM BNP(1-32,) 10 μM BNP(1-32), 10 μM norepinephrine (NE) or Ringers solution. Outgoing dialysate glycerol concentration (DGC) was measured as an index of lipolysis. RESULTS Spontaneous lipolysis was higher in HF patients compared with control subjects (DGC: 189 ± 37 μmol/l vs. 152 ± 35 μmol/l, p < 0.01). Response to NE was similar (p = 0.35) in HF patients and control subjects (DGC increase of 1.7 ± 0.2-fold vs. 1.7 ± 0.4-fold). BNP(1-32) 10 μM markedly increased lipolysis in both HF patients and control subjects (DGC increase of 2.8 ± 0.5-fold vs. 3.2 ± 0.3-fold), whereas the response to 0.1 μM BNP(1-32) was more pronounced in HF patients (p = 0.02). In HF patients, spontaneous lipolysis positively correlated with insulin resistance and the response to BNP(1-32) negatively correlated with adiposity. CONCLUSIONS BNP(1-32) exerts strong lipolytic effects in humans. Despite marked elevation of plasma immunoreactive BNP, the responsiveness of adipose tissue to BNP(1-32) is not attenuated in HF, possibly reflecting a deficiency of endogenous bioactive BNP. Lipolytic effects of BNP can contribute to excessive fatty acid mobilization in advanced HF.

Association of Fibroblast Growth Factor-23 Levels and Angiotensin-Converting Enzyme Inhibition in Chronic Systolic Heart Failure.

OBJECTIVES The aim of this study was to evaluate the association of fibroblast growth factor (FGF)-23 with clinical and laboratory findings, the prognostic value of FGF-23, and the relationship between angiotensin-converting enzyme inhibitor (ACEi) therapy, FGF-23 levels, and outcomes in patients with chronic systolic heart failure (HF). BACKGROUND FGF-23 is a bone-derived hormone regulating mineral metabolism. Higher FGF-23 levels are associated with an increased risk of cardiovascular mortality or HF development. Mechanisms leading to increased FGF-23 and its prognostic value have not been thoroughly studied in HF. METHODS FGF-23 was measured in 369 patients (mean age 59 ± 11 years, 84% male) with systolic HF. Patients were followed for adverse events (e.g., death, urgent heart transplantation, ventricular assist device implantation). RESULTS Tricuspid regurgitation severity, chronic kidney disease (CKD), alkaline phosphatase concentrations, inferior vena cava dilation, and absence of ACEi therapy were independently associated with FGF-23. FGF-23 was independently associated with outcomes in patients without CKD (hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.14 to 1.78), but not in CKD patients (HR: 1.12, 95% CI: 0.87 to 1.45). In patients without CKD and with FGF-23 in the highest tertile, ACEi therapy was associated with a lower risk of adverse events (HR: 0.42, 95% CI: 0.21 to 0.81), whereas no association was seen in the remaining patients (HR: 1.18, 95% CI: 0.52 to 2.70). CONCLUSIONS In systolic HF, elevated FGF-23 is an independent predictor of adverse events, particularly in patients with preserved renal function. The association of FGF-23 with adverse events likely reflects early alterations of renal hemodynamics and renin-angiotensin system activation. Increased FGF-23 may identify a subset of HF patients benefiting from ACEi therapy.

Analytical evaluation of the automated galectin-3 assay on the Abbott ARCHITECT immunoassay instruments.

Abstract Background: Galectin-3 is secreted from macrophages and binds and activates fibroblasts forming collagen. Tissue fibrosis is central to the progression of chronic heart failure (CHF). We performed a European multicentered evaluation of the analytical performance of the two-step routine and Short Turn-Around-Time (STAT) galectin-3 immunoassay on the ARCHITECT i1000SR, i2000SR, and i4000SR (Abbott Laboratories). Methods: We evaluated the assay precision and dilution linearity for both routine and STAT assays and compared serum and plasma, and fresh vs. frozen samples. The reference interval and biological variability were also assessed. Measurable samples were compared between ARCHITECT instruments and between the routine and STAT assays and also to a galectin-3 ELISA (BG Medicine). Results: The total assay coefficient of variation (CV%) was 2.3%–6.2% and 1.7%–7.4% for the routine and STAT assays, respectively. Both assays demonstrated linearity up to 120 ng/mL. Galectin-3 concentrations were higher in plasma samples than in serum samples and correlated well between fresh and frozen samples (R=0.997), between the routine and STAT assays, between the ARCHITECT i1000 and i2000 instruments and with the galectin-3 ELISA. The reference interval on 627 apparently healthy individuals (53% male) yielded upper 95th and 97.5th percentiles of 25.2 and 28.4 ng/mL, respectively. Values were significantly lower in subjects younger than 50 years. Conclusions: The galectin-3 routine and STAT assays on the Abbott ARCHITECT instruments demonstrated good analytical performance. Further clinical studies are required to demonstrate the diagnostic and prognostic potential of this novel marker in patients with CHF.

