Intermittent levosimendan treatment in patients with severe congestive heart failure.

OBJECTIVE: Levosimendan (LS) is a novel inodilator for the treatment of severe congestive heart failure (CHF). In this study, we investigated the potential long-term effects of intermittent LS treatment on the pathophysiology of heart failure. METHODS: Thirteen patients with modest to severe CHF received three 24-h intravenous infusions of LS at 3-week intervals. Exercise capacity was determined by bicycle ergospirometry, well-being assessed by Minnesota Living with Heart Failure Questionnaire (MLHFQ) and laboratory parameters of interest measured before and after each treatment. RESULTS: One patient experienced non-sustained periods of ventricular tachycardia (VT) during the first infusion and had to discontinue the study. Otherwise the LS infusions were well tolerated. Exercise capacity (VO2max) did not improve significantly during the study although symptoms decreased (P < 0.0001). Levels of plasma NT-proANP, NT-proBNP and NT-proXNP decreased 30-50% during each infusion (P < 0.001 for all), but the changes disappeared within 3 weeks. Although norepinephrine (NE) appeared to increase during the first treatment (P = 0.019), no long-term changes were observed. CONCLUSION: Intermittent LS treatments decreased effectively and repetitively plasma vasoactive peptide levels, but no carryover effects were observed. Patients' symptoms decreased for the whole study period although there was no objective improvement of their exercise capacity. The prognostic significance of these effects needs to be further studied.

Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy.

OBJECTIVE: To investigate the role of inflammation in the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy (HCM). DESIGN: Clinical study. SETTING: Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland. SUBJECTS: Twenty-four patients with a single HCM-causing mutation D175N in the α-tropomyosin gene and 17 control subjects. MAIN OUTCOME MEASURES: Endomyocardial biopsy samples taken from the patients with HCM were compared with matched myocardial autopsy specimens. Levels of high-sensitivity C-reactive protein (hsCRP) and proinflammatory cytokines were measured in patients and controls. Myocardial late gadolinium enhancement (LGE) in cardiac MRI (CMRI) was detected. RESULTS: Endomyocardial samples in patients with HCM showed variable myocyte hypertrophy and size heterogeneity, myofibre disarray, fibrosis, inflammatory cell infiltration and nuclear factor kappa B (NF-κB) activation. Levels of hsCRP and interleukins (IL-1ß, IL-1RA, IL-6, IL-10) were significantly higher in patients with HCM than in control subjects. In patients with HCM, there was a significant association between the degree of myocardial inflammatory cell infiltration, fibrosis in histopathological samples and myocardial LGE in CMRI. Levels of hsCRP were significantly associated with histopathological myocardial fibrosis. hsCRP, tumour necrosis factor α and IL-1RA levels had significant correlations with LGE in CMRI. CONCLUSIONS: A variable myocardial and systemic inflammatory response was demonstrated in patients with HCM attributable to an identified sarcometric mutation. Inflammatory response was associated with myocardial fibrosis, suggesting that myocardial fibrosis in HCM is an active process modified by an inflammatory response.

Flow-mediated vasodilation is not attenuated in hypertensive pregnancies despite biochemical signs of inflammation.

Background. Our objective was to evaluate endothelial function and markers of inflammation during and after pregnancy in normal pregnancies compared to pregnancies complicated with hypertension or preeclampsia (PE). Methods and Results. We measured endothelium-dependent brachial artery flow-mediated vasodilation (FMD) and high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α) in 32 women with normal pregnancy and in 28 women whose pregnancy was complicated with hypertensive disorder in the second half of pregnancy and minimum 3-month postpartum. Enhancement of endothelial function was greater in hypertensive than normal pregnancies, the mean FMD% being 11.0% versus 8.8% during pregnancy (P = 0.194) and 8.0% versus 7.9% postpartum (P = 0.978). Concentrations of markers of inflammation were markedly increased in pregnant hypertensive group compared to those after delivery (hsCRP 4.5 versus 0.80 mg/L, P = 0.023, IL-6 2.1 versus 1.2 pg/mL, P = 0.006; TNF-α 1.9 versus 1.5 pg/mL, P = 0.030). There were no statistically significant associations between the markers of inflammation and FMD. Conclusions. Brachial artery FMD was not attenuated in the third trimester hypertensive pregnancies compared to normal pregnancies, whereas circulating concentrations of hsCRP and IL-6 and TNF-α reacted to hypertensive complications.

