Myeloperoxidase and protein carbonyl levels are elevated in plasma after acute MI, apparently via independent mechanisms. High MPO is a risk factor for long-term mortality and adds prognostic value to LVEF and plasma NT-proBNP measurements.

Australian New Zealand Clinical Trial Registry (ACTRN12610000374066).

AimsSince their identification in the circulation, microRNAs have received considerable interest as putative biomarkers of cardiovascular disease. We have investigated the diagnostic utility of microRNAs in differentiating between patients with heart failure (HF) and non-HF-related breathlessness, and between HF with reduced (HF-REF) and preserved (HF-PEF) EF. Methods and resultsMicroRNA profiling was performed on plasma from 32 HF and 15 COPD patients, as well as 14 healthy controls. Seventeen microRNAs were selected for validation in 44 HF, 32 COPD, 59 other breathless, and 15 controls. Cases of HF were split evenly between HF-REF and HF-PEF. Diagnostic utility was compared with NT-proBNP and high sensitivity troponin T (hs-troponin T). MiR-103 [area under the curve (AUC) ¼ 0.642,, and miR-342-3p (AUC ¼ 0.644, P ¼ 0.007) were associated with HF diagnosis in regression and receiver operating characteristic (ROC) analyses. Individually, NT-proBNP (AUC ¼ 0.896, P ¼ 9.68 × 10 214 ) and hs-troponin T (AUC ¼ 0.750, P ¼ 2.50 × 10 26 ) exhibited greater sensitivity and specificity. However, combining significantly associated microRNAs with NT-proBNP improved the AUC of NT-proBNP by 4.6% (P ¼ 0.013). Four microRNAs, miR-103, miR-142-3p, miR-30b, and miR-342-3p, were differentially expressed between HF and controls, COPD, and other breathless patients (P ¼ 0.002-0.030). Eight microRNAs that distinguished between HF-REF and HF-PEF in screening (P ¼ 0.017-0.049) were not replicated in the validation. ConclusionsFour microRNAs distinguished between HF and exacerbation of COPD, other causes of dyspnoea, and controls. Seven were associated with HF diagnosis in regression and ROC analysis. Although individually NT-proBNP was far superior in predicting HF, combining microRNA levels with NT-proBNP may add diagnostic value.--

Background— Urocortin 2 (Ucn2) has potent cardiovascular actions and may participate in the pathophysiology of heart failure (HF). The integrated hemodynamic, endocrine, and renal effects of Ucn2 are unknown. Methods and Results— Eight sheep received incremental intravenous boluses of murine Ucn2 (10, 50, and 100 μg at 2-hour intervals) before (normal) and during pacing-induced HF. Compared with control data, Ucn2 induced rapid and dose-dependent increases in cardiac output (peak effects: normal 4.3±0.2 versus 6.1±0.2 L/min, P <0.001; HF 2.3±0.1 versus 4.5±0.2 L/min, P <0.001) and reductions in peripheral resistance (normal 20.2±1.0 versus 15.2±0.8 mm Hg/L per minute, P <0.01; HF 32.2±1.7 versus 13.6±0.5 mm Hg/L per minute, P <0.001) and left atrial pressure (normal 4.3±0.3 versus 0.5±0.2 mm Hg, P <0.01; HF 22.9±0.6 versus 5.1±1.8 mm Hg, P <0.001). Mean arterial pressure was minimally elevated in normals and decreased in HF (both P <0.01). In both states, Ucn2 reduced plasma atrial natriuretic peptide levels (normal 13±2 versus 10±2 pmol/L; HF 200±20 versus 72±10 pmol/L) and similarly increased corticotropin, cortisol, and Ucn1 (all P <0.001). In HF only, Ucn2 dose dependently decreased plasma vasopressin (3.09±0.36 versus 1.62±0.12 pmol/L, P <0.01), renin (2.98±1.17 versus 0.69±0.10 nmol/L per hour, P <0.001), aldosterone (1186±303 versus 364±122 pmol/L, P <0.001), endothelin-1 (3.39±0.23 versus 2.56±0.18 pmol/L, P <0.01), epinephrine (1633±260 versus 657±142 pmol/L, P <0.01), and brain natriuretic peptide (36±3 versus 18±4 pmol/L, P <0.001) concentrations. Renal effects, including increased urine volume (1.7-fold, P <0.05), sodium excretion (>12-fold, P <0.01), and creatinine excretion (1.3-fold, P <0.001), also occurred only in HF. Conclusions— Ucn2 has marked and beneficial hemodynamic, hormonal, and renal effects in experimental HF. These results support a role for Ucn2 in pressure/volume homeostasis in HF and suggest that the peptide may have therapeutic potential in this disease.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones, secreted by the atria and ventricles, respectively, in the normal adult heart. They participate in the regulation of blood pressure and body fluid homeostasis and modify growth and development of cardiovascular tissues and bone. Levels of ANP are higher in the fetal circulation than in adults, and fetal ventricles express higher levels of ANP and BNP than adult ventricles. The reappearance of ventricular ANP expression in adults is recognized as a marker of the induction of the embryonic gene program in ventricular hypertrophy. The natriuretic peptide system appears to be functional by midgestation, to respond to volume stimuli, and to regulate blood pressure and salt and water balance in the developing embryo. In addition, the natriuretic peptides may help regulate the blood supply to the fetus, acting as vasodilators in the placental vasculature. Peaks of ANP and BNP expression during gestation coincide with significant events in cardiac organogenesis, suggesting a role for ANP/BNP in the formation of the heart. In knockout mice lacking the natriuretic peptide receptor (NPR)-A gene (Npr1(-/-)), survival is reduced, with hearts enlarged at birth and possible cardiac developmental abnormalities. Surviving adult Npr1(-/-) mice have elevated blood pressure and marked cardiac hypertrophy and fibrosis, indicating that the ANP/BNP system is an important regulator of myocyte growth during development.

