Stefano Tedeschi

Serum adipokine zinc α2-glycoprotein and lipolysis in cachectic and noncachectic heart failure patients: relationship with neurohormonal and inflammatory biomarkers

Chronic heart failure is often complicated by the development of cachexia with the loss of fat mass. Zinc α2-glycoprotein (ZAG) is a serum adipokine with lipolytic effects in cancer cachexia. We evaluated in patients with advanced heart failure with (CxHF) or without cachexia (nCxHF) the relationship of ZAG with circulating free fatty acid (FFA), as an index of lipolysis, and with other neurohormonal and inflammatory biomarkers. Two groups, nCxHF (n = 46) and CxHF (n = 18), the latter having a documented, involuntary, edema-free loss of body weight of at least 7.5% in the previous 6 months, underwent plasma determination of FFA, ZAG, norepinephrine (NE), tumor necrosis factor-α, and natriuretic peptide levels (atrial natriuretic, B-type natriuretic peptide). The patients were compared with age-matched healthy controls (CTR) (n = 21). Zinc α2-glycoprotein, atrial natriuretic peptide, B-type natriuretic peptide, and tumor necrosis factor-α circulating levels were similarly greater in CxHF and nCxHF than in CTR. Free fatty acid and NE were higher in CxHF than in nCxHF. A positive correlation between FFA and NE was found in both CxHF (r = 0.73, P < .01) and nCxHF (r = 0.48, P < .01) but only in CxHF between ZAG and FFA (r = 0.54, P = .02) and between ZAG and NE (r = 0.70, P < .01). No correlations between natriuretic peptides and ZAG were found. Serum ZAG levels are increased in advanced heart failure patients compared with CTR, without differences between CxHF and nCxHF. Only in CxHF, ZAG levels are directly correlated to circulating levels of FFA and NE, suggesting a close interaction of ZAG with sympathetic-mediated lipolysis.

Zinc-α2-glycoprotein as a marker of fat catabolism in humans.

Purpose of review Cachexia development is a feature of cancer as well as other chronic diseases. Fat mass loss appears of greatest importance in cachexia, as it is related to poorer survival. Zinc-&agr;2-glycoprotein (ZAG), firstly isolated in human plasma 50 years ago, has emerged as a novel adipokine, which plays an important role in mobilization and utilization of lipids. This review will focus on recent evidences of ZAG as a fat catabolic marker in cancer and other diseases complicated by cachexia. Recent findings ZAG is a lipolytic factor produced by certain cachexia-inducing tumuors and by adipose tissue. It increases lipolysis in white adipose tissue through cyclic-AMP pathway and stimulates uncoupling protein-1 in brown adipose tissue leading to heat generation. In cancer cachexia, ZAG release from white adipocytes is elevated and closely related to body weight loss. In cardiac cachexia, ZAG and circulating free fatty acids are closely related, suggesting a causative role in fat catabolism. Summary ZAG may play an important role, probably as an autocrine/paracrine modulator of adipose mass in cachexia. A better comprehension of ZAG involvement in fat wasting mechanisms will be useful in the development of new therapeutic agents.

Low Serum Ferroxidase I Activity Is Associated With Mortality in Heart Failure and Related to Both Peroxynitrite-Induced Cysteine Oxidation and Tyrosine Nitration of Ceruloplasmin