Serum interleukin 1 receptor antagonist as an independent marker of non-alcoholic steatohepatitis in humans.

BACKGROUND & AIMS: Mechanisms leading to non-alcoholic steatohepatitis (NASH) have remained unclear, and non-invasive diagnosis of NASH is challenging. In this study, we investigated the benefits of measuring serum interleukin 1 receptor antagonist (IL-1RA) levels. METHODS: Liver biopsies from 119 morbidly obese individuals (47.5 ± 9.0 years, BMI 44.9 ± 5.9 kg/m(2)) were used for histological and gene expression assessment. In a cross-sectional population-based cohort of 6447 men (58 ± 7 years, BMI 27.0 ± 3.9 kg/m(2)) the association of serum IL1-RA with serum alanine aminotransferase (ALT) levels was investigated. RESULTS: Serum levels of IL-1RA, and liver mRNA expression of IL1RN are associated with NASH and the degree of lobular inflammation in liver (p<0.05). The decrease in serum IL-1RA level and expression of IL1RN after obesity surgery correlated with the improvement of lobular inflammation (p<0.05). We developed a novel NAFLD Liver Inflammation Score, including serum Il-1RA concentration, which performed better to diagnose NASH than did previously published scores. Results from the population study confirmed the potential of measuring serum IL-1RA level. The strongest determinants of the ALT concentration at the population level were Matsuda insulin sensitivity index (r(2)=0.130, p=7 × 10(-197)) and serum IL-1RA concentration (r(2)=0.074, p=1 × 10(-110)). IL-1RA concentrations associated significantly with ALT levels even after adjusting for BMI, alcohol consumption and insulin sensitivity (p=2 × 10(-21)). CONCLUSIONS: IL-1RA serum levels associate with liver inflammation and serum ALT independently of obesity, alcohol consumption and insulin resistance, suggesting a potential use of IL-1RA as a non-invasive inflammatory marker for NASH.

Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index.

Anemia of chronic disease (ACD) and iron deficiency anemia (IDA) are the most prevalent forms of anemia and often occur concurrently. Standard tests of iron status used in differential diagnosis are affected by inflammation, hindering clinical interpretation. In contrast, soluble transferrin receptor (sTfR) indicates iron deficiency and is unaffected by inflammation. Objectives of this prospective multicenter clinical trial were to evaluate and compare the diagnostic accuracy of sTfR and the sTfR/log ferritin index (sTfR Index) for differential diagnosis using the automated Access(®) sTfR assay (Beckman Coulter) and sTfR Index. We consecutively enrolled 145 anemic patients with common disorders associated with IDA and ACD. Subjects with IDA or ACD + IDA had significantly higher sTfR and sTfR Index values than subjects with ACD (P < 0.0001). ROC curves produced the following cutoffs for sTfR: 21 nmol/L (or 1.55 mg/L), and the sTfR Index: 14 (using nmol/L) (or 1.03 using mg/L). The sTfR Index was superior to sTfR (AUC 0.87 vs. 0.74, P < 0.0001). Use of all three parameters in combination more than doubled the detection of IDA, from 41% (ferritin alone) to 92% (ferritin, sTfR, sTfR Index). Use of sTfR and the sTfR Index improves detection of IDA, particularly in situations where routine markers provide equivocal results. Findings demonstrate a significant advantage in the simultaneous determination of ferritin, sTfR and sTfR Index. Obtaining a ferritin level alone may delay diagnosis of combined IDA and ACD.

The diagnostic accuracy of the percentage of hypochromic red blood cells (%HYPOm) and cellular hemoglobin in reticulocytes (CHr) in differentiating iron deficiency anemia and anemia of chronic diseases.