Recent evidence from rodents and humans shows that C-type natriuretic peptide (CNP) plays an essential role in endochondral bone growth. We recently identified a stable product of proCNP, amino-terminal proCNP (NT-proCNP), which unlike CNP is readily measurable in human and ovine plasma. Hypothesizing that plasma NT-proCNP concentrations reflect in part CNP synthesis within growth plates of rapidly growing cartilage, we studied levels of CNP forms in both children and lambs and related these to age, growth velocity, and biochemical markers of bone turnover. Plasma NT-proCNP levels were elevated at birth and fell progressively with age. Significant associations between plasma NT-proCNP and height velocity, alkaline phosphatase, and type 1 collagen C telopeptide were identified in children (aged 5-18 y). In longitudinal animal studies, elevated plasma concentration of NT-proCNP in 1-wk-old lambs fell progressively to mature adult levels at age 27 wk. Plasma NT-proCNP showed a highly significant association with alkaline phosphatase and metacarpal growth velocity. Glucocorticoids, a treatment known to inhibit cartilage proliferation, reduced metacarpal growth elongation in 4-wk-old lambs and markedly lowered circulating NT-proCNP levels during the treatment period. In summary, NT-proCNP levels in blood show a strong association with growth velocity and markers of bone formation and may well serve as a useful marker of growth plate activity in humans and other mammals. Skeletal growth results from a coordinated sequence of events involving proliferation and hypertrophy of chondrocytes within growth plates of long bones and deposition of intercellular matrix (1). Regulation of this process (endochondral growth) is complex and dependent on numerous paracrine and endocrine factors that variably modulate growth in utero and during the postnatal growing period. Despite increasing knowledge of the importance of paracrine factors, including bone morphogenetic proteins, Indian hedgehog, fibroblast growth factor, and PTH-related peptide, none of these has yet been used to assess growth plate activity in the clinical setting.Atrial (ANP), B-type (BNP), and C-type natriuretic peptides (CNP), each the product of a separate gene, constitute a family of structurally related peptides that regulate blood pressure and volume homeostasis (2). CNP, the most conserved across species of the three hormones, in contrast to ANP and BNP is not readily detected in blood, and circulating CNP has minimal natriuretic or vasodepressor activity in humans (3). Acting via its specific guanylyl cyclase receptor NPR-B (4), CNP has antiproliferative actions in vascular tissue (5), which may serve to regulate vascular remodeling and regeneration (6). Whereas the role of CNP in cardiovascular health is still unclear, several recent lines of evidence indicate that CNP plays an essential part in endochondral growth. CNP transcripts and their receptor NPR-B are expressed in chondrocytes of growth plates (7), and the addition of CNP stimulates both prolifer...