Rationale: Ceruloplasmin antioxidant function is mainly related to its ferroxidase I (FeOxI) activity, which influences iron-dependent oxidative and nitrosative radical species generation. Peroxynitrite, whose production is increased in heart failure (HF), can affect ceruloplasmin antioxidant function through amino acid modification. Objective: We investigated the relationship between FeOxI and ceruloplasmin tyrosine and cysteine modification and explored in a cohort of patients with HF the potential clinical relevance of serum FeOxI. Methods and Results: In patients with chronic HF (n=96, 76±9 years; New York Heart Association class, 2.9±0.8) and age-matched controls (n=35), serum FeOxI, FeOxII, ceruloplasmin, nitrotyrosine-bound ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were measured, and the patients were followed up for 24 months. Ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were increased in HF versus controls. FeOxI was decreased in HF (−20%) and inversely related to nitrotyrosine-bound ceruloplasmin (r, −0.305; P=0.003). In HF, FeOxI lower tertile had a mortality rate doubled compared with middle-higher tertiles. FeOxI emerged as a mortality predictor (hazard ratio, 2.95; 95% confidence intervals [1.29–6.75]; P=0.011) after adjustment for age, sex, hypertension, smoking, sodium level, estimated glomerular filtration rate, and high-sensitivity C-reactive protein. In experimental settings, peroxynitrite incubation of serum samples and isolated purified ceruloplasmin reduced FeOxI activity while increasing ceruloplasmin tyrosine nitration and cysteine thiol oxidation. Reduced glutathione prevented peroxynitrite-induced FeOxI drop, tyrosine nitration, and cysteine oxidation; flavonoid(−)-epicatechin, which prevented ceruloplasmin tyrosine nitration but not cysteine oxidation, partially impeded peroxynitrite-induced FeOxI drop. Conclusions: Reduced activity of serum FeOxI is associated with ceruloplasmin nitration and reduced survival in patients with HF. Both ceruloplasmin tyrosine nitration and cysteine thiol oxidation may be operant in vivo in peroxynitrite-induced FeOxI activity inhibition.

Cerebral blood flow decreases during intermittent hemodialysis in patients with acute kidney injury, but not in patients with end-stage renal disease

BACKGROUND Cerebral blood flow (CBF) may decrease during intermittent hemodialysis (IHD). Patients with acute kidney injury (AKI) may be more vulnerable to cerebral hypoperfusion than patients with end-stage renal disease (ESRD), due to concomitant critical illness and hemodynamic instability. METHODS In this observational, prospective study, we measured mean flow velocity at the level of the middle cerebral artery by transcranial Doppler at the start, after 2 h and at the end of a hemodialysis session in 15 consecutive patients with AKI and critical illness referred to the nephrological intensive care unit of a university hospital and in 12 patients with ESRD on regular treatment thrice weekly, who served as controls. We compared end-dialysis changes from baseline in mean flow velocity between the study groups and examined the correlation between this change and that of other relevant clinical parameters. RESULTS Mean flow velocity decreased significantly at end-dialysis in the patients with AKI, but not in those with ESRD (P = 0.02). This difference persisted after adjusting for baseline mean flow velocity and net ultrafiltration volume. No significant correlations were found in either group between changes in mean flow velocity and changes in mean blood pressure (AKI: r = -0.27, P = 0.34; ESRD: r = 0.15, P = 0.68), SUN (AKI: r = -0.33, P = 0.25; ESRD: r = 0.06, P = 0.85), plasma HCO(3)(-) (AKI: r = -0.52, P = 0.24; ESRD: r = -0.18, P = 0.59), hematocrit (AKI: r = 0.08, P = 0.71; ESRD: r = -0.19, P = 0.65) or arterial oxygen content (AKI: r = -0.17, P = 0.36; ESRD: r = -0.33, P = 0.43). CONCLUSIONS Our data suggest that AKI patients may be more vulnerable than ESRD patients to cerebral hypoperfusion during IHD. Our findings do not support a clear-cut role of rapid changes in blood osmolarity, rheological properties or vasoreactivity of the cerebral circulation to O(2) supply in modulating CBF during hemodialysis.

Prealbumin improves death risk prediction of BNP-added Seattle Heart Failure Model: Results from a pilot study in elderly chronic heart failure patients