Resting heart rate and heart rate reserve in advanced heart failure have distinct pathophysiologic correlates and prognostic impact: A prospective pilot study

OBJECTIVES The purpose of this study was to compare the prognostic impact of clinical and biomarker correlates of resting heart rate (HR) and chronotropic incompetence in heart failure (HF) patients. BACKGROUND The mechanisms and underlying pathophysiological influences of HR abnormalities in HF are incompletely understood. METHODS In a prospective pilot study, 81 patients with advanced systolic HF (97% were receiving beta-blockers) and 25 age-, sex-, and body-size matched healthy controls underwent maximal cardiopulmonary exercise testing with sampling of neurohormones and biomarkers. RESULTS Two-thirds of HF patients met criteria for chronotropic incompetence. Resting HR and HR reserve (HRR, a measure of chronotropic response) were not correlated with each other and were associated with distinct biomarker profiles. Resting HR correlated with increased myocardial stress (B-type natriuretic peptide [BNP]: r = 0.26; pro-A-type natriuretic peptide: r = 0.24; N-terminal-proBNP: r = 0.32) and inflammation (leukocyte count: r = 0.28; high-sensitivity C-reactive protein assay: r = 0.25). In contrast, HRR correlated with the neurohumoral response to HF (copeptin: r = -0.33; norepinephrine: r = -0.29) but not with myocyte stress or injury reflected by natriuretic peptides or hs-troponin I. Patients in the lowest chronotropic incompetence quartile (HRR ≤0.38) displayed more advanced HF, reduced exercise capacity, ventilatory inefficiency, and poorer quality of life. Over a median follow-up of 17 months, the combined endpoint of death or urgent transplant/assist device implantation occurred more frequently in patients with higher resting HR (>67 beats/min) or lower HRR, with both markers providing additive prognostic information. CONCLUSIONS Increased resting HR and chronotropic incompetence may reflect different pathophysiological processes, provide incremental prognostic information, and represent distinct therapeutic targets.

Quality of serum creatinine measurement in light of EQA programs.

Abstract Background: The aim of our study was to identify the role of External Quality Assessment (EQA) programs in improving the quality of serum creatinine measurement and glomerular filtration rate (GFR) estimation. Comparison of results achieved during EQA with National Kidney Disease Education Program and College of American Pathologists guidelines identified an urgent need for an improvement in measurement quality. We compared actual results for serum creatinine measurement within the Czech Republic EQA with the requirements of EC Directive 98/79. Methods: We used the results for 2005–2006 EQA programs. There were seven surveys involved with two samples each, and a 2006 questionnaire on the post-analytical phase survey. Results: Bias depended strongly on the creatinine concentration. However, this dependence varied for different in vitro diagnostic manufacturers, although they should all follow the same directive. We chose biological variation as the significance rate for bias and a resulting overall error of 6.9%. The proportion of results with total error <6.9% ranged from 11% to 80%. The total error for a reference sample of 94.8 μmol/L also showed significant dependence on the working calibrator used and ranged from 1% to 17%. Conclusions: The main role of EQA programs in improving the quality of creatinine measurement results and GFR calculation should be in monitoring the quality of IVD products, enabling users to adapt their use of these products accordingly. EQA programs can also educate on performing GFR estimation in a unified way. Highly commutable control materials with certified creatinine values or, alternatively, lyophilized materials with sufficient commutability proved by comparison with native frozen human sera, should become an important EQA tool. Clin Chem Lab Med 2007;45:685–8.

The role of timely measurement of galectin-3, NT-proBNP, cystatin C and hsTnT in predicting prognosis and heart function after heart transplantation.