BACKGROUND: The percentages of hypochromic red blood cells (%HYPOm) and cellular hemoglobin in reticulocytes (CHr) are suggested to be useful screening markers of iron deficiency. The aim of this study was to investigate the diagnostic accuracy of %HYPOm and CHr in differentiating iron deficiency anemia (IDA) and anemia of chronic disease (ACD). METHODS: The retrospective population consisted of 58 IDA patients, 129 ACD patients and 63 controls, on whom bone marrow examination and blood count with %HYPOm and CHr had been performed. Receiver operating characteristic (ROC) analyses with area under the ROC curves (AUC) were used as statistical tests. RESULTS: AUCs for differentiating the groups using %HYPOm were as follows: IDA vs. controls 0.99, ACD vs. controls 0.85 and IDA vs. ACD 0.88. AUCs for CHr in distinguishing the groups were as follows: IDA vs. controls 0.95, ACD vs. controls 0.65 and IDA vs. ACD 0.83. CONCLUSIONS: IDA and ACD patients were efficiently differentiated by using %HYPOm and CHr. Additionally, %HYPOm was higher and CHr was lower in IDA patients and in ACD patients than in controls. Thus, %HYPOm is higher and CHr is lower not only in absolute iron deficiency, but also when iron availability for erythropoiesis is restricted.

Transferrin receptor expression on reticulocytes as a marker of iron status in dialyzed patients.

BACKGROUND: Erythropoietin therapy should be accompanied by an adequate iron supply in order to avoid functional iron deficiency (FID) related to enhanced erythropoiesis. Therefore, accurate monitoring of the body's iron homeostasis is needed. This study was conducted to investigate whether transferrin receptor (TfR) expression on reticulocytes can reflect iron status in patients with chronic renal failure (CRF). METHODS: TfR expression [antibody binding capacity (ABC)] and the proportion of TfR positive reticulocytes (%TfR+ Ret) relative to all reticulocytes were measured by a quantitative flow cytometric method at baseline and at 3 weeks in 34 dialysis patients. Iron status (plasma ferritin and soluble TfR) and hemoglobin (Hb) with advanced cellular indices, such as the percentage of hypochromic reticulocytes (%HYPOr) and cellular Hb in reticulocytes (CHr), were also analyzed. RESULTS: Patients with FID had significantly higher TfR ABC and %TfR+ Ret compared with patients with replete iron status (p=0.034 and p=0.006, respectively). In patients whose Hb concentrations showed a reduction, the mean increase (3 weeks- baseline) in TfR ABC was four-fold higher and %TfR(+)Ret was three-fold higher when compared with patients whose Hb was stable or had increased. The changes in TfR expression correlated significantly with the changes in reticulocyte indices [CHr (negatively), %HYPOr (positively)] and plasma ferritin (negatively). CONCLUSIONS: Reticulocyte TfR expression reflected the changes in the Hb level and the iron availability at the cellular level, and therefore it might be useful in the assessment of iron status in patients with CRF.

Maternal serum hepcidin is low at term and independent of cord blood iron status.

OBJECTIVES: Hepcidin is the key regulator of iron homeostasis. The aims of this study were to determine serum hepcidin concentrations and reference ranges in pregnant women and cord blood of newborns at term and to evaluate the associations between hepcidin concentrations and iron status parameters. METHODS: A total of 191 pregnant women-newborn pairs were studied in Kuopio University Hospital, Finland. The measured parameters were serum hepcidin, ferritin, transferrin receptor, transferrin saturation, red cell indices, and erythropoietin. RESULTS: The hepcidin concentration in pregnant women was significantly lower than in cord blood at term [geometric mean concentration (GMC) (95% confidence intervals) in pregnant women 10.7 ng/mL (8.5-13.4 ng/mL) vs. GMC of cord blood hepcidin 69.3 ng/mL (55.3-86.8 ng/mL), P<0.001, adjusted analysis of variance]. Hepcidin was undetectable in 12% of mothers. Hepcidin concentration in pregnant women was the lowest in those who had the lowest iron status. However, maternal hepcidin concentration was not associated with cord blood hepcidin or iron status markers. Hepcidin concentration in cord blood was associated with cord blood iron status, but not with maternal iron status. CONCLUSIONS: At term pregnancy, hepcidin concentrations are very low, allowing maximal availability of iron for the fetus. Maternal and cord blood hepcidin levels were independently associated with either maternal or cord blood iron status.

Changes in cytokine levels during acute hyperinsulinemia in offspring of type 2 diabetic subjects.