BACKGROUND An accurate prognosis prediction represents a key element in chronic heart failure (CHF) management. Seattle Heart Failure Model (SHFM) prognostic power, a validated risk score for predicting mortality in CHF, is improved by adding B-type natriuretic peptide (BNP). We evaluated in a prospective study the incremental value of several biomarkers, linked to different biological domains, on death risk prediction of BNP-added SHFM. METHODS Troponin I (cTnI), norepinephrine, plasma renin activity, aldosterone, high sensitivity-C reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin 2 soluble receptor, leptin, prealbumin, free malondialdehyde, and 15-F2t-isoprostane were measured in plasma from 142 consecutive ambulatory, non-diabetic stable CHF (mean NYHA-class 2.6) patients (mean age 75±8years). Calibration, discrimination, and risk reclassification of BNP-added SHFM were evaluated after individual biomarker addition. RESULTS Individual addition of biomarkers to BNP-added SHFM did not improve death prediction, except for prealbumin (HR 0.49 CI: (0.31-0.76) p=0.002) and cTnI (HR 2.03 CI: (1.20-3.45) p=0.009). In fact, with respect to BNP-added SHFM (Harrells C-statistic 0.702), prealbumin emerged as a stronger predictor of death showing the highest improvement in model discrimination (+0.021, p=0.033) and only a trend was observed for cTn I (+0.023, p=0.063). These biomarkers showed also the best reclassification statistic (Integrated Discrimination Improvement-IDI) at 1-year (IDI: cTnI, p=0.002; prealbumin, p=0.020), 2-years (IDI: cTnI, p=0.018; prealbumin: p=0.006) and 3-years of follow-up (IDI: cTnI p=0.024; prealbumin: p=0.012). CONCLUSIONS Individual addition of prealbumin allows a more accurate prediction of mortality of BNP enriched SHFM in ambulatory elderly CHF suggesting its potential use in identifying those at high-risk that need nutritional surveillance.

Characterization of myocardial hypertrophy in prehypertensive spontaneously hypertensive rats: interaction between adrenergic and nitrosative pathways.

Objective and methods Left ventricular hypertrophy in human and experimental hypertension is not always associated with pressure overload but seems to precede an increase in blood pressure. In this study, performed in male 5-week-old prehypertensive spontaneously hypertensive rats (SHR; n = 65) and age-matched Wistar–Kyoto rats (n = 56), the relationship between myocardial structure and activation of the adrenergic and nitric oxide systems was evaluated. Results Body weight, blood pressure and heart rate were similar in both groups. A higher left ventricle/body weight ratio was found in SHR, as a result of greater mononuclear (+47%) and binuclear (+43%) myocyte volumes, without changes in interstitial collagen. Both adrenergic and nitric oxide pathways were activated in SHR, as expressed by higher myocardial norepinephrine content, tyrosine hydroxylase activity, myocardial nitric oxide synthase 3 expression and protein nitration, indicating greater peroxynitrite (ONOO−) generation from nitric oxide and superoxide. No difference was measured in nitric oxide synthase 1 expression, whereas nitric oxide synthase 2 was undetectable. A positive correlation between myocardial tyrosine hydroxylase activity and protein nitration was observed in SHR (r2 = 0.328; P < 0.01). Early treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, from the third to the fifth week of age, reduced ONOO− generation, protein nitration and sympathetic activation in SHR without changes in myocardial structure. Conclusion In prehypertensive SHR, left ventricular hypertrophy is associated with adrenergic and nitrosative imbalance. Early superoxide dismutase mimetic treatment in SHR effectively reduces higher myocardial ONOO− generation, sympathetic activation, and heart rate without affecting the development of myocardial hypertrophy.

Myeloperoxidase-Related Chlorination Activity Is Positively Associated with Circulating Ceruloplasmin in Chronic Heart Failure Patients: Relationship with Neurohormonal, Inflammatory, and Nutritional Parameters