Abstract Background: Changes of biomarkers measured soon after heart transplantation (HTx) can reflect different processes: cardiomyocyte necrosis (troponins, high-sensitivity cardiac TnT and TnI), heart function (natriuretic peptides, BNP and NT-proBNP), fibrosis (galectin-3 and ST2), and global cardiorenal risk (cystatin C). We assessed the prognostic role of hsTnT, NT-proBNP, galectin-3 and cystatin C during the early post-transplant period. Methods: A total of 121 consecutive post-HTx patients were assessed. The main outcomes were survival, left ventricular ejection fraction (LVEF) and rejection periods. Survival was assessed after intermediate (12 months) and long periods (total follow-up during study, median of survival 763 days, IR 527–1038 days). LVEF was assessed 12 months after HTx. Rejection was evaluated during follow-up. We report biomarker concentrations measured 10 days and 12 months after HTx. Results: Ten days after HTx, cystatin C and hsTnT predicted death both under univariable and multivariable analysis. These two biomarkers along with galectin-3 were increased in patients with decreased LVEF measured 1 year after HTx. NT-proBNP did not show early prognostic power. None of the measured biomarkers predicted rejection, but hsTnT and NT-proBNP were increased significantly 12 months after HTx in patients with at least one rejection. Conclusions: Cystatin C and hsTnT measured 10 days after HTx can provide prognostic information on survival and galectin-3 measured at the same time may display a relationship to heart function assessed 1 year after HTx. Further study should be carried out in a large cohort of patients.

Comparison of Cystatin C and NGAL in Early Diagnosis of Acute Kidney Injury After Heart Transplantation

BACKGROUND Acute kidney injury (AKI) is a risk factor for adverse hospital outcomes in recipients of a heart transplantation (HTx). Timely recognition of AKI is crucial for the initiation of proper treatment. We hypothesized that serum or urine biomarkers can predict AKI. MATERIAL AND METHODS In this prospective study we evaluated 117 consecutive patients after HTx. AKI was defined as an increase of the serum creatinine level by ≥50% or a worsening of the renal function requiring renal replacement therapy during the first post-HTx week. We serially sampled serum cystatin C (S-cystatin C) as a marker of glomerular filtration and urinary neutrophil gelatinase-associated lipocalin (U-NGAL) as a marker of tubular damage. RESULTS A cohort of 30 patients (25.6%) fulfilled the criteria of AKI. S-cystatin C allowed the earliest separation between the AKI and non-AKI groups, with a significant difference present as soon as 3 h after surgery and it persisted on days 7, 10, and 30. The increase in S-cystatin C preceded the serum creatinine elevation by 4 days. In a multivariate analysis, S-cystatin C >1.6 mg/L at 3 h after HTx predicted AKI with OR 4.3 (95% CI: 1.6-11.5). U-NGAL was significantly higher at day 3 in the AKI group (p=0.003) and elevated S-cystatin C (≥2.54 mg/L on day 7) could predict 1-year mortality in these HTx recipients. CONCLUSIONS Our study showed that the measurement of S-cystatin C at 3 h after surgery may help to identify patients with high risk for renal complications. A persistent elevation of S-cystatin C also predicts 1-year mortality.

Selected markers of bone biochemistry

Publisher Summary Monitoring bone turnover and bone remodeling using biochemical methods is possible with the help of two types of parameters. This chapter reviews the selected markers used in bone biochemistry. Mature cortical and trabecular bone consistently undergo bone remodeling. Bone remodeling is in progress with variable intensity throughout life, and the connection of resorption to subsequent bone formation is essential. Some of the hormones and local agents used as markers are cytokines, dehydroepiandrosterone (DHEA), hormones of the thyroid gland, anabolic steroids, prolactin, and parathormone–related peptide (PTHrP). Systemic markers of bone remodeling are divided into: markers of bone formation produced by osteoblasts, markers of bone resorption produced by osteoclasts, and products of collagen type I degradation. The markers of bone remodeling change their concentration and activity in various diseases of the bone tissue, which are tabulated. The chapter also discusses the general potential, variability of the results, serum markers produced by osteoblasts and osteoclasts, and clinical usefulness of the markers of bone remodeling. Follow–up of the response to treatment is the principal current application of the measurement of the markers of bone remodeling.

Rational use of clinical chemistry investigations: from diagnoses to processes.

Agreed clinical protocols are probably the best way of selecting suitable investigations for the diagnosis or exclusion of a specific clinical condition.’ Problems arise when the clinical condition is thought of as a (morphological) diagnosis (by physicians) and not as a complex pathophysiological process (recognized by laboratory scientists). Furthermore, clinical chemists and physicians differ significantly when judging the utility of a particular quantity.* Processes should be evaluated more frequently. A typical example of this is osteoporosis, a disorder that may be the result of several pathological processes. Laboratory tests that might be requested include osteocalcin, bone alkaline phosphatase, propeptides or telopeptides of type I collagen, urinary deoxypyridinoline and others. Some results (of catalytic activity or substance concentrations) may fall within the reference interval, while others will be above or below this interval. There are many variations in this data set which can be consistent with the diagnosis of osteoporosis, but none which prove or exclude it. The presence of pathophysiological processes, which are reflected by the above mentioned quantities, do not necessarily confirm the diagnosis as a morphological disease.