OBJECTIVE: To investigate the changes in the levels of cytokines and adhesion molecules in response to acute hyperinsulinemia in the offspring of type 2 diabetic subjects. METHODS: Forty healthy offspring of type 2 diabetic subjects and 19 control offspring of healthy parents were included in the study. Twenty offspring had normal glucose tolerance (NGT) and twenty offspring impaired glucose tolerance (IGT). Insulin sensitivity was determined by the hyperinsulinemic euglycemic clamp and insulin secretion with the intravenous glucose tolerance test. The levels of cytokines and adhesion molecules were measured before and at the end of the clamp. RESULTS: Acute hyperinsulinemia induced by the euglycemic hyperinsulinemic clamp reduced the levels of TNF-alpha, IL-8, IL-10 and IL-18 in healthy controls but not in the offspring of type 2 diabetic subjects having NGT or IGT. In response to insulin, levels of hs-CRP decreased and levels of IL-6 increased significantly in all study groups. The levels of adhesion molecules (ICAM-1, VCAM-1, E-Selectin) remained unchanged in response to hyperinsulinemia. CONCLUSIONS: The suppression of cytokine levels (particularly proinflammatory cytokines) during acute hyperinsulinemia observed in healthy controls was not present in offspring of type 2 diabetic patients. This emphasizes the crucial role of low-grade inflammation in insulin resistance in subjects with high risk of developing diabetes.

The activation of the inflammatory cytokines in overweight patients with mild obstructive sleep apnoea.

It is widely accepted that obstructive sleep apnoea (OSA) is linked with cardiovascular diseases. The relationship is complex and remains still poorly understood. The presence of chronic systemic inflammation has been connected with pathogenesis of both OSA and cardiovascular diseases. While atherogenesis is believed to be a process of many years, little is known about the potential impact of the largest OSA subgroup, mild OSA, on the development of cardiovascular diseases. The aim of the present study was to assess whether untreated mild OSA is associated with an activation of inflammatory cytokine system. The adult study population consisted of two groups: 84 patients with mild OSA [apnoea-hypopnoea index (AHI) 5-15 h(-1)] and 40 controls (AHI <5 h(-1)). Serum concentrations of pro- and anti-inflammatory cytokines were measured before any interventions. After adjustments for age, sex, body mass index, fat percentage, most important cardiometabolic and inflammatory diseases, and non-steroidal anti-inflammatory medication, the mean level of tumour necrosis factor-alpha was significantly elevated (1.54 versus 1.17 pg mL(-1), P = 0.004), whereas the level of interleukin-1 beta (IL-1 beta) was reduced (0.19 versus 0.23 pg mL(-1), P = 0.004) in patients with mild OSA compared with controls. The concentrations of the protective anti-inflammatory cytokines, interleukin-10 (1.28 versus 0.70 pg mL(-1), P < 0.001) and interleukin-1 receptor antagonist (478 versus 330 pg mL(-1), P = 0.003) were elevated in the OSA group. The concentrations of C-reactive protein increased, but IL-1 beta decreased along with the increase of AHI. Mild OSA was found to be associated not only with the activation of the pro-inflammatory, but also with the anti-inflammatory systems.

ADMA concentration changes across the menstrual cycle and during oral contraceptive use: the Cardiovascular Risk in Young Finns Study.

OBJECTIVE: The aim of this study was to evaluate changes in the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) levels during different menstrual cycle phases in young adult women with or without oral contraceptive (OC) use. DESIGN AND METHODS: The subjects (n=1079) originated from a large population-based, prospective cohort study conducted in Finland. Plasma ADMA, symmetric dimethylarginine (SDMA), L-arginine, C-reactive protein, creatinine, and brachial artery flow-mediated dilatation (FMD) were measured. The use of OCs and menstrual cycle phase were determined from a questionnaire. RESULTS: In non-OC users, ADMA (P=0.017), L-arginine (P=0.002), and ADMA/SDMA ratio (P<0.001) were significantly lower in the luteal phase than in the follicular phase of the menstrual cycle. Non-OC users also had significantly higher ADMA and SDMA concentrations (P<0.001) and lower L-arginine concentrations (P<0.001) compared to OC users of estrogen-containing pills. Progestin-only contraceptive pills (POPs) did not lower the ADMA level, but maintained it at the same level as in non-OC users. In OC users, there were no significant differences found in ADMA, FMD, or FMD% across menstrual cycle, whereas brachial artery diameter was significantly more decreased in the luteal phase (P=0.013) than in the follicular phase. CONCLUSION: We observed that the circulating ADMA concentration varies across the menstrual cycle in young women not using OCs, and women on OCs displayed significantly lower circulating ADMA concentrations than non-OC users, though this was not the case with POP contraception.