Rationale. Heart failure (HF) is accompanied by the development of an imbalance between oxygen- and nitric oxide-derived free radical production leading to protein nitration. Both chlorinating and peroxidase cycle of Myeloperoxidase (MPO) contribute to oxidative and nitrosative stress and are involved in tyrosine nitration of protein. Ceruloplasmin (Cp) has antioxidant function through its ferroxidase I (FeOxI) activity and has recently been proposed as a physiological defense mechanism against MPO inappropriate actions. Objective. We investigated the relationship between plasma MPO-related chlorinating activity, Cp and FeOxI, and nitrosative stress, inflammatory, neurohormonal, and nutritional biomarkers in HF patients. Methods and Results. In chronic HF patients (n = 81, 76 ± 9 years, NYHA Class II (26); Class III (29); Class IV (26)) and age-matched controls (n = 17, 75 ± 11 years, CTR), plasma MPO chlorinating activity, Cp, FeOxI, nitrated protein, free Malondialdehyde, BNP, norepinephrine, hsCRP, albumin, and prealbumin were measured. Plasma MPO chlorinating activity, Cp, BNP, norepinephrine, and hsCRP were increased in HF versus CTR. FeOxI, albumin, and prealbumin were decreased in HF. MPO-related chlorinating activity was positively related to Cp (r = 0.363, P < 0.001), nitrated protein, hsCRP, and BNP and inversely to albumin. Conclusions. Plasma MPO chlorinated activity is increased in elderly chronic HF patients and positively associated with Cp, inflammatory, neurohormonal, and nitrosative parameters suggesting a role in HF progression.

Physical exercise for late-life depression: Effects on symptom dimensions and time course

BACKGROUND Physical exercise is increasingly recognized as a treatment for major depression, even among older patients. However, it is still unknown which depressive symptoms exercise affects most, (e.g. somatic vs. affective) and the timing of its effects. Thus, the aim of this study was to examine the changes of depressive symptoms after treatment with exercise. METHODS We analyzed data from the SEEDS study, a trial comparing the antidepressant effectiveness of sertraline (S) and sertraline plus exercise (S+EX). Exercise was delivered thrice weekly in small groups and monitored by heart rate meters. Patients with late life depression (n=121) were assessed at baseline, 4, 8, 12 and 24 weeks with the Hamilton Depression Scale. Scores of affective, vegetative, anxiety and agitation/insight factors were analyzed using Multilevel Growth Curve Models and sensitivity analyses (multiple imputation). RESULTS Compared with the S group, patients in the S+EX group displayed significantly greater improvements of the affective symptom dimension (total effect size = 0.79) with largest changes in the first 4 weeks and last 12 weeks. Improvements were mainly driven by depressed mood and psychomotor retardation. LIMITATIONS Sample size; lack of an exercise only treatment arm CONCLUSIONS: Adding exercise to antidepressant drug treatment may offer significant advantages over affective symptoms of depression, rather than somatic symptoms or other dimensions of depression. Compared with standard antidepressant treatment, clinical advantages should be expected both at an early (first 4 weeks) and later stage (after 12 weeks).

ZINC-ALPHA 2 GLYCOPROTEIN FACILITATES CATECHOLAMINE-INDUCED LIPOLYSIS IN HUMAN ADIPOCYTES THROUGH A CATALASE-LIKE EFFECT: FOCUS ON CARDIAC CACHEXIA

Objective: Cardiac cachexia development in heart failure is characterized by fat mass loss and elevated levels of circulating fatty acid (FA). Zinc alpha 2 glycoprotein (ZAG) has been demonstrated to induce lipolysis in vivo in rodents and in cardiac cachexia. We investigate ZAG mechanisms of action in human adipocytes obtained from healthy subjects (CTR), heart failure non cachectic patients (HFnCX) and cardiac cachectic patients (HFCX). Design and method: Two sets of experiments have been performed: in the first pilot study 6 CTR, 4 HFnCX and 3 HFCX subjects have been enrolled. Subcutaneous adipose tissue sample has been obtained during dermatological surgical procedure or at the moment of ICD or PM generator change. Isolate mature adipocytes were incubated with ZAG 25 ug/mL. H2O2 release in culture medium was evaluate before and after 1 and 2 hours of ZAG-incubation. Adipocytes have been also incubated with Norepinephrine (NE) 10-5 M, H2O2 10-4 M and 10-5 M and BRL44408 10-5 M (Selective alpha2A-adrenoceptor antagonist). Infranatant glycerol was measured as an index of lipolysis. In the second set of experiments 16 CTR, 19 HFnCX and 12 HFCX patients have been enrolled. Adipocytes were incubated with ZAG 25 ug/mL, Benzylamine (BZ) 1 mM and Tyramine (TY) 1 mM in different combination and H2O2 production was measured. Results: ZAG did not increased lipolysis but co-incubation with noradrenaline resulted in higher glycerol release in HFCX vs noradrenaline alone (+60%,p < 0.05). ZAG reduced H2O2 release from adipocytes to a greater extent in HFCX (+65%,p < 0.05) whitin the first hour of incubation. H2O2 incubation with adipocytes did not reduce glycerol release in the three group, nor reduced the NE-mediated lipolysis. H2O2 blunted the BRL44408-induced lipolysis when co-incubated with NE. A greater release of H2O2 from HFCX in basal condition and after incubation with BZ and TY was observed.ZAG reduced BZ-related H2O2 production in all the three groups, whereas TY did not. Conclusions: ZAG has a facilitating role in NE-induced lipolysis that could be linked to an antioxidant, reducing H2O2 levels especially in HFCX patients. ZAG reduced BZ-related semi-carbazide sensitive-oxidase H2O2 generation suggesting an involvment of this enzyme in its action.

