Pietro Coghi

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.

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.

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.

Isradipine in chronic renal failure: Antihypertensive effect and renal protection

Abstract Arterial hypertension is regarded as a major factor in the progression of chronic renal failure. Hyperfiltration in the surviving nephrons and increased protein leakage across the glomerular capillaries are thought to play a pathogenetic role. The effects of long-term treatment with the sustained-release formulation (SRO) of isradipine on blood pressure, renal function, and protein excretion were evaluated in patients with mild-to-moderate arterial hypertension and chronic renal failure (creatinine clearance 30 to 60 mL/min/1.73 m 2 ). Sixty-two patients (mean ± SD age, 56 ± 11 years) were included in the study. After a 14-day placebo period, a single 2.5-mg dose of isradipine SRO was administered each morning for 2 weeks. The dose was then increased to 5 mg/d if supine diastolic blood pressure (DBP) was ≥95 mm Hg; if adequate blood pressure control was not achieved, atenolol 25 to 100 mg or captopril 25 to 50 mg was added beginning at week 9. Thirty-six patients continued monotherapy throughout the study. After 8 weeks, mean casual blood pressure reduction was 10/7 mm Hg ( P P P P P = NS). Proteinuria decreased, although statistical significance was not achieved; median value for protein excretion in the urine collected during the night at week 24 was 361 mg compared with 755 mg at baseline ( P = 0.07). A similar decrease was apparent for protein fractions with different molecular weights (albumin, alpha 1 -microglobulin, retinol-binding protein, and beta 2 -microglobulin). Six patients (10%) reported minor side effects (flushing, ankle edema), none of which caused discontinuation of therapy. Long-term therapy with isradipine SRO is effective and well tolerated in patients with chronic renal failure; in addition, renal function appears to be preserved. Blood pressure reduction appears to favorably affect proteinuria and albuminuria; decreases in both are also desirable in antihypertensive therapy.

O-19: Primary aldosteronism in a referral hypertension center

1999. Screening of PA was performed with the captopril test. Final diagnosis was based on lack of suppression of aldosterone upon acute volume expansion. Aldosteronoma (A) was defined as a unilateral adrenal nodule on CT scan with enhanced uptake at I-cholesterol scintigraphy. The diagnosis of idiopathic hyperaldosteronism (IHA) was based on evidence of bilateral adrenal hyperplasia on CT scan and enhanced bilateral uptake at scintigraphy. Sixty-six (6.3%) pts were finally diagnosed as having PA. In 16 (24.2%) of these pts, A was demonstrated by adrenal CT and scintigraphy, and the diagnosis histologically confirmed in the 10 cases so far submitted to surgery. In the remaining 50 (75.8%) pts IHA was diagnosed. The pts with PA had slightly higher systolic blood pressure values than those with essential hypertension (EH)(171.8623.3 vs 166.9 614.1 mmHg, P,0.05 by t-test). Known duration of hypertension was greater in the pts with PA, although statistical significance was reached only in those with IHA (median (25°-75° percentile): EH 28 (6-60), IHA 60 (24-120), A 46 (5-87) mo; P50.004 by ANOVA). At the time of the first visit, 30/66 (45.4%) pts with PA were treated with 2 or more drugs, compared with 152/931 (16.3%) pts with EH ( x 33.117, P,0.0001); in the former group there were 23/50 (46%) cases of IHA and 9/16 (56.3%) cases of A ( x 0.182, P50.670). In the group of the untreated pts there were 536/931 (57.6%) cases of EH, 13/50 (26.0%) cases of IHA and 4/16 (25.0%) cases of A ( x 25.260, P,0.0001). In these untreated pts hypertension was classified as mild to moderate (i.e., 180/104 mmHg) in 318/536 (59.5%) cases of EH, 8/13 (61.5%) cases of IHA and 3/4 (75.0%) cases of A ( x 0.428, P50.807). Serum potassium values were significantly lower in the pts with either IHA or A compared with those with EH (EH 4.0 6 .3, IHA 3.660.3, A 3.360.5 mEq/l; P,0.0001 by ANOVA). However, 37/66 (56.1%) pts with PA had serum potassium values

Effects of the reduction of preload on left and right ventricular myocardial velocities analyzed by Doppler tissue echocardiography in healthy subjects

3.6 mEq/l; in this group there were 33/50 (66.1%) cases of IHA and 7/16 (43.7%) cases of A (x 1.668, P50.197). We conclude that: 1) PA is more frequent than traditionally thought; 2) it is not necessarily associated with severe and/or resistant hypertension; 3) IHA seems to be more prevalent than A; 4) hypokalemia is not a sensitive criterion for the screening of PA.