Maternal pro-hepcidin at term correlates with cord blood pro-hepcidin at birth.

OBJECTIVE: Hepcidin, a small 25 amino-acid antimicrobial peptide, has a significant role in the regulation of iron homeostasis. Pro-hepcidin, an 84 amino-acid peptide, is a precursor of the active hepcidin. The main aim of this study was to examine the association of maternal serum pro-hepcidin with cord blood pro-hepcidin levels in term pregnancies, and whether maternal and newborn iron status measurements correlate with the pro-hepcidin level. STUDY DESIGN: The population consisted of 193 pregnant women admitted to the Kuopio University Hospital (Finland) for delivery, and their full-term newborn infants (cord blood). The main outcome measures were serum pro-hepcidin (ELISA), blood count including red cell indices, serum iron status markers (including iron, transferrin, transferrin saturation (TfSat), transferrin receptor (TfR) and ferritin), birth weight and placental weight and relative placental size. A Mann-Whitney U-test and Spearman's correlation were used to test the associations between the parameters. RESULTS: Pregnant women had higher pro-hepcidin level than their newborns (325 microg/L vs. 235 microg/L, p<0.001). The Spearman's correlation between the maternal and cord blood serum pro-hepcidin level was highly significant (correlation coefficient 0.600, p<0.001). Additionally, both maternal and cord blood pro-hepcidin levels correlated weakly but significantly with placental weight and relative placental size. However, pro-hepcidin level did not correlate with iron status measurements in pregnant women or in their newborns. CONCLUSIONS: The present results suggest that pro-hepcidin is not associated with maternal or newborn iron homeostasis at term and birth, but may act in concert with the placenta, as evidenced by the correlation between maternal and fetal pro-hepcidin levels and their slight correlation with placental weight.

Cardiac sympathetic activity is associated with inflammation and neurohumoral activation in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Idiopathic dilated cardiomyopathy (IDC) is characterized by sympathetic nervous overactivity, inflammation and neurohumoral activation; however, their interrelationships are poorly understood. METHODS AND RESULTS: We studied 99 patients with IDC (age 54 +/- 1 years, left ventricular ejection fraction (EF) 40 +/- 1%, maximum oxygen uptake (VO(2)max) 20 +/- 1 ml kg(-1) min(-2), mean +/- SEM) by using (123)I-metaiodobenzylguanidine (MIBG) imaging. MIBG washout and MIBG heart/mediastinum (H/M)-ratio at 4 h postinjection were calculated. In addition, the plasma levels of interleukin (IL)-6 and N-terminal B-type natriuretic peptide (NT-proBNP) were measured. MIBG washout and MIBG H/M ratio had a significant correlation with IL-6 (r = 0.42, P<0.001 and r = -0.31, P<0.01) and NT-proBNP (r = 0.48, P<0.001 and r = -0.40, P<0.001). During a median follow-up of 4.1 years, 20 patients (20%) had an adverse cardiac event (death, heart transplantation or application of biventricular pacemaker or implantable cardioverter-defibrillator). In these patients, MIBG washout was higher (53 +/- 4 versus 40 +/- 2%, P = 0.01) and H/M ratio lower (1.38 +/- 0.04 versus 1.51 +/- 0.02, P = 0.01) than in patients without an event. CONCLUSIONS: In dilated cardiomyopathy, myocardial sympathetic innervation and activity are related to inflammation and neurohumoral activation. These relationships are at least partly independent of left ventricular function and exercise capacity.

Flow mediated vasodilation and circulating concentrations of high sensitive C-reactive protein, interleukin-6 and tumor necrosis factor-alpha in normal pregnancy--The Cardiovascular Risk in Young Finns Study.