Severity of community acquired hypernatremia is an independent predictor of mortality: a matter of water balance and rate of correction

Sodium balance disorders are the most frequent alterations among electrolyte disturbances. The subject of the retrospective single center study by Jung et al. [1] refers to an important clinical problem, mainly related to altered water balance responsible for dysnatremia. The results of this study indicate that the presence of hypernatremia (classified into mild 148–150 mEq/L, moderate 151–154 mEq/L and severe [155 mEq/L) at the time of admission or developing during the hospital stay represents an independent risk factor for development of longer hospital stay or mortality. In particular, the Authors evaluate in their study, the data collected from patients presenting to an urban tertiary hospital emergency department (ED), or from outpatients clinics during a period of 3 years. They label such a condition: community-acquired hypernatremia (CAH). With this premise, they find a low percentage (0.2% of all the admissions) of patients admitted to the hospital with hypernatremia of any degree (mild, moderate or severe). There are several points that should be carefully considered for the interpretation of the results observed in this study, and that should be taken as fundamental in the approach to hypernatremic patients. First, the prevalence of hypernatremia is rather low in the population considered in the study. The mean age of the studied population was almost 63 years-old. In the literature, the prevalence of hypernatremia, considering patients admitted to the ED, is reported to be from 5 to 10 times [2–4] up to 20 times [5]. In intensive care unit, several studies report an even higher prevalence of hypernatremia [6–8]. In their discussion, Jung et al. indicate that one of the possible causes of the prevalence discrepancies, might be partly ascribed to the older age of people evaluated in the majority of data reported in literature. This difference in ages might produce the variances, because water loss responsible for hypernatremia commonly develops in elderly patients whose access to water is limited as well as is their sense of thirst. In a recent paper, in contrast, it is reported that hypernatremia was the fourth most frequent electrolyte disorders in patients presenting to an ED (mean prevalence 4.4%) with a higher rate of presentation in a younger population (5.6 versus 3.7%) than in those older than 65 years of age (in contrast with what is expected) [5]. But Jung et al. clearly stated the different nature of CAH patients including outclinic patients from those hospitalized in intensive care units. Differences are observed in the pathogenesis of CAH and hospital acquired hypernatremia [9]. In the majority of all hypernatremic cases, hypernatremia is a hospital acquired condition. CAH is almost always hypovolemic, whereas hypernatremia acquired in hospital is not often linked to hypovolemia, and even in some patients, is related to fluid overload. It is important to distinguish hypernatremia linked to water loss also called dehydration from hypovolemia, where both sodium and water are lost [10]. Hypernatremia is most often related to unreplaced water loss from the gastrointestinal tract (vomiting or osmotic diarrhea due to laxatives), from the skin (excess of sweat because of fever or high ambient temperature), or from the urine (diabetes insipidus or an osmotic diuresis due to glucosuria in uncontrolled diabetes mellitus or to an excess of loop diuretic therapy such as furosemide). Because hypernatremia (through increased plasma osmolality) stimulates thirst and therefore the increase in water intake, this ionic disorder commonly occurs when patients are unable to sense thirst or to have an & Aderville Cabassi aderville.cabassi@unipr.it