We have studied the distribution of activin receptor gene expression in the brain, pituitary, ovary, and testis of the adult rat by in situ hybridization, using probes complementary to the mRNAs encoding the mouse activin receptor subtypes II and IIB (ActRII and ActRIIB). Throughout the brain, ActRII mRNA expression was stronger than that of ActRIIB, and the patterns of expression were similar, although not identical. The most intense sites of activin receptor gene expression were the hippocampal formation, especially the dentate gyrus (ActRII), taenia tecta, and induseum griseum; the amygdala, particularly the amygdaloid-hippocampal transition zone; and throughout the cortical mantle, including the primary olfactory cortex (piriform cortex and olfactory tubercle); other regions of the cortex showing lesser degrees of hybridization included the cingulate cortex, claustrum, entorhinal cortex, and subiculum. In addition, moderate levels of expression were observed in several hypothalamic areas involved in neuroendocrine regulation, such as the suprachiasmatic, supraoptic, paraventricular, and arcuate nuclei. Moreover, activin receptors were also expressed in regions with inputs to the hypothalamus, both in the forebrain (bed nucleus of the stria terminalis and medial preoptic area) and within the brainstem (nucleus of the solitary tract, dorsal motor nucleus of the vagus, locus coeruleus, and mesencephalic raphé system). ActRII mRNA was observed in the intermediate lobe of the pituitary and, less prominently, in the anterior lobe, whereas ActRIIB appeared to be weakly expressed throughout all three pituitary divisions. In both male and female gonads, activin receptor message was clearly present in germ cells, and ActRII was the predominant form. In the ovary, in addition to an intense signal in the oocyte, activin receptor was expressed in corpus luteum and granulosa cells during diestrous day 1. In the testis, there was a strong ActRII signal in rounded spermatids, and a moderate signal in pachytene spermatocytes. In contrast, ActRIIB was absent within tubules, but weakly expressed in interstitial and Leydig cells. This is the first report of the distribution of activin receptor message in adult mammalian tissues. Although consistent with some previously suggested functional associations of activin-containing pathways in the brain, this pattern of expression suggests a greater role for activin than was previously appreciated in cortical, limbic, and somatosensory pathways and in the maturation of germ cells in the gonads of both male and female rats.

The natriuretic peptides, atrial (ANP) and brain natriuretic peptide (BNP) are known to suppress cardiac hypertrophy and fibrosis. Both ANP and BNP exert their bioactivities through the Npr1 receptor, and Npr1 knockout mice (Npr1K/K) exhibit marked cardiac hypertrophy and fibrosis. In this study, we investigated which genes within the hypertrophic and fibrotic pathways are influenced by the lack of Npr1 signalling. cDNA microarray and quantitative real-time PCR (RT-PCR) analyses were performed on cardiac ventricles from Npr1K/K mice. Gene expression at early and late stages during development of hypertrophy was investigated in male and female Npr1K/K mice at 8 weeks and 6 months of age. Heart weight to body weight ratios (HW:BW) were maximally increased in 8-week males (P!0 . 01), whilst HW:BW in females continued to increase progressively up to 6 months (P!0 . 01). This was despite blood pressure being similarly elevated at both the ages in male and female knockout when compared with wild-type (WT) mice (P!0 . 001). Microarray analysis identified altered gene expression at the earliest steps in the hypertrophy-signalling cascade in Npr1K/K mice, particularly calcium-calmodulin signalling and ion channels, with subsequent changes in the expression of intracellular messengers including protein kinases and transcription factors. Real-time PCR analysis confirmed significant differences in gene expression of ANP, BNP, calmodulin 1, histone deacetylase 7a (HDAC7a), protein kinase C (PKC)i, (GATA) 4, collagen 1, phospholamban and transforming growth factor-b1 in Npr1K/K mice when compared with WT (P!0 . 05). The present study implicates the calmodulin-CaMK-Hdac-Mef2 and PKC-MAPK-GATA4 pathways in Npr1 mediation of cardiac hypertrophy.