BACKGROUND: Traditional risk factors such as hyperlipidemia induce a state of inflammation that impairs vascular function. Despite marked maternal hyperlipidemia, endothelial function improves during pregnancy. In non-pregnant state increased circulating levels of pro-inflammatory cytokines and high sensitive C-reactive protein (hsCRP) lead to attenuated flow mediated vasodilation. Relation between endothelial function and pro-inflammatory cytokines has not been studied thoroughly in pregnancy. The aim of this study was to evaluate the effect of pregnancy on hsCRP and pro-inflammatory cytokines and their associations with vascular endothelial function. METHODS: As part of population-based, prospective cohort Cardiovascular Risk in Young Finns study conducted in Finland we measured brachial artery flow mediated dilation (FMD) and serum concentrations of hsCRP, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in 57 pregnant Finnish women throughout gestation and 62 control women matched for age and smoking. RESULTS: HsCRP-concentration was greater in pregnancy compared to non-pregnant controls (median hsCRP 2.52 mg l(-1) versus 1.21 mg l(-1), P<0.001). IL-6-concentration was slightly increased in pregnancy compared with the non-pregnant controls (median 1.66 versus 1.32 mg l(-1), non-significant [NS]) and TNF-alpha-concentration was slightly decreased in pregnant group (2.11 versus 2.38 pg ml(-1), NS). FMD increased during pregnancy and IL-6 had a positive correlation to the FMD in pregnancy (R = 0.288, P = 0.031). CONCLUSIONS: Improvement of FMD in normal pregnancy was not affected by increase in hsCRP concentration. We found an association with IL-6 and FMD but we believe that improvement in endothelial function during normal pregnancy is not caused by variation in hsCRP, IL-6 or TNF-alpha.

Maternal serum ADMA is not associated with proinflammatory cytokines or C-reactive protein during normal pregnancy.

Normal pregnancy is associated with changes in the immune system. We studied whether asymmetrical dimethylarginine (ADMA) is associated with this immune system change by assaying high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). The cytokine and dimethylarginine serum concentrations were determined from women with normal pregnancy (n=77) and healthy non-pregnant controls (n=61) matched for age and smoking status as a part of a large population-based, prospective cohort study conducted in Finland. The hsCRP levels were significantly elevated in the second (P=0.016) and third trimesters (P=0.001) of pregnancy compared to the levels of non-pregnant women. IL-6 levels were significantly higher in the third trimester (P=0.029) of pregnancy than in non-pregnant state. TNF-alpha concentrations did not change significantly during pregnancy. ADMA and SDMA concentrations were significantly lower during pregnancy compared to the levels of non-pregnant women (P<0.001). There was no significant association between ADMA and inflammation markers regardless of the elevated serum concentrations of hsCRP and IL-6 in the third trimester of normal pregnancy. These results suggest that maternal systemic ADMA and SDMA concentrations are more likely to become decreased due to the hemodilution and increased renal clearance than being directly influenced by the change of cytokines during pregnancy.

Early signs of maternal iron deficiency do not influence the iron status of the newborn, but are associated with higher infant birthweight.

OBJECTIVE: To investigate the associations between maternal iron status, pregnancy outcome and newborn iron status using sensitive and specific red blood cell indices reflecting iron-deficient erythropoiesis. DESIGN AND SETTING: Cross-sectional study in Kuopio University Hospital, Finland. POPULATION: One hundred and ninety-two pregnant women and their full-term newborns (cord blood). METHODS: Quartile analysis and Spearman correlations were used to investigate the associations of the iron status of pregnant women with that of their newborns, and with pregnancy outcome. MAIN OUTCOME MEASURES: Maternal and cord blood analysis including indices reflecting the hemoglobin (Hb) content of red blood cells as well as serum iron, transferrin saturation, transferrin receptor and ferritin. Gestational age, birthweight and placental weight. RESULTS: The highest quartile of the maternal percentage of hypochromic red blood cells (%HYPOm) indicating the lowest iron status was associated with a high birthweight and a long duration of pregnancy. The newborns in this group did not show any signs of iron deficiency even though the maternal %HYPOm was elevated. CONCLUSIONS: In a well-nourished maternal population, lower maternal iron status did not affect the iron accumulation on the fetal side. However, longer duration of pregnancy and growth of the fetus appeared to be associated with a lower amount of iron for Hb synthesis in maternal red blood cells, as reflected by the increased maternal %HYPOm, birthweight and length of gestation.

Serum L-homoarginine concentration is elevated during normal pregnancy and is related to flow-mediated vasodilatation.

BACKGROUND: Normal pregnancy is associated with enhanced vasodilatation because of the increased nitric oxide (NO) production. Because L-homoarginine can act as a substrate for NO production, concentrations of L-homoarginine in normal pregnancy were assessed in the present study to test whether L-homoarginine is associated with endothelial function. METHODS AND RESULTS: Healthy non-pregnant (n=61) and pregnant women (n=58) were studied in a cross-sectional study. L-homoarginine, L-arginine, asymmetric dimethylarginine and symmetric dimethylarginine concentrations were determined simultaneously by high-performance liquid chromatography. Endothelium-dependent brachial artery flow-mediated dilation (FMD) was measured by ultrasound. The serum L-homoarginine concentration was significantly higher during the second and the third trimesters compared with the levels in the non-pregnant women (4.8+/-1.7 and 5.3+/-1.5 vs 2.7+/-1.0 micromol/L, p<0.001, respectively). In line with this, FMD increased in response to pregnancy (p<0.05). Three months after delivery, the L-homoarginine concentrations and FMD were comparable to those recorded in the non-pregnant females. The concentration of L-homoarginine correlated significantly with gestational age (r=0.426, p=0.001) and brachial artery diameter and FMD (r=0.362, p=0.006 and r=0.306, p=0.022, respectively) in pregnancy. CONCLUSIONS: L-homoarginine appears to be increased during the second and third trimesters of pregnancy and may contribute to the enhanced endothelial function in normal pregnancies.

Clinical significance of troponin I efflux and troponin autoantibodies in patients with dilated cardiomyopathy.

BACKGROUND: The appearance of circulating autoantibodies against cardiac troponin I (cTnAbs) in patients with heart failure has been reported. We sought to evaluate the role of circulating cardiac troponin I (cTnI) and cTnAbs in the pathophysiology and prognosis of idiopathic dilated cardiomyopathy. METHODS AND RESULTS: Circulating concentrations of cTnI and the presence of cTnAbs were determined in 95 patients with idiopathic dilated cardiomyopathy. The patients underwent laboratory testing, echocardiography, cardiopulmonary exercise testing, gated single photon emission computed tomography, and both-sided cardiac catheterization during a 3-day study period. Compared with cTnI- patients, the hearts of cTnI+ patients (cTnI > or = 0.01 ng/mL, n = 19) were significantly more dilated (left ventricular end-diastolic diameter 67 vs 61 mm, P < .05; left ventricular end-systolic dimension, 55 vs 49 mm, P < .01; echocardiography) and demonstrated greater intracardiac volumes (left ventricular end-diastolic volume 161 vs 132 mL, P = .060; left ventricular end-systolic volume 112 vs 82 mL, P < .05; gated single photon emission computed tomography), more disturbed systolic (ejection fraction 27 vs 33%, P < .05; gated single photon emission computed tomography) and cardiac sympathetic (123I-metaiodobenzylguanidine washout: 41% vs 34%; P < .05) function, and higher levels of vasoactive peptides (N-terminal proatrial natriuretic peptide 1030 vs 558 pmol/L, P < .05; N-terminal pro-B type natriuretic peptide 337 vs 115 pmol/L, P < .05). In addition, during a median follow-up time of 4.1 years, cTnI+ patients had clinical end points (cardiovascular death, heart transplantation, or clinical need for an automatic implantable cardioverter defibrillator) more often than cTnI- patients (37% vs 8%, P < .01). The presence of circulating cTnAbs (n = 15) was not associated with patients' clinical status or outcome. CONCLUSION: Patients with idiopathic dilated cardiomyopathy with cTnI efflux demonstrate more prominent changes in the indices of left ventricular remodeling and function than patients without signs of cTnI efflux. Moreover, elevated serum cTnI is associated with poor clinical outcome. The presence of circulating cTnAbs seems to have less utility in the clinical assessment of these patients. However, their pathogenic role in disease progression in the long term cannot be excluded.